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Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway

  • Xiaopeng Cao , Hui Zhao , Zhimin Liang , Yi Cao and Min Min EMAIL logo
Published/Copyright: December 26, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

Sepsis can impair gastrointestinal (GI) barrier integrity. Oral probiotics (PT) can maintain the balance of GI microflora and improve GI function. 5-Hydroxytryptamine (5-HT) is a key promoter of GI injury caused by sepsis. However, the mechanism by which PT attenuates sepsis by regulating 5-HT is not fully understood. In this study, C57BL6 mice were intragastric administrated with normal saline (NC) or PT once a day for 4 weeks before cecal ligation and puncture (CLP). Compared with NC-CLP mice, PT-CLP mice had lower clinical score, higher body temperature. The survival rate of PT-CLP mice was significantly improved. The levels of inflammatory cytokines and 5-HT were obviously decreased in PT-CLP mice, and GI peristalsis and barrier function were enhanced. Moreover, sepsis downregulated the expression of tight junction proteins, while PT pretreatment could maintain them at the level of sham operation group. Furthermore, PT pretreatment increased the expression of serotonin transporter and monoamine oxidase A. PT administration could inhibit NF-κB activity, and activate ERK activity. In conclusion, long-term supplementation of PT before CLP can prevent sepsis-induced GI mucosal barrier dysfunction in mice, which may be partially mediated by upregulating the 5-HT degradation pathway via activating ERK signaling.

Keywords: sepsis; probiotics; gastrointestinal barrier; 5-hydroxytryptamine; ERK signal

1 Introduction

Sepsis is a systemic inflammatory response syndrome caused by the invasion of bacteria and other pathogenic microorganisms, which can be caused by infection in any part of the body [1,2]. Sepsis often occurs in patients with serious diseases, such as severe burns, multiple injuries, postoperative patients, and so on, which has become one of the important causes of death in intensive care unit [3]. In the initial stage of sepsis, inflammatory cells such as macrophages and neutrophils are activated to produce a large number of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as reactive oxygen species lead to endothelial and epithelial damage, affect vascular permeability and heart function, and eventually result in tissue necrosis and organ failure [4]. The stress response caused by serious disorders often destroys the intestinal mucosal barrier, causes intestinal dysfunction, and microflora ecological imbalance, and then leads to the translocation of intestinal bacteria/endotoxin, which is closely related to the subsequent sepsis and multiple organ dysfunction [5].

Regulating intestinal microflora balance by taking probiotics (PT) has been shown to improve intestinal function and alleviate sepsis [6,7]. It is believed that PT can compete with pathogens for binding site and nutrients, and meanwhile can produce bacteriocins to kill pathogens. Yang et al. found that PT such as Lactobacillus rhamnosus GG (LGG) can eliminate pathogens, promote mucosal immunity, and resist Salmonella infection [8]. It is reported that LGG may also reduce rotavirus-associated diarrhea by increasing interferon-γ [9]. Moreover, PT can regulate immune response and reduce inflammation through IL-10 and transforming growth factor (TGF-β) signal [10,11].

5-Hydroxytryptamine (5-HT), also known as serotonin, is an important regulator of the gastrointestinal (GI) tract [12]. It has been confirmed that the intestinal microbiota can regulate production of 5-HT from the enterochromaffin cells [13]. During sepsis, dysregulation of 5-HT induced by microflora ecological imbalance may promote inflammation, damage the intestinal mucosal barrier, facilitate bacterial translocation, and increase the mortality of sepsis [14]. Recently, Wang et al. reported that PT intervention can reduce serotonin status [15]. So, can supplementing PT prevent the pathological response caused by sepsis through reducing 5-HT. Moreover, the mechanism by which PT regulate 5-HT is not fully understood. Therefore, in this study, a sepsis model induced by cecal ligation and puncture (CLP) was established in mice pre-fed with PT for 4 weeks to detect the preventive effect of PT supplementation on the GI mucosal barrier and explore how PT pretreatment can improve GI function by regulating the 5-HT pathway.

2 Methods

2.1 Animal studies

Animal protocols were approved by Committee on Ethics of the Affiliated Hospital of Academy of Military Medical Sciences (ky-2015-6-27). Male C57BL6 mice (4–5 weeks old) were purchased from Shanghai JieSiJie Laboratory Animal Co., Ltd (China) and kept under controlled conditions (room temperature of 23 ± 1°C, 12 h/12 h light/dark cycle, 50% humidity, free access to a sterile diet and water).

The PT with the trade name BIFICO are composed of triple viable microbe: Bifidobacterium, Lactobacillus, and Enterococcus, purchased from SPH Sine Pharmaceutical Laboratories Co. Ltd (China). Long-term oral administration of 200 μL of normal saline (NC-sham group, n = 20; NC-CLP group, n = 20) or PT (2 × 108 CFU/mL; PT-sham group, n = 20; PT-CLP group, n = 20) to mice before CLP, once a day for 4 weeks.

The experimental sepsis model of mice was established according to the previous studies [16,17]. Briefly, the mice fasted overnight before CLP but were allowed water ad libitum. The mice were anesthetized by intraperitoneal injection of a solution of 1:1 ketamine (75 mg/kg) and xylazine (15 mg/kg) at a dose of 30 μL/20 g body weight. A 1 cm incision was made on the left to midline of abdomen, and the cecum was moved out of peritoneal cavity through the incision carefully. In order to achieve a mid-grade sepsis, the cecum was ligated by 60% and punctured from mesenteric to anti-mesenteric side using a 21G needle. A small amount of feces was squeezed out of the holes and the cecum was put back into the peritoneal cavity. Finally, the abdominal musculature and abdominal skin were closed in layers. The sham mice received the same surgery except the cecum ligation and puncture. After operation, all mice were intraperitoneally injected with 1 mL of prewarmed NC to supplement heat and water lost during the procedure and placed under a heat lamp until recovery. Ten mice in each group were monitored to assess mortality for 120 h.

After 24 h of CLP, body temperature and clinical score were measured according to the literature [18]. When mice were anesthetized, the temperature was measured by inserting a temperature sensor into the rectum. The clinical score was assessed as follows (points): (i) appearance: normal (0), lack of grooming (1), piloerection (2), hunched up (3), above and eyes half closed (4); (ii) behavior-unprovoked: normal (0), minor changes (1), less mobile and isolated (2), restless or very still (3); behavior-provoked: responsive and alert (0), unresponsive and not alert (3); (iii) clinical signs: normal respiratory rate (0), slight changes (1), decreased rate with abdominal breathing (2), marked abdominal breathing and cyanosis (3); (iv) hydration status: normal (0), dehydrated (5). One-time evaluation was conducted at 24 h after CLP, with two evaluators scoring separately and taking the average of each indicator. The higher score indicates worse clinical situation of the animal.

2.2 Serum and colon tissues collection

After measuring the body temperature and clinical score, five mice in each group were sacrificed and blood samples and colon tissues were collected. The blood was collected into a tube free of anticoagulants and placed on the laboratory bench at room temperature for 30 min, then centrifuged at 3,000×g for 5 min under 4°C, carefully transferred the serum to a clean tube, and then stored at −80°C as soon as possible. The serums TNF-α, IL-1β, and IL-6 levels were subsequently detected using enzyme-linked immunosorbent assay. Colon tissues were collected and divided into two parts, one of which was stored in −80°C as soon as possible and used for protein expression determination, the other part was fixed in 4% paraformaldehyde (PFA) for histological analysis.

2.3 GI motility and permeability test

Based on previous studies [19,20], FD4 (#60842-46-8-FD4-1 G, Sigma-Aldrich, USA) was used to evaluate GI mobility and permeability. Briefly, three mice in each group were gavaged 100 μL of 50 mg/mL FD4 dissolved in NC, at 24 h after CLP. Three hours later, the mice were anesthetized. Portal vein blood was collected and immediately centrifuged at 8,000×g for 10 min under 4°C to obtain the supernatant. The supernatant FD4 concentration was then quantified with a standard curve using a Multiskan Mk3 microplate reader (Thermo, USA) at an excitation wavelength of 488 nm. At the same time, the whole GI tract from stomach to colon was removed and imaged with Caliper IVIS Lumina III (PerkinElmer, USA). To quantify GI motility, the whole GI tract was divided into 12 segments and flushed with distilled water. The fluorescence of the purified recovered flushing solution was measured using the fluorescence microplate reader, and then fluorescence percentage of flushing solution of each segment was calculated.

2.4 Enzyme-linked immunosorbent assay

The levels of serum IL-1β, IL-6, and TNF-α were measured using commercial ELISA kits according to the instructions of the manufacturer (China). In brief, 50 μL of sample (10 μL serum diluted with 40 μL sample dilution buffer) and 100 μL of horseradish peroxidise (HRP)-conjugated detection antibodies were successively added into each well. The plate was incubated for 1 h at 37°C and washed five times. The substrate was then added and incubated in the dark at 37°C for 15 min. Then 50 μL stop solution was added to stop the enzyme reaction and absorbance was measured at 450 nm. The concentration of inflammatory factors was calculated using the standard curve.

2.5 Histological analysis

The PFA-fixed colon tissues were dehydrated and embedded in paraffin, and then sectioned at 5 μm thickness. Sections were stained with hematoxylin and eosin (H&E) for histological observation to examine the pathology of colon injury. Immunohistochemical staining of 5-HT was performed to evaluate the effect of PT treatment on 5-HT production. Alcian blue and periodic acid-Schiff (AB-PAS) staining was used to observe the changes of mature goblet cells. The stained slices were examined under the light microscope, and the images were captured (three random ×200 magnified fields in one section per mouse, five mice per group). The images were then analyzed using the ImageJ software.

2.6 RNA isolation and real-time PCR analysis

RNA extraction and cDNA synthesis were carried out according to the manufacturer’s instructions. Total RNA in the colon tissues was isolated using RNAiso Plus reagent (TaKaRa Biotechnology Dalian Co. Ltd, Dalian, China) and reverse transcribed into cDNA using PrimeScript RT Master Mix (TaKaRa). Primers for each gene were designed using NCBI Primer-BLAST and were synthesized by Sangon Biotech (Shanghai, China). The primers were as follows: occludin, 5′-ATCTTGGGAGCCTGGACATT-3′ (forward) and 5′-CCTCTGTCCCAAGCAAGTGT-3′ (reverse); claudin-1, 5′-AAAGCACCGGGCAGATACAG-3′ (forward) and 5′-GGGGGTCAAGGGGTCATAGA-3′ (reverse); zonula occludens-1 (ZO-1), 5′-CTCTCCTGTACCTCTTGAGCC-3′ (forward) and 5′-CAGAAATCGTGCTGATGTGCC-3′ (reverse); mucins (Muc)-2, 5′-GCCCACCTCACAAGCAGTAT-3′ (forward) and 5′-GTCATAGCCAGGGGCAAACT-3′ (reverse); tryptophan hydroxylase 1 (TPH1), 5′-TAAAGCAGTCTTGCCTGGTCAC-3′ (forward) and 5′-GAGGCCCGTGGACATACTTCT-3′ (reverse); TPH2, 5′-CCAGTCGGTGAGTTGTGGAA-3′ (forward) and 5′-CTGTGATGCAAAGCGTGGAG-3′ (reverse); monoamine oxidase A (MAO-A), 5′-ACTTACCCATTCCGTGGTGC-3′ (forward) and 5′-ACCACAGGGCAGATACCTCA-3′ (reverse); serotonin reuptake transporter (SERT), 5′-GATCAGCACTCCAGGGACAC-3′ (forward) and 5′-TCAGAGATGAGGAGTCGGGG-3′ (reverse); β-actin, 5′-GCTTCTAGGCGGACTGTTACT-3′ (forward) and 5′-GCCTTCACCGTTCCAGTTTTT-3′ (reverse). RT-PCR was performed with 2 μL cDNA and SYBR Premix Ex Taq (TaKaRa) on ABI 7500 system (ABI, California, USA). PCR conditions: 40 cycles, 95°C for 30 s, 60°C for 34 s, and 72°C for 30 s. β-Actin was used as an internal control to normalize gene expression. The relative expression level of candidate genes was analyzed using the 2−ΔΔCt method.

2.7 Western blot analysis

Western blot was performed as previously described with modifications [21]. Briefly, the colon tissues were homogenized in cold RIPA lysis buffer, then centrifuged at 14,000×g for 15 min under 4°C to collect the supernatant. The protein concentration was quantified using BCA protein assay kit. The same amount of protein from each sample was dissolved in the loading buffer, denatured at 95°C for 5 min, and separated on 10% SDS-PAGE mini gels, then transferred to PVDF membranes. The membranes were blocked in 5% skimmed milk/Tris-buffered saline with 0.5‰ Tween-20 for 1 h at room temperature, then probed with primary antibodies, including β-actin (1:5,000, #3700; Cell Signaling Technology [CST], USA), p65 (1:1,000, #8242; CST), phospho-p65 (1:1,000, #3031; CST), p38 (1:1,000, #8690; CST), phospho-p38 (1:1,000, #4511; CST), p44/42 MAPK (Erk1/2) (1:1,000, #4695; CST), and phospho-p44/42 MAPK (Erk1/2) (1:1,000, #4370; CST). After incubation with primary antibodies overnight at 4°C, the membranes were blotted with the corresponding HRP-conjugated secondary antibodies (anti-rabbit IgG or anti-mouse IgG). The signals were detected by Western Blotting Luminol Reagent (sc-2048; Santa Cruz Biotechnology, CA, USA). The membranes were imaged with BioRad ChemiDocTM XRS+ System. Quantity One software (BioRad, CA, USA) was used to quantify the band intensity. The relative expression level of protein was expressed as the value of density ratio (target protein to β-actin in the same sample).

2.8 Statistical analysis

The data are expressed as mean ± SD. One-way ANOVA was used to compare the inflammatory factors, proteins, and histological variables among different groups. The survival study was conducted by log-rank test. GraphPad Prism 8 (GraphPad Software, Inc., La Jolla, CA, USA) was used for statistical analysis. p < 0.05 was considered statistically significant.

3 Results

3.1 Long-term supplementation of PT before CLP reduces mortality and inflammatory response in septic mice

Mouse sepsis model was established to explore the preventive effect of long-term supplementation of PT on sepsis. After 4 weeks of PT gavage, the mice underwent CLP operation, and then the clinical score, body temperature, survival rate, and serum inflammatory cytokine level were measured. Compared with NC-CLP mice, PT-CLP mice had lower clinical scores (Figure 1a), better body temperature and close to normal body temperature (Figure 1b). The survival rate of PT-CLP mice was significantly increased (Figure 1c), but all animals died within 72 h after CLP. Inflammatory hallmark cytokines IL-1β, IL-6, and TNF-α constitute the cytokine storm during sepsis. ELISA analysis showed that PT pretreatment obviously reduced the levels of these three inflammatory cytokines (Figure 1d–f). This suggests that long-term oral pre-administration with PT has a preventive effect on CLP-induced sepsis in mice.

Figure 1 Supplementation with probiotics alleviates inflammatory reaction and increases survival of mice after CLP. (a) Clinical score: the clinical score of each animal was assessed at 24 h after CLP. The higher score indicates worse clinical situation of the animal (n: NC-sham or PT-sham = 10, NC-CLP = 8, PT-CLP = 9, mice that died before the evaluation were excluded). (b) Body temperature: the temperature of each animal was measured by rectal insertion of a temperature sensor while the mouse was under anesthesia at 24 h after CLP (n: NC-sham or PT-sham = 10, NC-CLP = 8, PT-CLP = 9, mice that died before the evaluation were excluded). (c) Survival curve: the mice were monitored to assess mortality for 120 h after CLP (n = 10/group). (d–f) Levels of IL-1β, IL-6, and TNF-α in serum were measured at 24 h after CLP (n = 5/group). The data represent mean ± SD, p < 0.05 was set as the threshold for significance. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 1

Supplementation with probiotics alleviates inflammatory reaction and increases survival of mice after CLP. (a) Clinical score: the clinical score of each animal was assessed at 24 h after CLP. The higher score indicates worse clinical situation of the animal (n: NC-sham or PT-sham = 10, NC-CLP = 8, PT-CLP = 9, mice that died before the evaluation were excluded). (b) Body temperature: the temperature of each animal was measured by rectal insertion of a temperature sensor while the mouse was under anesthesia at 24 h after CLP (n: NC-sham or PT-sham = 10, NC-CLP = 8, PT-CLP = 9, mice that died before the evaluation were excluded). (c) Survival curve: the mice were monitored to assess mortality for 120 h after CLP (n = 10/group). (d–f) Levels of IL-1β, IL-6, and TNF-α in serum were measured at 24 h after CLP (n = 5/group). The data represent mean ± SD, p < 0.05 was set as the threshold for significance. *p < 0.05, **p < 0.01, ***p < 0.001.

3.2 PT pre-administration improves GI peristalsis and permeability of septic mice

Sepsis has been shown to cause impaired GI motility. So, we first performed GI motility test after CLP operation to analyze the protective effect of PT on GI function. The representative images of different groups are shown in Figure 2a. Overall, after intragastric administration of fluorescein isothiocyanate-conjugated dextran (FD4) to mice for 3 h, mice in NC-sham and PT-sham groups showed high fluorescence intensity in cecum and colon, while FD4 mainly remained in the upper intestine of NC-CLP mice, indicating that sepsis weakened the GI peristalsis. Through probiotic pretreatment, the GI peristalsis of PT-CLP mice was enhanced, which showed that the fluorescence intensity from stomach to upper intestine was weak, while it was strong in the lower intestine segment (Figure 2a and b). Further detection of FD4 plasma concentration proved that PT pretreatment could reduce the high permeability caused by sepsis. The portal blood of NC-CLP mice contained higher levels of FD4, which was a sign of increased intestinal permeability after CLP surgery, while the concentration of FD4 in portal blood of PT-CLP mice decreased significantly (Figure 2c).

Figure 2 Supplementation with probiotics improves GI peristalsis and permeability of septic mice at 24 h after CLP. (a) Representative images: after intragastric administration of FD-4 in mice for 3 h, the whole GI tract from stomach to colon was taken and imaged with caliper IVIS lumina III. (b) Quantitative analysis showing the distribution of FD-4 in GI segments: the whole GI tract was divided into 12 segments and flushed with distilled water. The fluorescence of the recovered flushing solution was measured using a Multiskan Mk3 microplate reader at an excitation wavelength of 488 nm, and then fluorescence percentage of flushing solution of each segment was calculated. (c) Concentration of FD-4 in blood: the serum FD4 concentration was quantified with a standard curve using the fluorescence microplate reader. The data represent mean ± SD, p < 0.05 was set as the threshold for significance, n = 3/group. *p < 0.05, **p < 0.01 compared to the NC-sham group; # p < 0.05 compared to the NC-CLP group.
Figure 2

Supplementation with probiotics improves GI peristalsis and permeability of septic mice at 24 h after CLP. (a) Representative images: after intragastric administration of FD-4 in mice for 3 h, the whole GI tract from stomach to colon was taken and imaged with caliper IVIS lumina III. (b) Quantitative analysis showing the distribution of FD-4 in GI segments: the whole GI tract was divided into 12 segments and flushed with distilled water. The fluorescence of the recovered flushing solution was measured using a Multiskan Mk3 microplate reader at an excitation wavelength of 488 nm, and then fluorescence percentage of flushing solution of each segment was calculated. (c) Concentration of FD-4 in blood: the serum FD4 concentration was quantified with a standard curve using the fluorescence microplate reader. The data represent mean ± SD, p < 0.05 was set as the threshold for significance, n = 3/group. *p < 0.05, **p < 0.01 compared to the NC-sham group; # p < 0.05 compared to the NC-CLP group.

3.3 PT pre-administration protects GI barrier function of septic mice

The decrease of GI motility may be caused by the injury of GI barrier. We further analyzed whether oral administration of PT could improve the GI barrier function after CLP operation. H&E staining showed that the colonic epithelium of NC-CLP mice was separated from the basement membrane, and the villi were also damaged, while the situation of PT-CLP mice was ameliorated, and the appearance of colon epithelium seemed regular (Figure 3a–d). Tight junctions are intercellular adhesion complexes that are critical to the barrier function of the epithelium. Dysregulated expression or dysfunction of tight junction proteins may lead to the destruction of tight junction integrity [22–24]. The mRNA levels of three tight junction proteins (occludin, ZO-1, and claudin-5) were detected. The results showed that their expression was lower in NC-CLP mice, indicating that the physical barrier of colon was destroyed, while probiotic pretreatment up-regulated the expression of these proteins (Figure 3e–g). In addition, mature intestinal goblet cells produce Muc, which is composed of the inner and outer layers of mucus, forming a protective mucus layer in the lumen [25]. The expression of Muc2 was significantly reduced in NC-CLP mice, but was upregulated by PT gavage (Figure 3h). AB-PAS histochemical staining showed that the number of mature goblet cells in the colon of NC-CLP mice decreased, while probiotic pretreatment before CLP maintained a high number (Figure 3i–l). These suggest that PT supplementation may protect GI barrier function of septic mice.

Figure 3 Probiotics supplementation protects GI barrier function of septic mice at 24 h after CLP. (a–d) Hematoxylin and eosin (e–h) staining of colon sections 24 h after CLP (representative images of n = 5/group are shown). (e–h) mRNA levels of tight junction proteins (occludin, ZO-1, and claudin-1) and Muc2 in colon were measured by real-time PCR (n = 5/group). (i–l) AB-PAS staining of mature goblet cells in colon sections (n = 5/group). a/i: NC-sham group, b/j: PT-sham group, c/k: NC-CLP group, d/l: PT-CLP group. Scale bar, 100 μm. The data represent mean ± SD, p < 0.05 was set as the threshold for significance. **p < 0.01, ***p < 0.001.
Figure 3

Probiotics supplementation protects GI barrier function of septic mice at 24 h after CLP. (a–d) Hematoxylin and eosin (e–h) staining of colon sections 24 h after CLP (representative images of n = 5/group are shown). (e–h) mRNA levels of tight junction proteins (occludin, ZO-1, and claudin-1) and Muc2 in colon were measured by real-time PCR (n = 5/group). (i–l) AB-PAS staining of mature goblet cells in colon sections (n = 5/group). a/i: NC-sham group, b/j: PT-sham group, c/k: NC-CLP group, d/l: PT-CLP group. Scale bar, 100 μm. The data represent mean ± SD, p < 0.05 was set as the threshold for significance. **p < 0.01, ***p < 0.001.

3.4 PT pre-administration upregulates 5-HT degradation pathway in the GI of septic mice

During sepsis, the dysregulation of 5-HT induced by microflora ecological imbalance may promote inflammation, damage the intestinal mucosal barrier, facilitate bacterial translocation, and increase the mortality of sepsis [14]. PT intervention can reduce the high serotonin state [15]. Accordingly, the level of 5-HT in the colon of NC-CLP mice was remarkably increased after CLP operation, which was reduced by PT supplementation (Figure 4a–e). In addition, IL-1β, IL-6, and TNF-α were also significantly raised in the gut of NC-CLP mice, indicating the disturbed immune state, while the expression of these inflammatory cytokines was notably reduced in mice pre-fed with PT (Figure 4f–h).

Figure 4 Probiotics supplementation upregulates 5-HT degradation pathway in the GI of septic mice. (a–d) Immunohistochemical staining of 5-HT in colon sections 24 h after CLP (representative images of n = 5/group are shown): (a) NC-sham group, (b) PT-sham group, (c) NC-CLP group, and (d) PT-CLP group. (e–h) ELISA analysis of 5-HT and the inflammatory cytokines (IL-1β, IL-6, and TNF-α) in colon tissues (n = 5/group). (i–l) mRNA expression levels of 5-HT reuptake transporter (SERT), synthases (THP-1, THP-2), and degradation enzyme (MAO-A) were detected by real-time PCR (n = 5/group). The data represent mean ± SD, p < 0.05 was set as the threshold for significance. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 4

Probiotics supplementation upregulates 5-HT degradation pathway in the GI of septic mice. (a–d) Immunohistochemical staining of 5-HT in colon sections 24 h after CLP (representative images of n = 5/group are shown): (a) NC-sham group, (b) PT-sham group, (c) NC-CLP group, and (d) PT-CLP group. (e–h) ELISA analysis of 5-HT and the inflammatory cytokines (IL-1β, IL-6, and TNF-α) in colon tissues (n = 5/group). (i–l) mRNA expression levels of 5-HT reuptake transporter (SERT), synthases (THP-1, THP-2), and degradation enzyme (MAO-A) were detected by real-time PCR (n = 5/group). The data represent mean ± SD, p < 0.05 was set as the threshold for significance. *p < 0.05, **p < 0.01, ***p < 0.001.

However, the mechanism by which PT regulate 5-HT is not fully understood. 5-HT in the GI tract is mainly synthesized by intestinal chromaffin cells through the rate limiting enzyme TPH1 and released under mechanical and chemical stimulation of the intestinal cavity [26]. The termination of 5-HT signaling is almost dependent on the intracellular transport of selective SERT, which is expressed in all intestinal epithelial cells [27,28]. MAO-A is mainly responsible for 5-HT degradation in colon tissues [29]. Therefore, we tested whether probiotic pretreatment could affect the level of 5-HT by regulating the expression of THPs, SERT, and MAO-A. The mRNA levels of these key factors in the colon tissues were detected by real-time PCR. The results showed that the expression of THP-1 and THP-2 increased significantly in NC-CLP mice, which was decreased in PT-CLP mice pretreated with PT. While SERT and MAO-A of NC-CLP mice increased slightly, it remarkably increased in PT-CLP mice after administration of PT (Figure 4i–l). These evidence suggest that long-term supplementation with PT before CLP can inhibit 5-HT synthesis and promote 5-HT clearance in the gut of septic mice.

3.5 PT pre-administration inhibits NF-κB pathway, while activates ERK pathway

The above experiments show that PT supplementation can reduce the inflammatory response caused by sepsis. It is well known that NF-κB is responsible for the early activation of inflammatory genes and is a key promoter of pathological processes such as inflammation, autoimmune diseases, and septic shock [30]. Therefore, we analyzed the effect of PT supplementation on NF-κB activity, and also tested its effect on p38 and ERK activity in vivo. We found that sepsis significantly activated NF-κB, p38, and ERK, as evidenced by their notably increased phosphorylation levels after CLP operation, while PT supplementation inhibited NF-κB and p38, but further activated ERK (Figure 5). It is reported that activation of NF-κB can promote the expression of THPs, suggesting that PT supplementation downregulated THPs expression through inhibiting NF-κB signal. Moreover, enhancing the activity of ERK by supplementing PT may be one of the reasons for the high level expression of SERT in the gut. These data suggest the multiple regulatory effects of PT supplementation on sepsis.

Figure 5 Probiotics supplementation inhibits NF-κB pathway, while activates ERK pathway. The expression levels of p-p65, p65, p-p38, p38, p-ERK, and ERK in colon tissues were detected by western blotting (upper panel, n = 3/group). Using actin as the internal reference, the density of related proteins was analyzed (lower panel). The data represent mean ± SD, p < 0.05 was set as the threshold for significance. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 5

Probiotics supplementation inhibits NF-κB pathway, while activates ERK pathway. The expression levels of p-p65, p65, p-p38, p38, p-ERK, and ERK in colon tissues were detected by western blotting (upper panel, n = 3/group). Using actin as the internal reference, the density of related proteins was analyzed (lower panel). The data represent mean ± SD, p < 0.05 was set as the threshold for significance. *p < 0.05, **p < 0.01, ***p < 0.001.

4 Discussion

During sepsis, the dysregulation of 5-HT may promote inflammation, disrupt the intestinal mucosal barrier, facilitate bacterial translocation, and increase the mortality of sepsis [14]. At the same time, the gut microbiota also participates in the regulation of 5-HT production [13]. Oral administration of PT can alter the gut microflora and downregulate 5-HT [15,31,32], thus being considered as an adjuvant therapy to reduce bacterial translocation and prevent sepsis [6,7]. However, the underlying mechanism is not entirely clear. In the present study, we pre-fed mice with PT for 4 weeks and then established a CLP mouse sepsis model to detect the effect of PT supplementation on sepsis-induced GI mucosal barrier dysfunction and explore the underlying mechanism, revealing the preventive effect of PT pre-administration on GI mucosal barrier during sepsis, and its mechanism may be partially mediated by activating the ERK signaling to upregulate the 5-HT degradation pathway.

The gut microbiome has been proven to regulate many homeostatic mechanisms of the host, including immune function and gut barrier protection [33]. Abnormalities in the gut microbiota will enable the expansion of intestinal pathogens, generate a strong pro-inflammatory response in the immune system, and reduce the production of beneficial microbial products such as short chain fatty acids, making the host susceptible to sepsis and having a negative impact on the outcome of sepsis [6,33,34]. Long-term administration of PT can maintain a balance of gut microbiota and reduce the risk of sepsis. Chen et al. demonstrated that LGG pretreatment improved the richness and diversity of intestinal microbiota in mice, reversing the imbalance of microbiota caused by sepsis, e.g., reducing conditional pathogenic bacteria, LPS producing bacteria, and facultative anaerobic bacteria, while increasing the abundance of bacteria related to energy acquisition and colon barrier recovery bacteria [4,6]. Based on this, in our study, long-term high concentration probiotic pretreatment may also first alter the structure of the mouse GI microbiota, thereby improving the clinical, histological, and molecular parameters of the GI mucosa of PT-CLP mice before CLP, making it different from NC-CLP mice and becoming the physiological basis for the subsequent formation of multiple pathways to defense against sepsis.

The CLP model of mouse sepsis can simulate the nature and evolution of severe sepsis in humans, and is currently considered the gold standard for sepsis research and the most widely used model for experimental sepsis [35–40]. In the process of sepsis, cytokines such as TNF-α, IL-1β, and IL-6 mediated inflammatory response plays an important role [37], which may lead to endothelial and epithelial damage, affect vascular permeability and heart function, and eventually result in tissue necrosis and organ failure [4]. In this study, we found that PT pretreatment significantly reduced the levels of serum TNF-α, IL-1β, and IL-6 induced by sepsis. Accordingly, the activity of NF-κB, one of the key inflammatory promoters responsible for the early activation of these inflammatory genes [30], was remarkably downregulated by PT pretreatment. Meanwhile, PT pretreatment also ameliorated colonic pathological damage, enhanced GI peristalsis, and reduced high permeability caused by sepsis. Our findings indicated that PT pretreatment can alleviate inflammation and maintain the integrity of GI epithelium to prevent GI mucosal barrier dysfunction in sepsis.

Tight junctions are intercellular adhesion complexes that are crucial for the barrier function of the epithelium. The expression imbalance or dysfunction of tight junction proteins may lead to the destruction of tight junction integrity [22–24]. Yoseph et al. measured the expression of tight junction proteins including claudins 1, 2, 3, 4, 5, 7, 8, 13, and 15, JAM-A, occludin, and ZO-1 in mice after CLP to determine the potential mechanisms of increased intestinal permeability. They found that occludin and claudin-5 decreased due to sepsis [41]. Tan et al. reported that CLP mice exhibited severe intestinal damage, with significantly reduced levels of occludin and ZO-1 [42]. A recent study showed that the intestinal barrier of mice with ulcerative colitis induced by sodium dextran sulfate was severely damaged. Treatment with Scutellaria baicalensis polysaccharides significantly increased the abundance of Firmicutes, Bifidobacteria, Lactobacillus, and Rosaceae in the intestine, and upregulated the expression of occludin, claudin-5, and ZO-1 to repair the intestinal barrier [43]. In our study, the expressions of occludin, ZO-1, and claudin-5 were reduced in NC-CLP mice, indicating that the physical barrier of intestine was disrupted, while PT pretreatment upregulated these proteins in PT-CLP mice. In addition, mature intestinal goblet cells produce Muc, which is composed of inner and outer layers of mucus, forming a protective mucus layer in the lumen [25]. The expression of Muc2 was significantly reduced in NC-CLP mice, but upregulated by long-term pretreatment with PT. These results suggest that PT supplementation may restore GI barrier function of septic mice by upregulating the tight junction proteins.

5-HT is an important signaling molecule in the GI tract. Under physiological conditions, 5-HT targets intestinal cells, smooth muscles, and intestinal neurons, mainly regulating GI motility, epithelial secretion, and vasodilation through 5-HT3 and 5-HT4 receptors [12,44]. However, 5-HT also exerts nonconventional roles under pathophysiological conditions. The increased availability of mucosal 5-HT may promote inflammation, reduce fecal excretion, delay upper GI transit, and increase permeability [44,45]. In this study, we demonstrated that pre-administration of PT can reduce the levels of 5-HT and inflammatory cytokines in the colon of septic mice.

5-HT in the GI tract is mainly synthesized by the rate limiting enzyme TPH1 in intestinal chromaffin cells and released under mechanical and chemical stimulation in the intestinal cavity [26]. The termination of 5-HT signaling is almost dependent on the intracellular transport of SERT, which is expressed in all intestinal epithelial cells [27,28]. However, MAO-A is mainly responsible for the degradation of 5-HT in colon tissues [29]. Many studies have shown that the decrease of intestinal SERT level in IBS-D patients is related to the increase of serotonin and the deterioration of symptoms [46]. It is also reported that SERT expression in colon biopsy specimens of IBS-D patients is significantly reduced [47]. We found that the expression of THP-1 and THP-2 increased significantly in NC-CLP mice, which was decreased in PT-CLP mice pretreated with PT. While SERT and MAO-A of NC-CLP mice increased slightly, it increased remarkably in PT-CLP mice after administration of PT. Further research revealed that NF-κB and ERK signals may be involved in the regulation of SERT and MAO-A expression by pre-feeding with PT. These evidence suggest that PT pretreatment can inhibit the synthesis of 5-HT in the intestine of septic mice and promote the clearance of 5-HT, thereby playing a preventive role in sepsis.

So far, increasing evidence indicate that improving the GI microbiota through long-term pre-feeding of PT can generate multiple pathways to protect the GI mucosa and prevent adverse reactions caused by sepsis. For example, (1) regulating the host’s immune response: oral administration of LGG can activate the IL-22BP/IL-22/STAT3 pathway in the ileum to improve inflammation [8], Lactobacillus flexneri WiKim38 induces IL-10 production from dendritic cells and alleviates mouse colitis [10], and Lactobacillus carinii SBT2055 induces TGF-β in dendritic cells and activation of TLR2 signaling to produce IgA in the small intestine [11]. (2) Regulating metabolic profile: LGG can reduce the mortality rate of septic mice by regulating the composition and metabolic profile of intestinal microbiota, especially the production of short-chain fatty acids, which are crucial for immune effects and epithelial cell function [6,33]. Therefore, the regulation of the 5-HT pathway revealed in this study is only one of the mechanisms by which PT improve GI function in septic mice. However, our research still has some limitations. For example, changes in gut microbiota after long-term administration of PT have not yet been detected, and further research is needed on the downstream pathways of 5-HT.

5 Conclusions

Based on the findings of this study, we conclude that the mechanism of PT pretreatment prevents GI mucosal barrier dysfunction in septic mice and may be partly through upregulation of 5-HT degradation pathway by inhibiting NF-κB signal and activating ERK signal.

  1. Funding information: This work was supported by the Clinical Research Support Fund of the PLA General Hospital (2018FC-304M-TSYS-06).

  2. Author contributions: X.P.C. and M.M. conceived and designed the study. X.P.C., H.Z., Z.M.L., and Y.C. performed the experiments and data processing. X.P.C. and M.M. drafted the manuscript. All authors read and approved the final manuscript.

  3. Conflict of interest: The authors declare that they have no conflict of interest.

  4. Data availability statement: The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

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Received: 2023-04-26
Revised: 2023-09-22
Accepted: 2023-11-12
Published Online: 2023-12-26

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0869
Keywords for this article
sepsis; probiotics; gastrointestinal barrier; 5-hydroxytryptamine; ERK signal
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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