Exploring the toxicity mechanisms and detoxification methods of Rhizoma Paridis
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Sun Jianwei
Abstract
Although there has been research on the toxicity of Rhizoma Paridis (Chong Lou), a systematic and comprehensive evaluation, as well as targeted strategies for mitigating its toxicity, remains lacking. This review aims to provide a thorough assessment of the toxicological properties of Rhizoma Paridis, offering reliable guidance for its safe application. The article focuses on the toxicity and underlying mechanisms of Rhizoma Paridis and reviews the applications of both traditional Chinese medicine and modern scientific technologies in detoxification. Finally, it proposes future research directions, emphasizing the need for further exploration of chronic toxicity mechanisms and advocating for the integration of traditional and modern detoxification methods to ensure the safe clinical use of Rhizoma Paridis. This review provides the latest theoretical foundation for the safe use and further development of Rhizoma Paridis.
1 Introduction
Rhizoma Paridis, a traditional Chinese herbal medicine, is derived from the dried rhizomes of Dian Paris (Paris polyphylla Smith var. Mazz.) and seven-leaved Paris (P. polyphylla Smith var.), both belonging to the genus Paris in the Liliaceae family [1,2]. Its medicinal properties are well-documented in classical texts of Traditional Chinese Medicine (TCM), such as the Shennong Bencao Jing [3]. Rhizoma Paridis is particularly recognized for its effects in clearing heat, detoxifying the body, reducing swelling, alleviating pain, cooling the blood, and stopping bleeding [4]. Historically, it has been used for centuries to treat a variety of conditions, including mumps, bleeding disorders, snake bites, fractures, and abscesses [5].
Pharmacological studies have demonstrated that Rhizoma Paridis possesses a range of bioactive properties, including antitumor, antimicrobial, anti-inflammatory, etc. (Figure 1) [6–14]. Due to these pharmacological activities, Rhizoma Paridis is commonly included in TCM formulations for both internal and external use, treating a variety of conditions such as inflammation, tumors, snake bites, and traumatic infections. Additionally, it serves as the raw material for 90 proprietary Chinese medicines and is widely used in clinical practice (Table 1) [15–31].
Pharmacological activities of Rhizoma Paridis.
Representative proprietary chinese medicines containing Rhizoma Paridis
| Category | Drug name | Effects | Clinical indications | Approval number |
|---|---|---|---|---|
| Analgesics [15,20] | ||||
| Baibao Dan | Dispel blood stasis and reduce swelling, stop bleeding and relieve pain | Knife and gun injuries, traumatic injuries, menstrual irregularities, dysmenorrhea, amenorrhea, chronic gastralgia, and joint pain | Guoyao Zhunzi Z53021108 | |
| Changchun hongyao capsule | Promote blood circulation and remove blood stasis, reduce swelling and relieve pain | Traumatic injuries with blood stasis and pain | Guoyao Zhunzi Z20026502 | |
| Yili Zhitongwan | Clear heat and detoxify, promote blood circulation, and relieve pain | Pain caused by knife and gun injuries, traumatic injuries, dysmenorrhea in women, and pain associated with advanced malignant tumors | Guoyao Zhunzi Z50020232 | |
| Zhongtong Qiwuji | Reduce swelling, alleviate pain, promote blood circulation, remove blood stasis, relax tendons and activate collaterals, resolve masses, and disperse nodules | Traumatic injuries, rheumatic joint pain, frozen shoulder, gouty arthritis, and mammary gland hyperplasia | Guoyao Zhunzi Z20025741 | |
| Chanwu Babugao | Promote blood circulation, remove blood stasis, reduce swelling, and relieve pain | Treatment of cancer-related pain; also applicable to acute and chronic sprains, traumatic injuries, bone hyperplasia, rheumatism, and rheumatoid pain, as well as conditions like stiff neck, frozen shoulder, lumbar muscle strain, and injuries | Guoyao Zhunzi Z20027885 | |
| Diedabang Yaojiu | Reduce swelling and relieve pain | Traumatic injuries with blood stasis, swelling, and pain | Guoyao Zhunzi Z44023384 | |
| Shennong Zhentong Gao | Activate blood circulation, disperse blood stasis, reduce swelling, and relieve pain | Traumatic injuries, rheumatic joint pain, and lumbar and back soreness | Guoyao Zhunzi Z44020387 | |
| Xiongdan Diedagao | Activate blood circulation, disperse blood stasis, reduce swelling, and relieve pain | Traumatic injuries, rheumatic joint pain, and lumbar and back soreness | Guoyao Zhunzi Z20026055 | |
| Anticancer drugs [15,21–24] | ||||
| Boerning capsule | Support healthy energy, expel pathogenic factors, replenish qi, activate blood circulation, soften and disperse nodules, reduce swelling, and relieve pain | Adjunctive treatment for cancer | Guoyao ZhunziZ20054459 | |
| Ganfule Pian | Strengthen the spleen and regulate qi, resolve blood stasis, soften nodules, and clear heat and detoxify | Primary liver cancer | Guoyao Zhunzi Z10940066 | |
| Loulian capsule | Regulate qi, dissolve blood stasis, and clear heat and detoxify | Adjunctive treatment for primary liver cancer | Guoyao Zhunzi Z10980133 | |
| Qizhen Capsule | Replenish qi, resolve blood stasis, and clear heat and detoxify | Treatment of cancers such as lung cancer, breast cancer, and gastric cancer | Guoyao Zhunzi Z20010074 | |
| Ruan-Jian oral liquid | Resolve blood stasis, soften nodules, detoxify, and replenish qi | Primary liver cancer | Guoyao Zhunzi Z20184027 | |
| Xiongdan capsule | Possess the effects of clearing heat and dispersing nodules, activating blood circulation, eliminating masses, and strengthening the body | Adjunctive treatment for nasopharyngeal cancer, esophageal cancer, gastric cancer, and rectal cancer | Guoyao Zhunzi Z19983163 | |
| Gastrointestinal drugs [15] | ||||
| Quyu Yiwei Capsule | Strengthen the spleen and harmonize the stomach, resolve blood stasis, and relieve pain | Gastric pain caused by spleen deficiency, qi stagnation, and blood stasis, as well as symptoms of chronic superficial gastritis | Guoyao Zhunzi Z20174017 | |
| Xuedan Weichangwan | Warm the middle, dispel cold, regulate qi, and relieve pain | Cold deficiency in the middle burner causing gastric cold pain, belching, acid regurgitation, loose stools, gastric ulcers, duodenal ulcers, duodenitis, and proctitis | Guoyao Zhunzi Z20025385 | |
| Gynecological drugs [15,25–27] | ||||
| Gongxuening capsule | Cool the blood, stop bleeding, clear heat, eliminate dampness, and relieve pain | Excessive uterine bleeding, heavy menstruation, postpartum or post-abortion uterine atony bleeding, uterine bleeding due to blood heat, and chronic pelvic inflammation causing lower abdominal pain, lumbosacral pain, and increased vaginal discharge | Guoyao Zhunzi Z20020087 | |
| Sanjie Zhitonggao | Soften and disperse nodules, reduce swelling, and relieve pain | Cystic hyperplasia of the mammary gland, mastalgia, and gynecomastia in males | Guoyao Zhunzi Z44023492 | |
| Heat-clearing and detoxification [15,28] | ||||
| Hongwei Sheyaopiao | Clear heat, detoxify, reduce swelling, relieve pain, cool the blood, and disperse blood stasis | Used for snake bites and poisonous insect bites | Guoyao Zhunzi Z36021580 | |
| Jideshengshe tablet | Clear heat, detoxify, reduce swelling, and relieve pain | Snake and poisonous insect bites | Guoyao Zhunzi Z32020048 | |
| Zhanjiang Sheyao | Neutralize snake venom, relieve pain, and reduce swelling | Snake bites, centipede bites, and other poisonous insect stings | Guoyao Zhunzi Z44023712 | |
| Liver-related drugs [15] | ||||
| Biyunsha Yigan Keli | Clear the liver, detoxify, and regulate qi and blood circulation | Hepatitis B caused by liver and gallbladder damp-heat syndrome | Guoyao Zhunzi Z20026322 | |
| Caoxian Yigan Capsule | Clear heat, detoxify, strengthen the spleen, and drain dampness | Chronic hepatitis B, flank pain, abdominal distension due to hepatitis B | Guoyao Zhunzi Z20204009 | |
| Qinggan Baiduwan | Clear heat, drain dampness, and detoxify | Acute and chronic hepatitis due to liver and gallbladder damp-heat syndrome | Guoyao Zhunzi Z20026098 | |
| Respiratory system drugs [15,29] | ||||
| Xiaoer Tuire Chongji | Dispel wind and release the exterior, detoxify, and relieve throat discomfort | Pediatric cold and fever caused by external wind-heat, as well as upper respiratory tract infections with similar symptoms | Guoyao Zhunzi Z37021424 | |
| Fufang Chuanbei Zhiketangjiang | Suppress cough and resolve phlegm, moisten the lungs, and calm asthma | Cold with cough, excessive phlegm, and shortness of breath | Guoyao ZhunziZ44023581 | |
| Fufang Shedan Chuanbeisan | Suppress cough and resolve phlegm | Wind-heat cough and chronic cough with excessive phlegm | Guoyao Zhunzi Z44022008 | |
| Fufang Yanlian Pian | Clear heat, detoxify, dissolve phlegm, and relieve cough | Cold, cough caused by upper respiratory tract infections, acute and chronic bronchitis, pharyngitis, and tonsillitis | Guoyao Zhunzi Z52020427 | |
| Houshu Kouhanpian | Clear heat, detoxify, moisten the lungs, and relieve throat discomfort | Sore throat, throat itching, and dryness | Guoyao Zhunzi Z53020605 | |
| Biyan Qingdu Ji | Clear heat, detoxify, reduce inflammation, and disperse nodules | Chronic inflammation of the nasopharynx, sore throat, and increased secretions after radiotherapy for nasopharyngeal cancer | Guoyao Zhunzi Z44022386 | |
| Qingre Zhike Keli | Clear heat, resolve phlegm, open the lungs, and relieve cough | Cough with phlegm or heat-related cough | Guoyao Zhunzi Z20000016 | |
| Redu Qingpian | Heat-clearing detoxification tablets: clear heat, detoxify, reduce swelling, and disperse nodules | Parotitis, tonsillitis, laryngitis, and upper respiratory tract infections caused by internal heat toxins | Guoyao Zhunzi Z53020800 | |
| Shenbei Zhike Keli | Clear the lungs, dissolve phlegm, and relieve cough | Chronic bronchitis with cough | Guoyao Zhunzi Z20026126 | |
| Jiuwei Shaungjie Koufuye | Release the exterior and clear heat, purge fire, and detoxify | Wind-heat colds | Guoyao Zhunzi Z20240002 | |
| Lanhua Kening Pian | Treat wind-heat attacking the lungs, clear heat, detoxify, astringe the lungs, and relieve cough | Acute and chronic bronchitis, chronic cough, and scanty phlegm | Guoyao Zhunzi Z20043682 | |
| Xiaoer Qingreling | Clear heat, detoxify, relieve throat discomfort, and stop coughing | Cold with fever, sore throat, cough, and shortness of breath | Guoyao Zhunzi Z22022819 | |
| Rendong Ganmao Keli | Clear heat and detoxify | Fever and throat pain caused by upper respiratory tract infections | Guoyao Zhunzi Z20025083 | |
| Rheumatology drugs [15] | ||||
| Gufengning capsule | Detoxify, dissolve blood stasis, and activate collaterals to relieve pain | Rheumatoid arthritis and ankylosing spondylitis | Guoyao Zhunzi Z20026229 | |
| Lujin Zhuanggu Jiu | Dispel wind and dampness, relax muscles, and activate blood circulation | Numbness of limbs and rheumatic arthritis | Guoyao Zhunzi Z22024875 | |
| Xuanqi Tongbi Capsule | Nourish and tonify the liver and kidneys, activate blood circulation, remove stasis, reduce swelling, and relieve pain | Rheumatoid arthritis | Guoyao Zhunzi Z19990041 | |
| Jingutengtong Jiu | Expel wind and dampness, relax muscles, and activate blood circulation | Muscular and joint pain, limb numbness, and rheumatic arthritis | Guoyao ZhunziZ34020072 | |
| Skin, eczema, and dermatitis drugs [15,30] | ||||
| Jianghuang Xiaocuo Chaji | Clear heat, eliminate dampness, and promote blood circulation to treat acne | Acne (pimples) | Guoyao Zhunzi Z20025149 | |
| Yinbing Xiaocuoting | Clear heat, detoxify, cool the blood, and reduce swelling | Acne | Guoyao Zhunzi Z20025294 | |
| Keyangminxu | Astringe to stop itching, reduce inflammation, and detoxify | Acute and chronic eczema, urticaria, insect-bite dermatitis, contact dermatitis, and skin itching | Guoyao Zhunzi Z44022982 | |
| Chonglou Jieduting | Clear heat, detoxify, and relieve pain by dispersing blood stasis | Herpes zoster, skin itching, insect-bite dermatitis, and epidemic parotitis | Guoyao Zhunzi Z20025808 | |
| Xiaozhi Jiefu Ruangao | Clear heat, detoxify, resolve blood stasis, reduce swelling, and eliminate dampness to stop itching | Athlete's foot, body ringworm, groin ringworm, damp sores, internal and external hemorrhoids with swelling, pain, and bleeding caused by damp-heat accumulation | ZF018200 | |
| Trauma and hemostasis [15,31] | ||||
| Yunnan Baiyao | Stop bleeding, relieve pain, reduce inflammation, and promote wound healing | Small open wounds in surgery | Guoyao Zhunzi Z53021102 | |
| Shangyi Qiwuji | Reduce swelling, relieve pain, stop bleeding, and disperse blood stasis | Traumatic injuries and mild burns or scalds | Guoyao Zhunzi Z20026238 | |
| Yunnanhongyao capsule | Stop bleeding and relieve pain, promote blood circulation, disperse blood stasis, and expel wind and dampness | Gastric ulcer bleeding, bronchiectasis with hemoptysis, functional uterine bleeding, menorrhagia, fundus hemorrhage, conjunctival hemorrhage, epistaxis, hemorrhoidal bleeding, soft tissue contusions, rheumatic arthritis, and rheumatic lumbar-leg pain | Guoyao Zhunzi Z53020129 | |
| Sanqi Xueshangning Capsule | Stop bleeding and relieve pain, remove stasis, and promote tissue regeneration | Gastric and duodenal ulcer bleeding, bronchiectasis bleeding, pulmonary tuberculosis with hemoptysis, functional uterine bleeding, trauma and hemorrhoidal bleeding, menstrual disorders, dysmenorrhea, amenorrhea, excessive menstrual bleeding, postpartum blood stasis, gastric disorders, and intercostal neuralgia | Guoyao Zhunzi Z45020612 | |
| Urinary system drugs [15] | ||||
| Jiedutonglin Wan | Clear heat, eliminate dampness, and promote urination | Non-gonococcal urethritis caused by lower burner damp-heat | Guoyao Zhunzi Z20025507 | |
| Niaoqingshu Keli | Clear heat, drain dampness, and promote urination | Acute and chronic prostatitis, urinary tract infections, cystitis, and other urological conditions | Guoyao Zhunzi Z20026440 | |
| Others [15] | ||||
| Waiyong Wudigao | Expel wind, remove dampness, activate blood circulation, reduce swelling, relieve pain, clear heat, detoxify, and relieve obstruction and pain | Traumatic injuries, rheumatic numbness, lumbar and shoulder pain, and abscesses with redness, swelling, and pain | Guoyao Zhunzi Z53020661 | |
| Weisheng San | Remove filth, clear heat, detoxify, relieve spasms, and calm the mind | High fever with coma, neck stiffness with convulsions, stroke with phlegm retention causing jaw clenching and phlegm obstruction, pediatric convulsions, acute gastroenteritis, vomiting, diarrhea, abscesses, and carbuncles | Guoyao Zhunzi Z21022012 | |
Despite its significant medicinal benefits, the potential toxicity of Rhizoma Paridis must not be overlooked. Research has identified several chemical compounds, including steroidal saponins and alkaloids, which contribute to its therapeutic effects but may also trigger toxic reactions [32]. Therefore, it is crucial to understand the toxic constituents and the mechanisms underlying their toxicity to ensure the safe use of Rhizoma Paridis in medical practice. Comprehensive studies on its toxicity, as well as strategies for prevention and detoxification, are essential not only for advancing the modernization of traditional medicine but also for promoting the safe and rational application of Rhizoma Paridis.
This study provides a systematic examination of the chemical composition, toxicological profiles, and mechanisms of toxicity associated with Rhizoma Paridis. It further investigates prevention and detoxification strategies, methods of toxicity assessment, and potential directions for future research. The findings aim to offer a comprehensive framework for ensuring the safe application of Rhizoma Paridis in clinical practice and guiding further scientific exploration.
2 Chemical composition of Rhizoma Paridis
Rhizoma Paridis contains a diverse range of natural compounds. To date, more than 200 chemical constituents have been isolated and identified from Rhizoma Paridis [33–35].
2.1 Steroidal saponins
Steroidal saponins are the primary active compounds in Rhizoma Paridis, renowned for their diverse biological activities [36,37]. Their chemical structure, which resembles that of steroid hormones, allows them to exert various pharmacological effects in the body. To date, 136 distinct steroidal saponins have been isolated and identified from Rhizoma Paridis, with spirostanol and furostanol being the most predominant, together accounting for approximately 80% of the total saponins [38–42]. Notable examples of these saponins include Polyphyllin I (PPI), Polyphyllin II (PPII), and Polyphyllin VII (PPVII).
2.2 C21 steroids
C21 steroids have attracted considerable attention due to their distinctive chemical structures and a wide range of pharmacological effects, including antitumor, anti-inflammatory, sedative, and analgesic properties [43–45]. As key constituents of Rhizoma Paridis, these compounds are responsible for many of its biological activities [46].
2.3 Flavonoid
Flavonoids are lipophilic constituents of Rhizoma Paridis [47]. Although present in relatively low concentrations, these compounds demonstrate notable antioxidant and anti-inflammatory activities. Their effects are primarily mediated through the scavenging of free radicals and the inhibition of inflammatory mediator release [48].
2.4 Others
In addition to the aforementioned components, Rhizoma Paridis contains other classes of compounds, including plant growth regulators, plant sterols, quinones, fatty acids, alkaloids, and phenylpropanoids, as identified in relevant pharmaceutical research [49].
3 Toxicological studies on Rhizoma Paridis
Although Rhizoma Paridis plays a significant therapeutic role in clinical practice, there remains a limited understanding of its toxicity and the underlying mechanisms of its toxic effects. This section reviews and analyzes previous studies to provide a comprehensive understanding of the toxicological properties of Rhizoma Paridis, offering a theoretical foundation and data support for future research.
3.1 Hepatotoxicity
The liver is the primary organ for drug metabolism in the body and is also a key target for drug-induced toxicity [50–52]. Hepatotoxicity is a common cause of liver damage, manifesting in a variety of clinical symptoms [53,54]. A thorough understanding of the hepatotoxic effects of TCMs is crucial, particularly in the context of new drug development and clinical drug use, to ensure safety assessments and minimize drug-induced liver damage. The following sections will discuss in detail the clinical manifestations and specific mechanisms by which Rhizoma Paridis saponins induce hepatocellular injury.
3.1.1 Clinical manifestations
Rhizoma Paridis is a toxic herb, and its hepatotoxicity exhibits a clear dose-dependent relationship. Experimental studies have shown that when the total saponin dose exceeds 4–5 times the recommended amount, significant liver damage occurs. For instance, in a zebrafish model, high doses of Rhizoma Paridis saponins caused scattered necrosis in liver tissue, disrupted hepatocyte arrangement, and triggered apoptosis and vacuolation. Additionally, in rat models, when the total saponin dose exceeded 265 mg/kg (approximately five times the equivalent dose for humans), noticeable hepatocellular damage was observed. Histopathological analysis of liver tissue revealed the disappearance of hepatocyte membranes, cell enlargement, prominent binucleation, and severe nuclear fragmentation. These pathological changes further confirm the hepatotoxic effects of Rhizoma Paridis saponins [55].
3.1.2 Mechanisms of hepatotoxicity
3.1.2.1 Induction of apoptosis
Apoptosis is a key mechanism underlying liver injury induced by Rhizoma Paridis. Studies have shown that Rhizoma Paridis triggers hepatocyte apoptosis by activating both intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways. These pathways ultimately converge on a caspase cascade, leading to hepatocellular death. Additionally, oxidative stress and the generation of reactive oxygen species (ROS) exacerbate the apoptotic process (Figure 2) [56,57].
Intrinsic pathway: Mitochondrial pathway
Mitochondria are the primary source of ROS within cells. PPⅡ stimulates the production of ROS in mitochondria, inducing oxidative stress. Excessive ROS not only directly damage cellular lipids, proteins, and DNA, but also activate the tumor suppressor protein p53. p53 serves as a DNA damage sensor, and in response to ROS, it upregulates the pro-apoptotic protein Bax while downregulating the anti-apoptotic protein Bcl-2, altering the Bax/Bcl-2 ratio. This disruption leads to a loss of mitochondrial membrane potential (Δψm), increased mitochondrial membrane permeability, and the release of cytochrome c into the cytoplasm. Cytochrome c activates downstream caspases, including caspase-9 and caspase-3, which ultimately result in hepatocyte apoptosis. ROS play a crucial role in amplifying liver damage by potentiating this mitochondrial apoptotic pathway [58,59].
Extrinsic pathway: Death receptor pathway
In the extrinsic apoptotic pathway, the binding of Fas (death receptor 1) to its ligand FasL initiates the activation of caspase-8. Caspase-8 subsequently activates caspase-3 and cleaves poly (ADP-ribose) polymerase, further promoting apoptosis. PPII have been shown to upregulate Fas, Bax, and cytochrome c expression, while activating caspase-3, caspase-8, and caspase-9 in a dose- and time-dependent manner, thereby enhancing hepatocyte apoptosis [59].
The mechanism of Rhizoma Paridis saponin-induced apoptosis in hepatocytes.
3.1.2.2 Impact on cytochrome P450 (CYP450) enzymes
CYP450 enzymes are essential metabolic enzymes in hepatocytes, playing a key role in the metabolism of most drugs by enhancing their polarity and water solubility [60–62]. Upon entering the body, PPI can influence the CYP450 enzyme system, leading to alterations in the expression of drug-metabolizing enzymes such as CYP1A1, CYP1A2, and phase II enzymes like GSTA3. These changes in enzyme expression may disrupt normal drug metabolism, potentially contributing to liver damage.
3.1.2.3 Hepatic energy and lipid metabolism imbalance
Dysfunction in mitochondrial respiratory chain reactions and lipid metabolism in the liver are key contributors to the development of liver fibrosis and injury [63–65]. Studies have shown that PPI and PPII can induce severe hepatotoxicity in a dose-dependent manner by disrupting lipid and energy metabolism pathways. These disruptions are mediated through mitochondrial dysfunction and the inhibition of key enzymes involved in lipid metabolism [66].
PPI impairs mitochondrial function by inhibiting β-oxidation, preventing the metabolism of free fatty acids. As a result, free fatty acids are converted into triglycerides, leading to lipid accumulation in the liver. The peroxisome proliferator-activated receptor (PPAR) signaling pathway, essential for lipid metabolism, is significantly affected by PPI. Both PPARα, which regulates genes involved in lipid clearance, and PPARγ, which promotes adipocyte differentiation and glucose uptake, are inhibited. This suppression reduces the activity of key enzymes in the PPAR pathway, including stearoyl-CoA desaturase-1, acyl-CoA oxidase 1, and CD36 (a fatty acid transporter), highlighting the pathway’s critical role in lipid metabolism and accumulation.
Furthermore, proteomic and transcriptomic analyses in human liver cell lines (L-02) and zebrafish models have revealed that exposure to PPI and PPII disrupts the cholesterol biosynthesis pathway, as evidenced by the downregulation of critical enzymes such as HMG-CoA reductase (HMGCR) and squalene epoxidase.
3.2 Hematotoxicity
Drug-induced hemolysis refers to the rupture and destruction of red blood cells (RBCs) caused by certain drugs or their metabolites, resulting in the release of hemoglobin into the plasma [67]. Common mechanisms include oxidative stress, immune reactions, direct toxicity, and interference with metabolic pathways [68,69]. Hemolysis can result in clinical symptoms such as anemia, jaundice, and kidney dysfunction, and in severe cases, it may be life-threatening [70–72].
3.2.1 Clinical manifestations
Studies have shown that no hemolysis occurs when the concentration of total Rhizoma Paridis saponins is ≤0.01 g/L. However, when the concentration exceeds 0.01 g/L, hemolysis occurs, and its intensity is dose-dependent [73]. Fang and colleagues, using visual inspection and spectrophotometry, evaluated the hemolytic activity of total Rhizoma Paridis saponins, pennogenin saponins, and dioscin. They found that pennogenin saponins exhibited stronger hemolytic effects than dioscin, suggesting that pennogenin saponins are the primary hemolytic compounds in Rhizoma Paridis. Additionally, research indicates that compounds with similar structures, such as PPI, PPII, and PPD, also exhibit strong in vitro hemolytic activity.
The mechanism of blood toxicity induced by Rhizoma Paridis saponins.
3.2.2 Mechanisms of hematotoxicity (Figure 3)
3.2.2.1 Binding to cholesterol on RBC membrane
The steroid saponins in Parnassia compounds may bind to cholesterol on the erythrocyte membrane, forming insoluble complexes. This binding enhances lipid peroxidation reactions within the membrane, leading to membrane structural instability. As a result, the normal osmotic pressure of the erythrocytes is disrupted, ultimately causing hemolysis due to the rupture of the RBCs [74].
3.2.3 Binding to anion channels and inhibiting GLUT1
Anion channels, such as Band 3, are essential proteins on the RBC membrane that maintain the ionic balance between the intracellular and extracellular environments [75]. Studies have shown that saponins from Rhizoma Paridis, particularly PPII, can bind to Band 3 and inhibit its transport activity. This disruption alters the ion transport function of the RBC membrane, resulting in an imbalance of ion concentrations across the membrane. As a consequence, intracellular osmotic pressure increases, leading to RBC rupture and hemolysis. Additionally, PPII may alter the structure of Band 3 and other membrane proteins, thereby damaging the RBC cytoskeleton and causing the loss of normal cell morphology and function. This damage compromises the structural integrity of the RBC membrane, causing partial detachment of membrane proteins and increasing the cell’s susceptibility to hemolysis.
Furthermore, PPII competitively inhibits GLUT1, reducing glucose transmembrane transport. This inhibition impairs the energy supply to RBCs and disrupts intracellular osmotic pressure, leading to cell swelling and rupture [76]. Studies have demonstrated that GLUT1 inhibition promotes hemolysis, further supporting the mechanism by which PPII induces hemolysis through the suppression of glucose transport.
The interaction between anion channels and GLUT1 may jointly regulate RBC morphology and function by forming protein complexes, such as the Band 3–GLUT1 interaction. By binding to both channels, PPII may alter their structure or function, disrupting the transport of ions and glucose, which exacerbates the increase in intracellular osmotic pressure, promoting RBC swelling and rupture [77].
3.2.4 Potential mechanism of polyphyllin D (PD)-induced hemolysis
Recent studies have demonstrated that PD exhibits significant blood toxicity, capable of inducing hemolysis and apoptosis in human RBCs. The mechanism underlying PD-induced hemolysis begins with the activation of calcium channels on the RBC membrane, leading to an increase in intracellular calcium ion concentration. This calcium influx promotes the externalization of phosphatidylserine, cell shrinkage, and the activation of caspase-3, which are hallmark features of apoptosis (eryptosis). In addition, PD directly affects the RBC membrane, increasing its permeability and facilitating the exchange of calcium ions between the intracellular and extracellular environments. This further amplifies the activation of the calcium-dependent apoptotic pathway. Due to its strong hemolytic and cytotoxic effects, PD’s clinical application is limited. Therefore, future research should focus on developing more efficient drug delivery systems to mitigate its toxicity to RBCs while preserving its anticancer potential [78].
3.3 Gastrointestinal toxicity
3.3.1 Clinical manifestations
Gastrointestinal toxicity induced by Rhizoma Paridis is a significant concern in its clinical application. Excessive intake of Rhizoma Paridis can result in gastrointestinal side effects, including nausea, vomiting, and diarrhea. Studies have shown that a single administration of Rhizoma Paridis saponins inhibits gastric emptying in a dose-dependent manner without affecting intestinal transit in mice, indicating gastric irritation [79].
3.3.2 Mechanisms of gastrointestinal toxicity
Research has demonstrated that the cytotoxicity of saponins is primarily due to their membrane toxicity, which may result from the depletion of cholesterol in cell membranes [74]. When saponins reach a certain concentration in the small intestine, they increase the permeability of intestinal mucosal cells, inhibit active nutrient transport, and facilitate the absorption of substances that are normally impermeable to the intestinal epithelium [80]. Despite these findings, the precise mechanisms underlying the gastrointestinal irritation caused by Rhizoma Paridis remain poorly understood. Further research is needed to ensure its effective and safe clinical use.
3.4 Cardiovascular toxicity
3.4.1 Clinical manifestations
Drug-induced cardiovascular side effects contribute significantly to morbidity and mortality rates [81]. Clinical reports indicate that excessive intake of Rhizoma Paridis can lead to cardiotoxic effects, manifesting as symptoms such as arrhythmias and muffled heart sounds. Furthermore, studies have demonstrated that three saponins – PPⅠ, PPⅡ, and PPⅦ – strongly inhibit the proliferation of cardiovascular cells, including H9c2, HUVEC, and HCMEC. Notably, PPⅠ has shown significant cardiotoxicity in both zebrafish and mouse models, suggesting a potential risk of cardiovascular damage [82].
3.4.2 Mechanisms of cardiovascular toxicity
The cardiovascular toxicity of Rhizoma Paridis is primarily associated with a significant inhibition of cell viability, migration, invasion, and angiogenesis. The underlying mechanisms of PPI-induced cardiovascular toxicity occur via two major pathways: inhibition of angiogenesis and induction of endothelial cell apoptosis.
First, PPI suppresses the tyrosine phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), thereby reducing VEGF signaling. This, in turn, inhibits endothelial cell proliferation and migration through several downstream signaling pathways, including PI3K/Akt/mTOR, Src/eNOS, p38, and PLCγ/ERK/MEK. These effects ultimately block new blood vessel formation. Additionally, PPI inhibits the JAK2/STAT3 signaling pathway, further suppressing endothelial cell activity and reducing angiogenesis.
Second, PPI induces apoptosis in cardiovascular cells, as evidenced by the release of lactate dehydrogenase, morphological changes such as apoptotic body formation and chromatin condensation, and cell cycle arrest, particularly in the S and G2/M phases, leading to cell death. At the molecular level, PPI upregulates Bax, downregulates Bcl-2, and activates caspase-9, thereby initiating the mitochondrial pathway to induce apoptosis.
In summary, PPI likely exerts cardiovascular toxicity through the combined effects of multiple signaling pathways, inhibiting angiogenesis and inducing endothelial cell apoptosis (Figure 4) [83].
The mechanism of cardiovascular toxicity induced by Rhizoma Paridis saponins.
3.5 Reproductive toxicity
Shen et al. investigated the effects of Rhizoma Paridis on sperm viability through in vitro sperm incubation. Their study found that pennogenin saponins and dioscin, isolated and purified from Rhizoma Paridis, significantly reduced sperm viability in mice. At a final concentration of 40 mg/L, dioscin completely killed all sperm, while some sperm remained viable when exposed to pennogenin saponins at the same concentration [84]. However, it is important to note that Rhizoma Paridis has not undergone systematic reproductive toxicity studies in accordance with international and national guidelines [85]. Most existing studies have focused on reproductive organ toxicity, indicating potential reproductive risks but failing to precisely characterize the types and severity of toxicity (e.g., fertility toxicity, early embryonic development toxicity, fetal development toxicity, perinatal toxicity, and maternal toxicity). As a result, current research offers limited guidance for the clinical application of Rhizoma Paridis, highlighting the need for further studies.
3.6 Long-term toxicity
Long-term toxicity studies of Rhizoma Paridis saponins have shown significant chronic toxicity, particularly affecting the liver and gastrointestinal systems. High doses (350 mg/kg) of Rhizoma Paridis saponins in rats led to weight loss, reduced food and water intake, indicating impaired gastrointestinal function. Prolonged exposure caused liver cell damage, oxidative stress, and elevated liver markers (ALT and AST), with the high-dose group showing the most severe effects. The medium and low doses (50 and 100 mg/kg) also caused some liver damage [86].
Although research on pulmonary toxicity is limited, other saponins from TCM suggest lung damage mechanisms involving inflammation and oxidative stress. Further studies are needed to assess pulmonary risks of Rhizoma Paridis saponins.
However, liver function in all dose groups returned to normal after a 4-week withdrawal, suggesting the chronic toxicity of Rhizoma Paridis saponins may be reversible, likely due to compensatory mechanisms like antioxidant system activation and tissue repair.
3.7 Summary
In summary, the hepatotoxicity, hemolysis, gastrointestinal toxicity, and cardiovascular toxicity associated with Rhizoma Paridis are primarily attributed to its saponin content. However, the severity and specific nature of these toxic effects vary among the different saponins present in Rhizoma Paridis, including Polyphyllin I, Polyphyllin II, and Polyphyllin Ⅶ [82,87–89] (Table 2).
Comparison of toxicity profiles of different Rhizoma Paridis saponins
| Characteristic | Polyphyllin I | Polyphyllin II | Polyphyllin VII |
|---|---|---|---|
| Toxicity intensity | Strongest | Moderate | Weakest |
| Toxicity targets | Liver, cardiovascular system, RBCs, kidneys, lungs, sperm | Liver, kidneys, heart, sperm | Liver, kidneys, sperm |
| Organ toxicity features | Liver: severe liver toxicity, vacuolization, necrosis; heart: Severe cardiovascular toxicity, impacts heart rate, promotes cardiac cell apoptosis; Kidneys: Mild toxicity, no renal edema; lungs: Thickened alveolar walls | Liver: Hepatocyte necrosis; kidneys: Mild tubular damage | Liver: Mild hepatocyte vacuolization; kidneys: Slight lipid metabolism disorder |
| Experimental models | Cells (heart, liver, kidney) | Cells (heart, liver, kidney) | Cells (heart, liver, kidney) |
| Zebrafish | Zebrafish | Zebrafish | |
| LC50 121 ng/mL | LC50 213 ng/mL | LC50 570 ng/mL | |
| LC10 109 ng/mL | LC10 178 ng/mL | LC10 456 ng/mL | |
| MNLC 99 ng/mL | MNLC 146 ng/mL | MNLC 357 ng/mL | |
| Mice LC50 24.5 mg/kg | No data available | No data available | |
| Conclusion | Significant toxicity with multiple targets, requires strict dose control, suitable for short-term applications, clinical use must be cautious, especially at high doses | Relatively mild toxicity with concentrated targets, suitable for combination therapy or single-drug development | Lowest toxicity, high potential for application, suitable for further clinical studies |
| References | [87–90] | [87–89] | [87,89] |
The inclusion of a comparison of the toxicity of different saponins is crucial because it helps to better understand the varying risks associated with Rhizoma Paridis. These saponins have unique pharmacological properties that contribute to different toxicity mechanisms. By identifying the specific saponins present in a formulation, clinicians can make more informed decisions regarding dosage, treatment regimens, and monitoring strategies. This comparison also highlights the need for individualized treatment plans, tailored to the specific toxicity risks posed by the particular saponin content, thereby optimizing therapeutic outcomes while minimizing adverse effects.
4 Toxicity prevention and treatment of Rhizoma Paridis
Understanding the toxicity of medicinal herbs and developing effective prevention and detoxification strategies are crucial in the application of TCM. Effective toxicity management not only enhances therapeutic efficacy but also ensures the safety of the treatment. This section reviews both traditional and modern detoxification methods for Rhizoma Paridis, critically evaluating their scientific potential and limitations, with the aim of providing guidance for its safe clinical use.
4.1 Considerations in the use of Rhizoma Paridis
Existing evidence suggests that Rhizoma Paridis possesses a certain degree of toxicity, necessitating careful attention to dosage control and appropriate usage methods.
4.1.1 Dosage control
Effective management of Rhizoma Paridis dosage is critical to mitigate potential toxicity risks. Clinical studies underscore the importance of strict dosage control, typically recommending a range of 3–9 g per administration. However, individualization of dosage is paramount, considering factors such as the patient’s age, body weight, health status, and tolerance levels. Overdosing on Rhizoma Paridis can lead to severe adverse reactions, particularly hepatotoxicity characterized by liver damage. Monitoring of liver enzymes and other relevant biomarkers during treatment is advisable to promptly detect and manage any emerging toxicity.
4.1.2 Contraindicated populations
Rhizoma Paridis should be avoided by pregnant and breastfeeding women, as well as individuals with impaired liver or kidney function. Populations with compromised metabolic and detoxification abilities, such as the malnourished or those with chronic diseases, are at heightened risk of toxic reactions and should use this herb with caution. Additionally, individuals with a history of allergies should avoid its use.
4.2 Methods of reducing toxicity
TCM has developed extensive strategies for managing toxicity, primarily through herbal combinations, preparation techniques, and formulation adjustments that reduce toxicity while enhancing efficacy.
4.2.1 Herb pairing for toxicity reduction
In TCM, herb pairing is a crucial strategy for enhancing therapeutic effects and mitigating toxicity [90–92]. Rhizoma Paridis is often combined with other herbs to reduce its toxic effects. For example, pairing it with Glycyrrhiza and Curcuma longa can alleviate liver toxicity. Modern pharmacological studies suggest that the flavonoids in Glycyrrhiza can repair liver tissue by reducing inflammation, enhancing antioxidant enzyme activity, and decreasing oxidative stress in the liver. Furthermore, Glycyrrhiza saponins may also reduce oxidative stress and inflammation by inhibiting ROS production and regulating the NF-κB pathway, potentially reducing liver toxicity [93]. However, the specific detoxification mechanisms of Glycyrrhiza in combination with Rhizoma Paridis require further investigation.
C. longa has also shown potential in mitigating the toxicity of Rhizoma Paridis. Research indicates that combining C. longa with Rhizoma Paridis may alleviate toxicity in both the liver and lungs. The detoxification mechanism of C. longa likely involves the reduction of ROS, suppression of inflammatory markers, and activation of the Nrf2/HO-1 detoxification pathway. However, this mechanism needs further clinical and preclinical validation [94].
4.2.2 Processing methods for toxicity reduction
The processing of medicinal herbs plays a crucial role in reducing toxicity and enhancing efficacy. Proper preparation methods can decrease the toxicity of Rhizoma Paridis without compromising its therapeutic effects, while improper processing may exacerbate toxicity. For instance, vinegar processing of Rhizoma Paridis has been shown to reduce its gastrointestinal irritant effects. While traditional processing methods have demonstrated some effectiveness in reducing toxicity, they are not standardized, and scientific validation of their detoxifying effects is limited.
4.2.3 Application of modern scientific technologies
Modern pharmacology has provided important insights into the toxicological mechanisms of Rhizoma Paridis, facilitating the development of more precise preventive measures. Advanced toxicological evaluation techniques allow for a comprehensive understanding of Rhizoma Paridis’s toxic properties before clinical use, helping to minimize adverse reactions. The use of animal and cell models has expanded the scope of toxicity assessment, offering critical guidance for safe usage.
Innovative pharmaceutical technologies, such as microemulsions and liposomes, significantly improve the bioavailability of drugs while reducing liver damage. For instance, studies have demonstrated that encapsulating Saikosaponin D in liposomes can reduce its toxicity [95]. This approach may also provide a potential strategy for mitigating the toxicity of Rhizoma Paridis.
Additionally, modern research suggests that antioxidant supplements, such as Vitamin C and Vitamin E, can enhance liver detoxification and reduce oxidative stress associated with Rhizoma Paridis toxicity [96,97]. While these adjunctive treatments show promise in mitigating toxicity, further clinical data are needed to determine the best combinations of auxiliary herbs for use with Rhizoma Paridis.
4.3 Detoxification methods
When toxicity occurs, timely and effective detoxification measures are crucial to minimize damage. Upon poisoning, the use of Rhizoma Paridis must be immediately discontinued. Common detoxification methods, both traditional and modern, help reduce toxin absorption and promote elimination, thereby alleviating poisoning symptoms.
4.3.1 Traditional detoxification methods
TCM often employs herbal remedies for detoxification, including Scutellaria baicalensis, immature bitter orange, etc. [98,99]. S. baicalensis is known for its antioxidant, anti-inflammatory, and cell-regulating properties, which can alleviate liver damage caused by toxins. Modern pharmacological studies indicate that Scutellaria and its active compounds (such as baicalin) can synergize with other drugs to enhance efficacy, reduce toxicity, or overcome drug resistance [100,101]. Moreover, Chai Hu saponins can prevent liver toxicity induced by acetaminophen through inhibition of NF-κB and STAT3 signaling pathways. Licorice Decoction combined with rice vinegar and ginger juice are used for detoxifying Rhizoma Paridis poisoning [102].
Decoction therapy is a traditional detoxification method in Chinese medicine, with a rich history of clinical application. For example, in cases of poisoning from certain cardiac drugs (e.g., digoxin), the use of Shengmai San can help protect heart function [103]. Classic formulas such as Jiedu Tang, Huang Lian Jiedu Tang, and Da Cheng Qi Tang are commonly used to alleviate liver damage [104]. However, there is currently no specific formula available for liver injury caused by Rhizoma Paridis, indicating the need for further research to develop effective detoxification remedies. Decoctions, by gently promoting detoxification and facilitating the metabolism and excretion of toxins, are widely used in traditional clinical practice. However, their efficacy is often influenced by factors such as the patient’s constitution and the ratio of medicinal ingredients. Furthermore, a lack of scientific evidence for precision treatment calls for continued investigation to verify their effectiveness and clinical feasibility.
4.3.2 Modern detoxification methods
Advancements in modern medicine have introduced chemical detoxifiers and pharmaceutical technologies that offer new avenues for detoxification. These methods are typically more controllable and scientifically validated.
Common general detoxification treatments include gastric lavage, purgation, and the administration of diluted acetic acid. Gastric lavage effectively reduces toxin concentration in acute poisoning cases. For example, in cases of colchicine poisoning, where there is no clear distinction between toxic and lethal doses, clinicians often consider gastrointestinal decontamination or gastric lavage using activated charcoal [105].
Chemical detoxifiers, such as N-acetylcysteine (NAC), replenish glutathione levels and restore the liver’s antioxidant capacity, making it a cornerstone treatment for liver toxicity. Cholesterol inhibitors, such as lovastatin, have been shown to mitigate saponin-induced membrane damage by inhibiting HMGCR, thereby regulating cholesterol metabolism and stabilizing cholesterol levels within cell membranes. This stabilization helps alleviate hemolysis caused by saponins. Additionally, lovastatin provides hepatoprotective effects by reducing oxidative stress and inflammatory responses, thereby attenuating saponin-induced hepatotoxicity [106].
4.4 Comparison and integration of traditional and modern methods
Traditional detoxification methods, such as herb pairing and processing, offer advantages in the management of chronic toxicity, including lower costs and a wealth of historical experience. However, these methods lack molecular mechanism validation and their efficacy can vary across individuals. In contrast, modern methods like NAC and magnesium isoglycyrrhizinate offer more precise control over ROS and metabolic pathways, providing more effective solutions, particularly in the management of acute toxicity. However, modern methods are often costly and technically complex, limiting their widespread application in resource-constrained regions [107–116] (Table 3). Future research should explore the integration of traditional and modern approaches, such as combining herbal pairings (e.g., Glycyrrhiza, C. longa) with modern pharmaceutical technologies (e.g., nanomedicines), to achieve synergistic detoxification and promote the combined use of both strategies.
A comparative analysis of traditional and modern detoxification methods
| Aspect | Traditional methods | Modern methods |
|---|---|---|
| Mechanism | Based on herb combinations and processing | Using molecular biology, enzyme inhibition, and modern detox mechanisms |
| Efficacy | Relies on experience and intuition, adjusts overall effects | Quality and toxicity controlled via instrument testing and standardization |
| Processing time and efficiency | Long process, experience-based | Fast, standardized, easy to monitor quality |
| Advantages | Holistic approach, personalized treatment, accumulated historical experience | Scientifically-based, quantifiable detox effects, fast, stable efficacy |
| Disadvantages | Lack of scientific validation, unstable efficacy, long treatment time | High cost, potential introduction of new toxicity |
| References | [107–112] | [108,113–116] |
5 Evaluation of TCM toxicity
Although current toxicological studies provide a theoretical foundation for the clinical application of Rhizoma Paridis, they remain incomplete. Therefore, further research on its toxicity is essential. This section summarizes key aspects of toxicity studies for TCM, with the aim of offering more comprehensive guidance for the safe and effective use of Rhizoma Paridis.
5.1 Key aspects of toxicity studies
Key aspects of toxicity studies are essential for assessing the safety of a drug throughout its development, from preclinical to clinical stages. One critical area is acute and chronic toxicity, which involves evaluating the toxic effects of Rhizoma Paridis at varying doses and durations to identify both immediate and long-term risks. Another key aspect is organ-specific toxicity, where researchers examine the effects of Rhizoma Paridis on vital organs such as the liver, kidneys, and heart to assess potential organ damage. Reproductive toxicity assessments are also crucial, as they evaluate the herb’s impact on fertility and fetal development to ensure it does not adversely affect the reproductive system. Additionally, understanding the cytotoxic mechanisms at the cellular level is important for exploring how Rhizoma Paridis induces toxicity within cells, providing insights into how its harmful effects might be mitigated. Finally, studying drug interactions is vital for analyzing how Rhizoma Paridis interacts with other medications, as these interactions can influence its efficacy and safety profile, potentially leading to unexpected adverse effects. Together, these comprehensive toxicity studies form a solid foundation for the safe and effective clinical use of Rhizoma Paridis.
5.2 Research methods and techniques
The complexity of TCM components and their diverse biological targets necessitates the development of specialized safety assessment techniques tailored to the unique characteristics of TCM. Establishing these techniques is essential for conducting large-scale toxicity studies and achieving a comprehensive understanding of the potential risks associated with TCM.
5.2.1 Animal experiments
In TCM toxicity evaluations, rats and mice are commonly used for acute and subacute toxicity tests [117–119]. However, due to the complexity and multiple targets of TCM components, traditional mammalian models present challenges such as high costs, long testing durations, and limitations in high-throughput screening capacity.
As an alternative, the chick embryo model has gained popularity due to its ease of manipulation, relative transparency, and accessibility, making it an ideal platform for high-throughput screening. The physiological and pathological changes in chick embryos can be visualized using techniques such as candling, staining, and imaging, bridging the gap between in vivo and in vitro studies. This has established chick embryos as valuable tools for pharmacodynamics and toxicity research in TCM [120].
In recent years, zebrafish have become widely used in TCM toxicity studies. The advantages of the zebrafish model include its low cost, short lifecycle, ease of high-throughput screening, and exemption from strict ethical regulations before 5 days post-fertilization [121]. Studies have demonstrated the applicability of zebrafish in assessing various toxicities, including acute, hepatic, cardiac, renal, developmental, neurological, gastrointestinal, immunological, and ototoxicity [122]. For instance, zebrafish models have been used to evaluate the nephrotoxicity of aristolochic acid, confirming the model’s stability and accuracy in TCM toxicity screening [123]. Zebrafish have also been employed to assess the toxicity of artemisinin compounds [124]. However, it is important to note that physiological differences limit the zebrafish model’s comprehensive application [125]. Researchers have applied zebrafish models to study the toxicity of Rhizoma Paridis, providing evidence of its toxic properties.
Overall, integrating traditional mammalian models, chick embryos, and zebrafish provides a multi-tiered evaluation system for Rhizoma Paridis toxicity research. The combined use of these models offers a more comprehensive understanding of the toxicological properties of Rhizoma Paridis, thereby supporting its safe and effective clinical application.
5.2.2 Cell experiments
Developing cell models that replicate in vivo responses is essential for advancing scientific research and improving ethical standards [126]. These in vitro models allow researchers to conduct drug screening and toxicity assessments more efficiently, reducing the ethical concerns and costs associated with animal experiments. For example, cardiomyocytes derived from embryonic stem cells or human-induced pluripotent stem cells are increasingly used to predict cardiotoxicity in the early stages of drug development [127].
Furthermore, the advancement of organoid technology provides new opportunities for evaluating the toxicity of TCM. Organoids are three-dimensional miniature organs formed through the self-organization of stem cells and can closely mimic the structure and function of actual organs. Researchers have successfully created cardiac tissue models to assess the impact of TCM on heart health, and similar platforms have been developed to evaluate TCM-induced nephrotoxicity using organoid technology and advanced cell models [128,129]. These platforms offer efficient and precise tools for studying the toxicity of Rhizoma Paridis.
By integrating traditional mammalian models with advanced in vitro systems, a comprehensive evaluation framework can be established for the toxicity research of Rhizoma Paridis. The application of these models will provide deeper insights into the toxicological properties of Rhizoma Paridis, supporting its safe and effective clinical use.
6 Discussion
Increasing evidence supports the potential of natural medicines in disease treatment [130–138]. For example, Tu Youyou successfully extracted artemisinin from Chinese herbal medicine and applied it to treat malaria, saving millions of lives [139].
Rhizoma Paridis, a TCM with significant clinical potential, has shown promising preclinical therapeutic effects. Extensive research has demonstrated its pharmacological activities, including antitumor, anti-inflammatory, and antifibrotic effects [140–142]. For instance, preclinical studies have shown that PPII not only inhibits tumor growth but also enhances sensitivity to treatment by inducing pyroptosis in tumor cells, exhibiting strong anticancer effects in models such as lung cancer [143–145].
However, despite its great therapeutic potential, the toxicity of Rhizoma Paridis remains a major obstacle to its widespread application, particularly in relation to liver, cardiovascular, and gastrointestinal side effects [146]. Existing research mainly focuses on acute toxicity, while data on chronic toxicity are insufficient. Long-term use, particularly at high doses or over extended periods, may lead to additional adverse effects. Therefore, further investigation into its chronic toxicity is necessary to clarify the potential long-term risks to human health. Despite these concerns, when used within the recommended dosage range, Rhizoma Paridis demonstrates significant therapeutic effects, especially in treating cancer and immune system disorders. In fact, Rhizoma Paridis and its formulations have been used clinically with favorable outcomes. For example, Loulian capsules for primary liver cancer and Jinfukang oral liquid for primary non-small cell lung cancer have shown positive results. Clinical studies indicate that when administered at appropriate doses, the toxicity of Rhizoma Paridis is minimal, and it can effectively alleviate related symptoms. Therefore, it is crucial for clinicians to precisely control the dosage, develop individualized treatment plans, and closely monitor patients’ physiological responses to ensure safety. However, we also highlighted the need for additional clinical trials and randomized controlled studies to further confirm the efficacy and safety of Rhizoma Paridis, ensuring its rational use in clinical settings. We believe that such studies are essential to establish clearer guidelines for its application in clinical practice.
As research into the toxicological mechanisms of TCM advances, the safety and efficacy of Rhizoma Paridis can be further improved, contributing to the development of TCM and standardizing its clinical applications. Current TCM toxicity research mainly relies on cell and animal experiments; however, with the development of modern technologies such as network pharmacology and machine learning, valuable insights into the toxicological mechanisms of TCM will emerge in the future [147].
Additionally, with the rapid development of modern drug delivery systems, innovative technologies are emerging that not only enhance the bioavailability of drugs but also reduce their toxicity. Poly lactic-co-glycolic acid (PLGA) nanoparticles, a drug delivery system known for its excellent biocompatibility and controlled release properties, can significantly improve the solubility and targeting of drugs. For Rhizoma Paridis, combining modern drug delivery technology, especially the co-loading of PPII and IR780 into PLGA nanoparticles, effectively overcomes the limitations of traditional drug delivery, such as solubility and targeting issues. This delivery system enables high concentrations of PPII and IR780 to accumulate at tumor sites, and, through the photothermal effect of IR780, precisely kill tumor cells under laser irradiation. Furthermore, the pyroptotic effect induced by PPII, in combination with the photothermal therapy from IR780, generates a synergistic effect, enhancing anticancer efficacy while reducing toxicity to normal cells, thereby improving the safety and effectiveness of the treatment [148].
By integrating modern drug delivery technology with the traditional therapeutic effects of TCM, we can maximize the therapeutic potential of Rhizoma Paridis while minimizing its toxicity, thus promoting its safe clinical application.
7 Future and prospectives
In summary, Rhizoma Paridis shows great potential as a medicinal herb, but more research is needed to fully understand its effects and safety. Future studies should focus on understanding how it works in the body and its long-term effects, especially since most research has looked at short-term toxicity. It is also important to study its chronic toxicity to ensure that it is safe for long-term use. Combining traditional knowledge with modern research methods like systems biology could help identify key pathways and biomarkers for both its benefits and risks. Additionally, strategies to reduce toxicity, such as improving how the herb is processed or combining it with other herbs, should be explored. Researchers should also look into how Rhizoma Paridis interacts with other drugs and its effects on drug metabolism. Ultimately, clinical trials will be necessary to confirm its safety and effectiveness in real-world use. By addressing these areas, future research can help ensure that Rhizoma Paridis is used safely and effectively in medical practice.
Acknowledgments
The authors are grateful for the reviewer’s valuable comments that improved the manuscript.
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Funding information: The funding for this study was provided by various sources, including the Yunnan Province “Xing Dian Ying Talent” Support Programme Project (XDYC- MY- 2022-070), Provincial Science and Technology Department Kunming Medical Joint Special Project – Key Project (202301AY070001-037).
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and consented to its submission to the journal, reviewed all the results and approved the final version of the manuscript. SJW provided guidance, conceptualized the study, and contributed significantly to the writing and execution of the manuscript. ZGW and DZF participated in data acquisition, manuscript writing, and critical revision of the work. ZY contributed to data acquisition. ZMY focused on data analysis and interpretation. LHF coordinated communication among co-authors throughout the submission, review, and production process, secured final approval from all authors, and took accountability for the originality, accuracy, and integrity of every part of the manuscript.
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Conflict of interest: Authors state no conflict of interest.
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Data availability statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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© 2025 the author(s), published by De Gruyter
This work is licensed under the Creative Commons Attribution 4.0 International License.
Articles in the same Issue
- Biomedical Sciences
- Mechanism of triptolide regulating proliferation and apoptosis of hepatoma cells by inhibiting JAK/STAT pathway
- Maslinic acid improves mitochondrial function and inhibits oxidative stress and autophagy in human gastric smooth muscle cells
- Comparative analysis of inflammatory biomarkers for the diagnosis of neonatal sepsis: IL-6, IL-8, SAA, CRP, and PCT
- Post-pandemic insights on COVID-19 and premature ovarian insufficiency
- Proteome differences of dental stem cells between permanent and deciduous teeth by data-independent acquisition proteomics
- Optimizing a modified cetyltrimethylammonium bromide protocol for fungal DNA extraction: Insights from multilocus gene amplification
- Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway
- Efficacy of alginate-coated gold nanoparticles against antibiotics-resistant Staphylococcus and Streptococcus pathogens of acne origins
- Battling COVID-19 leveraging nanobiotechnology: Gold and silver nanoparticle–B-escin conjugates as SARS-CoV-2 inhibitors
- Neurodegenerative diseases and neuroinflammation-induced apoptosis
- Impact of fracture fixation surgery on cognitive function and the gut microbiota in mice with a history of stroke
- COLEC10: A potential tumor suppressor and prognostic biomarker in hepatocellular carcinoma through modulation of EMT and PI3K-AKT pathways
- High-temperature requirement serine protease A2 inhibitor UCF-101 ameliorates damaged neurons in traumatic brain-injured rats by the AMPK/NF-κB pathway
- SIK1 inhibits IL-1β-stimulated cartilage apoptosis and inflammation in vitro through the CRTC2/CREB1 signaling
- Rutin–chitooligosaccharide complex: Comprehensive evaluation of its anti-inflammatory and analgesic properties in vitro and in vivo
- Knockdown of Aurora kinase B alleviates high glucose-triggered trophoblast cells damage and inflammation during gestational diabetes
- Calcium-sensing receptors promoted Homer1 expression and osteogenic differentiation in bone marrow mesenchymal stem cells
- ABI3BP can inhibit the proliferation, invasion, and epithelial–mesenchymal transition of non-small-cell lung cancer cells
- Changes in blood glucose and metabolism in hyperuricemia mice
- Rapid detection of the GJB2 c.235delC mutation based on CRISPR-Cas13a combined with lateral flow dipstick
- IL-11 promotes Ang II-induced autophagy inhibition and mitochondrial dysfunction in atrial fibroblasts
- Short-chain fatty acid attenuates intestinal inflammation by regulation of gut microbial composition in antibiotic-associated diarrhea
- Application of metagenomic next-generation sequencing in the diagnosis of pathogens in patients with diabetes complicated by community-acquired pneumonia
- NAT10 promotes radiotherapy resistance in non-small cell lung cancer by regulating KPNB1-mediated PD-L1 nuclear translocation
- Phytol-mixed micelles alleviate dexamethasone-induced osteoporosis in zebrafish: Activation of the MMP3–OPN–MAPK pathway-mediating bone remodeling
- Association between TGF-β1 and β-catenin expression in the vaginal wall of patients with pelvic organ prolapse
- Primary pleomorphic liposarcoma involving bilateral ovaries: Case report and literature review
- Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study
- Sleep architecture in Alzheimer’s disease continuum: The deep sleep question
- Ephedra fragilis plant extract: A groundbreaking corrosion inhibitor for mild steel in acidic environments – electrochemical, EDX, DFT, and Monte Carlo studies
- Langerhans cell histiocytosis in an adult patient with upper jaw and pulmonary involvement: A case report
- Inhibition of mast cell activation by Jaranol-targeted Pirin ameliorates allergic responses in mouse allergic rhinitis
- Aeromonas veronii-induced septic arthritis of the hip in a child with acute lymphoblastic leukemia
- Clusterin activates the heat shock response via the PI3K/Akt pathway to protect cardiomyocytes from high-temperature-induced apoptosis
- Research progress on fecal microbiota transplantation in tumor prevention and treatment
- Low-pressure exposure influences the development of HAPE
- Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis
- AKAP12, mediated by transcription factor 21, inhibits cell proliferation, metastasis, and glycolysis in lung squamous cell carcinoma
- Association between PAX9 or MSX1 gene polymorphism and tooth agenesis risk: A meta-analysis
- A case of bloodstream infection caused by Neisseria gonorrhoeae
- Case of nasopharyngeal tuberculosis complicated with cervical lymph node and pulmonary tuberculosis
- p-Cymene inhibits pro-fibrotic and inflammatory mediators to prevent hepatic dysfunction
- GFPT2 promotes paclitaxel resistance in epithelial ovarian cancer cells via activating NF-κB signaling pathway
- Transfer RNA-derived fragment tRF-36 modulates varicose vein progression via human vascular smooth muscle cell Notch signaling
- RTA-408 attenuates the hepatic ischemia reperfusion injury in mice possibly by activating the Nrf2/HO-1 signaling pathway
- Decreased serum TIMP4 levels in patients with rheumatoid arthritis
- Sirt1 protects lupus nephritis by inhibiting the NLRP3 signaling pathway in human glomerular mesangial cells
- Sodium butyrate aids brain injury repair in neonatal rats
- Interaction of MTHFR polymorphism with PAX1 methylation in cervical cancer
- Convallatoxin inhibits proliferation and angiogenesis of glioma cells via regulating JAK/STAT3 pathway
- The effect of the PKR inhibitor, 2-aminopurine, on the replication of influenza A virus, and segment 8 mRNA splicing
- Effects of Ire1 gene on virulence and pathogenicity of Candida albicans
- Small cell lung cancer with small intestinal metastasis: Case report and literature review
- GRB14: A prognostic biomarker driving tumor progression in gastric cancer through the PI3K/AKT signaling pathway by interacting with COBLL1
- 15-Lipoxygenase-2 deficiency induces foam cell formation that can be restored by salidroside through the inhibition of arachidonic acid effects
- FTO alleviated the diabetic nephropathy progression by regulating the N6-methyladenosine levels of DACT1
- Clinical relevance of inflammatory markers in the evaluation of severity of ulcerative colitis: A retrospective study
- Zinc valproic acid complex promotes osteoblast differentiation and exhibits anti-osteoporotic potential
- Primary pulmonary synovial sarcoma in the bronchial cavity: A case report
- Metagenomic next-generation sequencing of alveolar lavage fluid improves the detection of pulmonary infection
- Uterine tumor resembling ovarian sex cord tumor with extensive rhabdoid differentiation: A case report
- Genomic analysis of a novel ST11(PR34365) Clostridioides difficile strain isolated from the human fecal of a CDI patient in Guizhou, China
- Effects of tiered cardiac rehabilitation on CRP, TNF-α, and physical endurance in older adults with coronary heart disease
- Changes in T-lymphocyte subpopulations in patients with colorectal cancer before and after acupoint catgut embedding acupuncture observation
- Modulating the tumor microenvironment: The role of traditional Chinese medicine in improving lung cancer treatment
- Alterations of metabolites related to microbiota–gut–brain axis in plasma of colon cancer, esophageal cancer, stomach cancer, and lung cancer patients
- Research on individualized drug sensitivity detection technology based on bio-3D printing technology for precision treatment of gastrointestinal stromal tumors
- CEBPB promotes ulcerative colitis-associated colorectal cancer by stimulating tumor growth and activating the NF-κB/STAT3 signaling pathway
- Oncolytic bacteria: A revolutionary approach to cancer therapy
- A de novo meningioma with rapid growth: A possible malignancy imposter?
- Diagnosis of secondary tuberculosis infection in an asymptomatic elderly with cancer using next-generation sequencing: Case report
- Hesperidin and its zinc(ii) complex enhance osteoblast differentiation and bone formation: In vitro and in vivo evaluations
- Research progress on the regulation of autophagy in cardiovascular diseases by chemokines
- Anti-arthritic, immunomodulatory, and inflammatory regulation by the benzimidazole derivative BMZ-AD: Insights from an FCA-induced rat model
- Immunoassay for pyruvate kinase M1/2 as an Alzheimer’s biomarker in CSF
- The role of HDAC11 in age-related hearing loss: Mechanisms and therapeutic implications
- Evaluation and application analysis of animal models of PIPNP based on data mining
- Therapeutic approaches for liver fibrosis/cirrhosis by targeting pyroptosis
- Fabrication of zinc oxide nanoparticles using Ruellia tuberosa leaf extract induces apoptosis through P53 and STAT3 signalling pathways in prostate cancer cells
- Haplo-hematopoietic stem cell transplantation and immunoradiotherapy for severe aplastic anemia complicated with nasopharyngeal carcinoma: A case report
- Modulation of the KEAP1-NRF2 pathway by Erianin: A novel approach to reduce psoriasiform inflammation and inflammatory signaling
- The expression of epidermal growth factor receptor 2 and its relationship with tumor-infiltrating lymphocytes and clinical pathological features in breast cancer patients
- Innovations in MALDI-TOF Mass Spectrometry: Bridging modern diagnostics and historical insights
- BAP1 complexes with YY1 and RBBP7 and its downstream targets in ccRCC cells
- Hypereosinophilic syndrome with elevated IgG4 and T-cell clonality: A report of two cases
- Electroacupuncture alleviates sciatic nerve injury in sciatica rats by regulating BDNF and NGF levels, myelin sheath degradation, and autophagy
- Polydatin prevents cholesterol gallstone formation by regulating cholesterol metabolism via PPAR-γ signaling
- RNF144A and RNF144B: Important molecules for health
- Analysis of the detection rate and related factors of thyroid nodules in the healthy population
- Artesunate inhibits hepatocellular carcinoma cell migration and invasion through OGA-mediated O-GlcNAcylation of ZEB1
- Endovascular management of post-pancreatectomy hemorrhage caused by a hepatic artery pseudoaneurysm: Case report and review of the literature
- Efficacy and safety of anti-PD-1/PD-L1 antibodies in patients with relapsed refractory diffuse large B-cell lymphoma: A meta-analysis
- SATB2 promotes humeral fracture healing in rats by activating the PI3K/AKT pathway
- Overexpression of the ferroptosis-related gene, NFS1, corresponds to gastric cancer growth and tumor immune infiltration
- Understanding risk factors and prognosis in diabetic foot ulcers
- Atractylenolide I alleviates the experimental allergic response in mice by suppressing TLR4/NF-kB/NLRP3 signalling
- FBXO31 inhibits the stemness characteristics of CD147 (+) melanoma stem cells
- Immune molecule diagnostics in colorectal cancer: CCL2 and CXCL11
- Inhibiting CXCR6 promotes senescence of activated hepatic stellate cells with limited proinflammatory SASP to attenuate hepatic fibrosis
- Cadmium toxicity, health risk and its remediation using low-cost biochar adsorbents
- Pulmonary cryptococcosis with headache as the first presentation: A case report
- Solitary pulmonary metastasis with cystic airspaces in colon cancer: A rare case report
- RUNX1 promotes denervation-induced muscle atrophy by activating the JUNB/NF-κB pathway and driving M1 macrophage polarization
- Morphometric analysis and immunobiological investigation of Indigofera oblongifolia on the infected lung with Plasmodium chabaudi
- The NuA4/TIP60 histone-modifying complex and Hr78 modulate the Lobe2 mutant eye phenotype
- Experimental study on salmon demineralized bone matrix loaded with recombinant human bone morphogenetic protein-2: In vitro and in vivo study
- A case of IgA nephropathy treated with a combination of telitacicept and half-dose glucocorticoids
- Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study
- Wound healing and signaling pathways
- Combination of immunotherapy and whole-brain radiotherapy on prognosis of patients with multiple brain metastases: A retrospective cohort study
- To explore the relationship between endometrial hyperemia and polycystic ovary syndrome
- Research progress on the impact of curcumin on immune responses in breast cancer
- Biogenic Cu/Ni nanotherapeutics from Descurainia sophia (L.) Webb ex Prantl seeds for the treatment of lung cancer
- Dapagliflozin attenuates atrial fibrosis via the HMGB1/RAGE pathway in atrial fibrillation rats
- Glycitein alleviates inflammation and apoptosis in keratinocytes via ROS-associated PI3K–Akt signalling pathway
- ADH5 inhibits proliferation but promotes EMT in non-small cell lung cancer cell through activating Smad2/Smad3
- Apoptotic efficacies of AgNPs formulated by Syzygium aromaticum leaf extract on 32D-FLT3-ITD human leukemia cell line with PI3K/AKT/mTOR signaling pathway
- Novel cuproptosis-related genes C1QBP and PFKP identified as prognostic and therapeutic targets in lung adenocarcinoma
- Bee venom promotes exosome secretion and alters miRNA cargo in T cells
- Treatment of pure red cell aplasia in a chronic kidney disease patient with roxadustat: A case report
- Comparative bioinformatics analysis of the Wnt pathway in breast cancer: Selection of novel biomarker panels associated with ER status
- Kynurenine facilitates renal cell carcinoma progression by suppressing M2 macrophage pyroptosis through inhibition of CASP1 cleavage
- RFX5 promotes the growth, motility, and inhibits apoptosis of gastric adenocarcinoma cells through the SIRT1/AMPK axis
- ALKBH5 exacerbates early cardiac damage after radiotherapy for breast cancer via m6A demethylation of TLR4
- Phytochemicals of Roman chamomile: Antioxidant, anti-aging, and whitening activities of distillation residues
- Circadian gene Cry1 inhibits the tumorigenicity of hepatocellular carcinoma by the BAX/BCL2-mediated apoptosis pathway
- The TNFR-RIPK1/RIPK3 signalling pathway mediates the effect of lanthanum on necroptosis of nerve cells
- Longitudinal monitoring of autoantibody dynamics in patients with early-stage non-small-cell lung cancer undergoing surgery
- The potential role of rutin, a flavonoid, in the management of cancer through modulation of cell signaling pathways
- Construction of pectinase gene engineering microbe and its application in tobacco sheets
- Construction of a microbial abundance prognostic scoring model based on intratumoral microbial data for predicting the prognosis of lung squamous cell carcinoma
- Sepsis complicated by haemophagocytic lymphohistiocytosis triggered by methicillin-resistant Staphylococcus aureus and human herpesvirus 8 in an immunocompromised elderly patient: A case report
- Sarcopenia in liver transplantation: A comprehensive bibliometric study of current research trends and future directions
- Advances in cancer immunotherapy and future directions in personalized medicine
- Can coronavirus disease 2019 affect male fertility or cause spontaneous abortion? A two-sample Mendelian randomization analysis
- Heat stroke associated with novel leukaemia inhibitory factor receptor gene variant in a Chinese infant
- PSME2 exacerbates ulcerative colitis by disrupting intestinal barrier function and promoting autophagy-dependent inflammation
- Hyperosmolar hyperglycemic state with severe hypernatremia coexisting with central diabetes insipidus: A case report and literature review
- Efficacy and mechanism of escin in improving the tissue microenvironment of blood vessel walls via anti-inflammatory and anticoagulant effects: Implications for clinical practice
- Merkel cell carcinoma: Clinicopathological analysis of three patients and literature review
- Genetic variants in VWF exon 26 and their implications for type 1 Von Willebrand disease in a Saudi Arabian population
- Lipoxin A4 improves myocardial ischemia/reperfusion injury through the Notch1-Nrf2 signaling pathway
- High levels of EPHB2 expression predict a poor prognosis and promote tumor progression in endometrial cancer
- Knockdown of SHP-2 delays renal tubular epithelial cell injury in diabetic nephropathy by inhibiting NLRP3 inflammasome-mediated pyroptosis
- Exploring the toxicity mechanisms and detoxification methods of Rhizoma Paridis
- Concomitant gastric carcinoma and primary hepatic angiosarcoma in a patient: A case report
- Ecology and Environmental Science
- Optimization and comparative study of Bacillus consortia for cellulolytic potential and cellulase enzyme activity
- The complete mitochondrial genome analysis of Haemaphysalis hystricis Supino, 1897 (Ixodida: Ixodidae) and its phylogenetic implications
- Epidemiological characteristics and risk factors analysis of multidrug-resistant tuberculosis among tuberculosis population in Huzhou City, Eastern China
- Indices of human impacts on landscapes: How do they reflect the proportions of natural habitats?
- Genetic analysis of the Siberian flying squirrel population in the northern Changbai Mountains, Northeast China: Insights into population status and conservation
- Diversity and environmental drivers of Suillus communities in Pinus sylvestris var. mongolica forests of Inner Mongolia
- Global assessment of the fate of nitrogen deposition in forest ecosystems: Insights from 15N tracer studies
- Fungal and bacterial pathogenic co-infections mainly lead to the assembly of microbial community in tobacco stems
- Influencing of coal industry related airborne particulate matter on ocular surface tear film injury and inflammatory factor expression in Sprague-Dawley rats
- Temperature-dependent development, predation, and life table of Sphaerophoria macrogaster (Thomson) (Diptera: Syrphidae) feeding on Myzus persicae (Sulzer) (Homoptera: Aphididae)
- Eleonora’s falcon trophic interactions with insects within its breeding range: A systematic review
- Agriculture
- Integrated analysis of transcriptome, sRNAome, and degradome involved in the drought-response of maize Zhengdan958
- Variation in flower frost tolerance among seven apple cultivars and transcriptome response patterns in two contrastingly frost-tolerant selected cultivars
- Heritability of durable resistance to stripe rust in bread wheat (Triticum aestivum L.)
- Molecular mechanism of follicular development in laying hens based on the regulation of water metabolism
- Animal Science
- Effect of sex ratio on the life history traits of an important invasive species, Spodoptera frugiperda
- Plant Sciences
- Hairpin in a haystack: In silico identification and characterization of plant-conserved microRNA in Rafflesiaceae
- Widely targeted metabolomics of different tissues in Rubus corchorifolius
- The complete chloroplast genome of Gerbera piloselloides (L.) Cass., 1820 (Carduoideae, Asteraceae) and its phylogenetic analysis
- Field trial to correlate mineral solubilization activity of Pseudomonas aeruginosa and biochemical content of groundnut plants
- Correlation analysis between semen routine parameters and sperm DNA fragmentation index in patients with semen non-liquefaction: A retrospective study
- Plasticity of the anatomical traits of Rhododendron L. (Ericaceae) leaves and its implications in adaptation to the plateau environment
- Effects of Piriformospora indica and arbuscular mycorrhizal fungus on growth and physiology of Moringa oleifera under low-temperature stress
- Effects of different sources of potassium fertiliser on yield, fruit quality and nutrient absorption in “Harward” kiwifruit (Actinidia deliciosa)
- Comparative efficiency and residue levels of spraying programs against powdery mildew in grape varieties
- The DREB7 transcription factor enhances salt tolerance in soybean plants under salt stress
- Using plant electrical signals of water hyacinth (Eichhornia crassipes) for water pollution monitoring
- Food Science
- Phytochemical analysis of Stachys iva: Discovering the optimal extract conditions and its bioactive compounds
- Review on role of honey in disease prevention and treatment through modulation of biological activities
- Computational analysis of polymorphic residues in maltose and maltotriose transporters of a wild Saccharomyces cerevisiae strain
- Optimization of phenolic compound extraction from Tunisian squash by-products: A sustainable approach for antioxidant and antibacterial applications
- Liupao tea aqueous extract alleviates dextran sulfate sodium-induced ulcerative colitis in rats by modulating the gut microbiota
- Toxicological qualities and detoxification trends of fruit by-products for valorization: A review
- Polyphenolic spectrum of cornelian cherry fruits and their health-promoting effect
- Optimizing the encapsulation of the refined extract of squash peels for functional food applications: A sustainable approach to reduce food waste
- Advancements in curcuminoid formulations: An update on bioavailability enhancement strategies curcuminoid bioavailability and formulations
- Impact of saline sprouting on antioxidant properties and bioactive compounds in chia seeds
- The dilemma of food genetics and improvement
- Bioengineering and Biotechnology
- Impact of hyaluronic acid-modified hafnium metalorganic frameworks containing rhynchophylline on Alzheimer’s disease
- Emerging patterns in nanoparticle-based therapeutic approaches for rheumatoid arthritis: A comprehensive bibliometric and visual analysis spanning two decades
- Application of CRISPR/Cas gene editing for infectious disease control in poultry
- Preparation of hafnium nitride-coated titanium implants by magnetron sputtering technology and evaluation of their antibacterial properties and biocompatibility
- Preparation and characterization of lemongrass oil nanoemulsion: Antimicrobial, antibiofilm, antioxidant, and anticancer activities
- Corrigendum
- Corrigendum to “Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells”
- Corrigendum to “Effects of Ire1 gene on virulence and pathogenicity of Candida albicans”
- Retraction
- Retraction of “Down-regulation of miR-539 indicates poor prognosis in patients with pancreatic cancer”
Articles in the same Issue
- Biomedical Sciences
- Mechanism of triptolide regulating proliferation and apoptosis of hepatoma cells by inhibiting JAK/STAT pathway
- Maslinic acid improves mitochondrial function and inhibits oxidative stress and autophagy in human gastric smooth muscle cells
- Comparative analysis of inflammatory biomarkers for the diagnosis of neonatal sepsis: IL-6, IL-8, SAA, CRP, and PCT
- Post-pandemic insights on COVID-19 and premature ovarian insufficiency
- Proteome differences of dental stem cells between permanent and deciduous teeth by data-independent acquisition proteomics
- Optimizing a modified cetyltrimethylammonium bromide protocol for fungal DNA extraction: Insights from multilocus gene amplification
- Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway
- Efficacy of alginate-coated gold nanoparticles against antibiotics-resistant Staphylococcus and Streptococcus pathogens of acne origins
- Battling COVID-19 leveraging nanobiotechnology: Gold and silver nanoparticle–B-escin conjugates as SARS-CoV-2 inhibitors
- Neurodegenerative diseases and neuroinflammation-induced apoptosis
- Impact of fracture fixation surgery on cognitive function and the gut microbiota in mice with a history of stroke
- COLEC10: A potential tumor suppressor and prognostic biomarker in hepatocellular carcinoma through modulation of EMT and PI3K-AKT pathways
- High-temperature requirement serine protease A2 inhibitor UCF-101 ameliorates damaged neurons in traumatic brain-injured rats by the AMPK/NF-κB pathway
- SIK1 inhibits IL-1β-stimulated cartilage apoptosis and inflammation in vitro through the CRTC2/CREB1 signaling
- Rutin–chitooligosaccharide complex: Comprehensive evaluation of its anti-inflammatory and analgesic properties in vitro and in vivo
- Knockdown of Aurora kinase B alleviates high glucose-triggered trophoblast cells damage and inflammation during gestational diabetes
- Calcium-sensing receptors promoted Homer1 expression and osteogenic differentiation in bone marrow mesenchymal stem cells
- ABI3BP can inhibit the proliferation, invasion, and epithelial–mesenchymal transition of non-small-cell lung cancer cells
- Changes in blood glucose and metabolism in hyperuricemia mice
- Rapid detection of the GJB2 c.235delC mutation based on CRISPR-Cas13a combined with lateral flow dipstick
- IL-11 promotes Ang II-induced autophagy inhibition and mitochondrial dysfunction in atrial fibroblasts
- Short-chain fatty acid attenuates intestinal inflammation by regulation of gut microbial composition in antibiotic-associated diarrhea
- Application of metagenomic next-generation sequencing in the diagnosis of pathogens in patients with diabetes complicated by community-acquired pneumonia
- NAT10 promotes radiotherapy resistance in non-small cell lung cancer by regulating KPNB1-mediated PD-L1 nuclear translocation
- Phytol-mixed micelles alleviate dexamethasone-induced osteoporosis in zebrafish: Activation of the MMP3–OPN–MAPK pathway-mediating bone remodeling
- Association between TGF-β1 and β-catenin expression in the vaginal wall of patients with pelvic organ prolapse
- Primary pleomorphic liposarcoma involving bilateral ovaries: Case report and literature review
- Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study
- Sleep architecture in Alzheimer’s disease continuum: The deep sleep question
- Ephedra fragilis plant extract: A groundbreaking corrosion inhibitor for mild steel in acidic environments – electrochemical, EDX, DFT, and Monte Carlo studies
- Langerhans cell histiocytosis in an adult patient with upper jaw and pulmonary involvement: A case report
- Inhibition of mast cell activation by Jaranol-targeted Pirin ameliorates allergic responses in mouse allergic rhinitis
- Aeromonas veronii-induced septic arthritis of the hip in a child with acute lymphoblastic leukemia
- Clusterin activates the heat shock response via the PI3K/Akt pathway to protect cardiomyocytes from high-temperature-induced apoptosis
- Research progress on fecal microbiota transplantation in tumor prevention and treatment
- Low-pressure exposure influences the development of HAPE
- Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis
- AKAP12, mediated by transcription factor 21, inhibits cell proliferation, metastasis, and glycolysis in lung squamous cell carcinoma
- Association between PAX9 or MSX1 gene polymorphism and tooth agenesis risk: A meta-analysis
- A case of bloodstream infection caused by Neisseria gonorrhoeae
- Case of nasopharyngeal tuberculosis complicated with cervical lymph node and pulmonary tuberculosis
- p-Cymene inhibits pro-fibrotic and inflammatory mediators to prevent hepatic dysfunction
- GFPT2 promotes paclitaxel resistance in epithelial ovarian cancer cells via activating NF-κB signaling pathway
- Transfer RNA-derived fragment tRF-36 modulates varicose vein progression via human vascular smooth muscle cell Notch signaling
- RTA-408 attenuates the hepatic ischemia reperfusion injury in mice possibly by activating the Nrf2/HO-1 signaling pathway
- Decreased serum TIMP4 levels in patients with rheumatoid arthritis
- Sirt1 protects lupus nephritis by inhibiting the NLRP3 signaling pathway in human glomerular mesangial cells
- Sodium butyrate aids brain injury repair in neonatal rats
- Interaction of MTHFR polymorphism with PAX1 methylation in cervical cancer
- Convallatoxin inhibits proliferation and angiogenesis of glioma cells via regulating JAK/STAT3 pathway
- The effect of the PKR inhibitor, 2-aminopurine, on the replication of influenza A virus, and segment 8 mRNA splicing
- Effects of Ire1 gene on virulence and pathogenicity of Candida albicans
- Small cell lung cancer with small intestinal metastasis: Case report and literature review
- GRB14: A prognostic biomarker driving tumor progression in gastric cancer through the PI3K/AKT signaling pathway by interacting with COBLL1
- 15-Lipoxygenase-2 deficiency induces foam cell formation that can be restored by salidroside through the inhibition of arachidonic acid effects
- FTO alleviated the diabetic nephropathy progression by regulating the N6-methyladenosine levels of DACT1
- Clinical relevance of inflammatory markers in the evaluation of severity of ulcerative colitis: A retrospective study
- Zinc valproic acid complex promotes osteoblast differentiation and exhibits anti-osteoporotic potential
- Primary pulmonary synovial sarcoma in the bronchial cavity: A case report
- Metagenomic next-generation sequencing of alveolar lavage fluid improves the detection of pulmonary infection
- Uterine tumor resembling ovarian sex cord tumor with extensive rhabdoid differentiation: A case report
- Genomic analysis of a novel ST11(PR34365) Clostridioides difficile strain isolated from the human fecal of a CDI patient in Guizhou, China
- Effects of tiered cardiac rehabilitation on CRP, TNF-α, and physical endurance in older adults with coronary heart disease
- Changes in T-lymphocyte subpopulations in patients with colorectal cancer before and after acupoint catgut embedding acupuncture observation
- Modulating the tumor microenvironment: The role of traditional Chinese medicine in improving lung cancer treatment
- Alterations of metabolites related to microbiota–gut–brain axis in plasma of colon cancer, esophageal cancer, stomach cancer, and lung cancer patients
- Research on individualized drug sensitivity detection technology based on bio-3D printing technology for precision treatment of gastrointestinal stromal tumors
- CEBPB promotes ulcerative colitis-associated colorectal cancer by stimulating tumor growth and activating the NF-κB/STAT3 signaling pathway
- Oncolytic bacteria: A revolutionary approach to cancer therapy
- A de novo meningioma with rapid growth: A possible malignancy imposter?
- Diagnosis of secondary tuberculosis infection in an asymptomatic elderly with cancer using next-generation sequencing: Case report
- Hesperidin and its zinc(ii) complex enhance osteoblast differentiation and bone formation: In vitro and in vivo evaluations
- Research progress on the regulation of autophagy in cardiovascular diseases by chemokines
- Anti-arthritic, immunomodulatory, and inflammatory regulation by the benzimidazole derivative BMZ-AD: Insights from an FCA-induced rat model
- Immunoassay for pyruvate kinase M1/2 as an Alzheimer’s biomarker in CSF
- The role of HDAC11 in age-related hearing loss: Mechanisms and therapeutic implications
- Evaluation and application analysis of animal models of PIPNP based on data mining
- Therapeutic approaches for liver fibrosis/cirrhosis by targeting pyroptosis
- Fabrication of zinc oxide nanoparticles using Ruellia tuberosa leaf extract induces apoptosis through P53 and STAT3 signalling pathways in prostate cancer cells
- Haplo-hematopoietic stem cell transplantation and immunoradiotherapy for severe aplastic anemia complicated with nasopharyngeal carcinoma: A case report
- Modulation of the KEAP1-NRF2 pathway by Erianin: A novel approach to reduce psoriasiform inflammation and inflammatory signaling
- The expression of epidermal growth factor receptor 2 and its relationship with tumor-infiltrating lymphocytes and clinical pathological features in breast cancer patients
- Innovations in MALDI-TOF Mass Spectrometry: Bridging modern diagnostics and historical insights
- BAP1 complexes with YY1 and RBBP7 and its downstream targets in ccRCC cells
- Hypereosinophilic syndrome with elevated IgG4 and T-cell clonality: A report of two cases
- Electroacupuncture alleviates sciatic nerve injury in sciatica rats by regulating BDNF and NGF levels, myelin sheath degradation, and autophagy
- Polydatin prevents cholesterol gallstone formation by regulating cholesterol metabolism via PPAR-γ signaling
- RNF144A and RNF144B: Important molecules for health
- Analysis of the detection rate and related factors of thyroid nodules in the healthy population
- Artesunate inhibits hepatocellular carcinoma cell migration and invasion through OGA-mediated O-GlcNAcylation of ZEB1
- Endovascular management of post-pancreatectomy hemorrhage caused by a hepatic artery pseudoaneurysm: Case report and review of the literature
- Efficacy and safety of anti-PD-1/PD-L1 antibodies in patients with relapsed refractory diffuse large B-cell lymphoma: A meta-analysis
- SATB2 promotes humeral fracture healing in rats by activating the PI3K/AKT pathway
- Overexpression of the ferroptosis-related gene, NFS1, corresponds to gastric cancer growth and tumor immune infiltration
- Understanding risk factors and prognosis in diabetic foot ulcers
- Atractylenolide I alleviates the experimental allergic response in mice by suppressing TLR4/NF-kB/NLRP3 signalling
- FBXO31 inhibits the stemness characteristics of CD147 (+) melanoma stem cells
- Immune molecule diagnostics in colorectal cancer: CCL2 and CXCL11
- Inhibiting CXCR6 promotes senescence of activated hepatic stellate cells with limited proinflammatory SASP to attenuate hepatic fibrosis
- Cadmium toxicity, health risk and its remediation using low-cost biochar adsorbents
- Pulmonary cryptococcosis with headache as the first presentation: A case report
- Solitary pulmonary metastasis with cystic airspaces in colon cancer: A rare case report
- RUNX1 promotes denervation-induced muscle atrophy by activating the JUNB/NF-κB pathway and driving M1 macrophage polarization
- Morphometric analysis and immunobiological investigation of Indigofera oblongifolia on the infected lung with Plasmodium chabaudi
- The NuA4/TIP60 histone-modifying complex and Hr78 modulate the Lobe2 mutant eye phenotype
- Experimental study on salmon demineralized bone matrix loaded with recombinant human bone morphogenetic protein-2: In vitro and in vivo study
- A case of IgA nephropathy treated with a combination of telitacicept and half-dose glucocorticoids
- Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study
- Wound healing and signaling pathways
- Combination of immunotherapy and whole-brain radiotherapy on prognosis of patients with multiple brain metastases: A retrospective cohort study
- To explore the relationship between endometrial hyperemia and polycystic ovary syndrome
- Research progress on the impact of curcumin on immune responses in breast cancer
- Biogenic Cu/Ni nanotherapeutics from Descurainia sophia (L.) Webb ex Prantl seeds for the treatment of lung cancer
- Dapagliflozin attenuates atrial fibrosis via the HMGB1/RAGE pathway in atrial fibrillation rats
- Glycitein alleviates inflammation and apoptosis in keratinocytes via ROS-associated PI3K–Akt signalling pathway
- ADH5 inhibits proliferation but promotes EMT in non-small cell lung cancer cell through activating Smad2/Smad3
- Apoptotic efficacies of AgNPs formulated by Syzygium aromaticum leaf extract on 32D-FLT3-ITD human leukemia cell line with PI3K/AKT/mTOR signaling pathway
- Novel cuproptosis-related genes C1QBP and PFKP identified as prognostic and therapeutic targets in lung adenocarcinoma
- Bee venom promotes exosome secretion and alters miRNA cargo in T cells
- Treatment of pure red cell aplasia in a chronic kidney disease patient with roxadustat: A case report
- Comparative bioinformatics analysis of the Wnt pathway in breast cancer: Selection of novel biomarker panels associated with ER status
- Kynurenine facilitates renal cell carcinoma progression by suppressing M2 macrophage pyroptosis through inhibition of CASP1 cleavage
- RFX5 promotes the growth, motility, and inhibits apoptosis of gastric adenocarcinoma cells through the SIRT1/AMPK axis
- ALKBH5 exacerbates early cardiac damage after radiotherapy for breast cancer via m6A demethylation of TLR4
- Phytochemicals of Roman chamomile: Antioxidant, anti-aging, and whitening activities of distillation residues
- Circadian gene Cry1 inhibits the tumorigenicity of hepatocellular carcinoma by the BAX/BCL2-mediated apoptosis pathway
- The TNFR-RIPK1/RIPK3 signalling pathway mediates the effect of lanthanum on necroptosis of nerve cells
- Longitudinal monitoring of autoantibody dynamics in patients with early-stage non-small-cell lung cancer undergoing surgery
- The potential role of rutin, a flavonoid, in the management of cancer through modulation of cell signaling pathways
- Construction of pectinase gene engineering microbe and its application in tobacco sheets
- Construction of a microbial abundance prognostic scoring model based on intratumoral microbial data for predicting the prognosis of lung squamous cell carcinoma
- Sepsis complicated by haemophagocytic lymphohistiocytosis triggered by methicillin-resistant Staphylococcus aureus and human herpesvirus 8 in an immunocompromised elderly patient: A case report
- Sarcopenia in liver transplantation: A comprehensive bibliometric study of current research trends and future directions
- Advances in cancer immunotherapy and future directions in personalized medicine
- Can coronavirus disease 2019 affect male fertility or cause spontaneous abortion? A two-sample Mendelian randomization analysis
- Heat stroke associated with novel leukaemia inhibitory factor receptor gene variant in a Chinese infant
- PSME2 exacerbates ulcerative colitis by disrupting intestinal barrier function and promoting autophagy-dependent inflammation
- Hyperosmolar hyperglycemic state with severe hypernatremia coexisting with central diabetes insipidus: A case report and literature review
- Efficacy and mechanism of escin in improving the tissue microenvironment of blood vessel walls via anti-inflammatory and anticoagulant effects: Implications for clinical practice
- Merkel cell carcinoma: Clinicopathological analysis of three patients and literature review
- Genetic variants in VWF exon 26 and their implications for type 1 Von Willebrand disease in a Saudi Arabian population
- Lipoxin A4 improves myocardial ischemia/reperfusion injury through the Notch1-Nrf2 signaling pathway
- High levels of EPHB2 expression predict a poor prognosis and promote tumor progression in endometrial cancer
- Knockdown of SHP-2 delays renal tubular epithelial cell injury in diabetic nephropathy by inhibiting NLRP3 inflammasome-mediated pyroptosis
- Exploring the toxicity mechanisms and detoxification methods of Rhizoma Paridis
- Concomitant gastric carcinoma and primary hepatic angiosarcoma in a patient: A case report
- Ecology and Environmental Science
- Optimization and comparative study of Bacillus consortia for cellulolytic potential and cellulase enzyme activity
- The complete mitochondrial genome analysis of Haemaphysalis hystricis Supino, 1897 (Ixodida: Ixodidae) and its phylogenetic implications
- Epidemiological characteristics and risk factors analysis of multidrug-resistant tuberculosis among tuberculosis population in Huzhou City, Eastern China
- Indices of human impacts on landscapes: How do they reflect the proportions of natural habitats?
- Genetic analysis of the Siberian flying squirrel population in the northern Changbai Mountains, Northeast China: Insights into population status and conservation
- Diversity and environmental drivers of Suillus communities in Pinus sylvestris var. mongolica forests of Inner Mongolia
- Global assessment of the fate of nitrogen deposition in forest ecosystems: Insights from 15N tracer studies
- Fungal and bacterial pathogenic co-infections mainly lead to the assembly of microbial community in tobacco stems
- Influencing of coal industry related airborne particulate matter on ocular surface tear film injury and inflammatory factor expression in Sprague-Dawley rats
- Temperature-dependent development, predation, and life table of Sphaerophoria macrogaster (Thomson) (Diptera: Syrphidae) feeding on Myzus persicae (Sulzer) (Homoptera: Aphididae)
- Eleonora’s falcon trophic interactions with insects within its breeding range: A systematic review
- Agriculture
- Integrated analysis of transcriptome, sRNAome, and degradome involved in the drought-response of maize Zhengdan958
- Variation in flower frost tolerance among seven apple cultivars and transcriptome response patterns in two contrastingly frost-tolerant selected cultivars
- Heritability of durable resistance to stripe rust in bread wheat (Triticum aestivum L.)
- Molecular mechanism of follicular development in laying hens based on the regulation of water metabolism
- Animal Science
- Effect of sex ratio on the life history traits of an important invasive species, Spodoptera frugiperda
- Plant Sciences
- Hairpin in a haystack: In silico identification and characterization of plant-conserved microRNA in Rafflesiaceae
- Widely targeted metabolomics of different tissues in Rubus corchorifolius
- The complete chloroplast genome of Gerbera piloselloides (L.) Cass., 1820 (Carduoideae, Asteraceae) and its phylogenetic analysis
- Field trial to correlate mineral solubilization activity of Pseudomonas aeruginosa and biochemical content of groundnut plants
- Correlation analysis between semen routine parameters and sperm DNA fragmentation index in patients with semen non-liquefaction: A retrospective study
- Plasticity of the anatomical traits of Rhododendron L. (Ericaceae) leaves and its implications in adaptation to the plateau environment
- Effects of Piriformospora indica and arbuscular mycorrhizal fungus on growth and physiology of Moringa oleifera under low-temperature stress
- Effects of different sources of potassium fertiliser on yield, fruit quality and nutrient absorption in “Harward” kiwifruit (Actinidia deliciosa)
- Comparative efficiency and residue levels of spraying programs against powdery mildew in grape varieties
- The DREB7 transcription factor enhances salt tolerance in soybean plants under salt stress
- Using plant electrical signals of water hyacinth (Eichhornia crassipes) for water pollution monitoring
- Food Science
- Phytochemical analysis of Stachys iva: Discovering the optimal extract conditions and its bioactive compounds
- Review on role of honey in disease prevention and treatment through modulation of biological activities
- Computational analysis of polymorphic residues in maltose and maltotriose transporters of a wild Saccharomyces cerevisiae strain
- Optimization of phenolic compound extraction from Tunisian squash by-products: A sustainable approach for antioxidant and antibacterial applications
- Liupao tea aqueous extract alleviates dextran sulfate sodium-induced ulcerative colitis in rats by modulating the gut microbiota
- Toxicological qualities and detoxification trends of fruit by-products for valorization: A review
- Polyphenolic spectrum of cornelian cherry fruits and their health-promoting effect
- Optimizing the encapsulation of the refined extract of squash peels for functional food applications: A sustainable approach to reduce food waste
- Advancements in curcuminoid formulations: An update on bioavailability enhancement strategies curcuminoid bioavailability and formulations
- Impact of saline sprouting on antioxidant properties and bioactive compounds in chia seeds
- The dilemma of food genetics and improvement
- Bioengineering and Biotechnology
- Impact of hyaluronic acid-modified hafnium metalorganic frameworks containing rhynchophylline on Alzheimer’s disease
- Emerging patterns in nanoparticle-based therapeutic approaches for rheumatoid arthritis: A comprehensive bibliometric and visual analysis spanning two decades
- Application of CRISPR/Cas gene editing for infectious disease control in poultry
- Preparation of hafnium nitride-coated titanium implants by magnetron sputtering technology and evaluation of their antibacterial properties and biocompatibility
- Preparation and characterization of lemongrass oil nanoemulsion: Antimicrobial, antibiofilm, antioxidant, and anticancer activities
- Corrigendum
- Corrigendum to “Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells”
- Corrigendum to “Effects of Ire1 gene on virulence and pathogenicity of Candida albicans”
- Retraction
- Retraction of “Down-regulation of miR-539 indicates poor prognosis in patients with pancreatic cancer”
