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Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?

  • Albert Despot , Rajko Fureš , Ana-Marija Despot , Mislav Mikuš , Gordan Zlopaša , Antonio D’Amato , Vito Chiantera , Pietro Serra , Andrea Etrusco EMAIL logo and Antonio Simone Laganà
Published/Copyright: October 21, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

Uterine cervical intraepithelial abnormalities and cancer development may also depend upon biological problems that arise as a result of complex molecular disturbances within the vaginal space, in addition to the widely known causative effect of human papillomavirus (HPV) infection. Chronic oxidative stress is a consequence of oxygen reduction in the vaginal space. Reactive oxygen species (ROS) and free radicals are yet unrecognizable causative agents and are probably very important factors for cervical intraepithelial neoplasia (CIN) and cancer development. The intermediate compounds of oxygen reduction on these metabolic pathways are superoxide anion ( O 2 ˙ − ), hydrogen peroxide (H2O2), hydroxide ions (OH−), and hydroxyl radical (HO˙). Considering these points, the aim of this work was to summarize how these compounds can damage all molecules, including DNA, of vulnerable metaplastic cervical epithelium. Finally, in some women with a poor immune defense system, ROS alone or accompanied by a high-risk HPV type may promote all levels of CIN and cancer development.

Keywords: cervical cancer; cervical intraepithelial neoplasia; oxygen reduction; oxidative stress; vaginal microbiota

1 Introduction

Cervical cancer is a global health problem. According to the latest data, 604,127 new cases and 341,831 deaths from cervical cancer were reported worldwide in 2020 [1]. Compared to reports from 2018, the frequency increased by 35,000 new cases and mortality by 30,000 women. All statistical indicators have shown an upward trend on graphical curves. In Europe, approximately 61,000 women develop uterine cervical cancer annually, resulting in approximately 26,000 deaths [2].

Despite classical diagnostic and therapeutic protocols (PAP smear, human papillomavirus [HPV] typing, colposcopy, biopsy, radical surgery, chemotherapy, and radiotherapy), cervical cancer still has a high level of incidence and mortality worldwide [2].

To date, recent investigations of vaginal Lactobacillus species and their hydrogen peroxide (H2O2) production have shed new light on this topic [3]. The H2O2 produced by Lactobacillus can catalyze and further produce hypochlorite [4]. This is a process that can prevent HPV from invading cervical epithelial cells and prevent cervical lesions [5]. Nevertheless, Lactobaccilus species are anaerobic bacteria without a described biological system for hydrogen peroxide production.

In addition, hydrogen peroxide (H2O2) production is only one-fourth of the well-known univalent pathway of ground-state oxygen reduction to water (H2O) through intermediate compounds such superoxide ( O 2 ˙ − ), hydrogen peroxide (H2O2), and the hydroxyl radical (OH) plus hydroxide ions (OH−) inside the vaginal space.

Third, the detection of hydrogen peroxide (H2O2) in the vagina is proof that this space can be influenced by reactive oxygen species (ROS) and free radicals.

Overall, current etiological and carcinogenesis explanations from molecular biology standpoints need further investigation.

Considering these points, we aimed to summarize the available pieces of evidence, hypothesizing whether the reduction of oxygen to ROS within the vaginal space may be a further promoter of cervical intraepithelial neoplasia (CIN) and/or the development of cervical cancer and what mechanisms underlie this phenomenon.

In particular, the hypothesis is discussed in the next sections, starting with the current knowledge on the correlation between HPV infection and cervical cancer, then moving on to assess the mechanisms of transformation from CIN to low- or high-grade squamous lesion (LSIL/HSIL), and finally to examine the potential effect that vaginal lactic acid may in some way have on the development of cervical cancer.

2 HPV and cervical cancer

Recent studies of the uterine cervical cancer incidence in Sweden and Denmark have added further insight into the classic model of its carcinogenesis. A Swedish study found that the increase in cervical cancer incidence was high among women repeatedly screened with normal results and not among unscreened women [6]. The reason has been found to be insufficient cytological diagnostic activities inside county laboratory mismanagement. On the other hand, after organized HPV vaccination at a youth clinic in Stockholm, nonvaccine high-risk HPV types remained at elevated levels [7].

In neighboring Denmark, HPV vaccination at the age of 23–24 years has produced a 95% decrease in comparison with the prevalence inside the same population of women before the vaccination era. Despite this impressive reduction, 35% of women after vaccination have remained HPV-positive [8], and high-grade cervical dysplasia may occur even in HPV-negative women [9].

Recently, published studies of HPV infection rates in postmenopausal women showed virus presence rates of 4.1% in Sweden [10] and 4.3% in Denmark [11]. The results of studies in Sweden and Denmark were very similar. It is paradoxical that HPV infection incidence in postmenopausal women has decreased, but the uterine cervical cancer rate has unexpectedly increased at the same time within the same population. A meta-analysis of real worldwide studies revealed that 12.7% of squamous cell carcinomas and 15–38% of cervical adenocarcinomas are HPV-negative [12–14].

In this scenario, other biological elements may be considered adjuvants for the initiation of cervical carcinogenesis.

3 Transformation from CIN to LSIL/HSIL

Over the last 50 years, our increased understanding of uterine cervical cancer pathogenesis has evolved [15,16]. HPV is a unique etiological factor for CIN as well as cancer development [17,18]. The strong correlation between woman’s age and CIN has been shown in almost all investigations and meta-analyses [19]. Investigations have revealed that the usual time for CIN events is from 20 to 30 years in women’s lives. In that period of life, sexual activity is more common than it is sooner or later.

Bluestein’s Pathology of Female Genital Tract (sixth edition) reports a meta-analysis of clinical follow-up studies of biopsy-confirmed CIN published in the mid-1990s [20,21]. According to this meta-analysis, in the absence of therapy, “the higher grade of lesion is more likely to persist and less likely to regress.” In addition, 22% of CIN II cases progress to carcinoma in situ (CIS), but CIN III has an unexpected progression rate of 12% to CIS.

Another recent meta-analysis, based on a large population study with 783 patients using histological data, found that the regression rates are notably higher in young women with CIN and showed that the effect is independent of CIN grade or the presence of HPV high-risk infection. Overall, this article highlighted that the progression rates for CIN I, CIN II, or CIN III were uncommon [22].

Recently, more and more evidence has accumulated suggesting that during progression to high-grade intraepithelial neoplasia and cervical cancer, nuclear factor kappaB (NF-kB) is constitutively reactivated [23]. The NF-kB family is composed of transcription factors that play a complex and essential role in the regulation of immune responses and inflammation. In particular, NF-kB can stimulate transcription of proliferation-regulating genes (e.g., cyclin D1 and c-myc) involved in metastasis, VEGF-dependent angiogenesis, and cell immortality through telomerase [24]. It has also attracted considerable interest because it has been implicated in human cancer initiation, progression, and treatment resistance [24,25]. NF-kB activation, triggered by HPV infection, plays an important role in the host innate and adaptive immune response. The virus induces a down regulation of NF-kB to eliminate the inhibitory activity for its replication triggered by the immune system, resulting in a persistent state of HPV infection. During progression to high-grade intraepithelial neoplasia and cervical cancer, NF-kB is constitutively reactivated. NF-kB activation can also induce the expression of activation-induced cytidine deaminase and APOBEC proteins, providing a mechanistic link between the NF-kB pathway and the mutagenic features of cervical cancer [23].

Mitochondrial dysfunction is also known to be involved in tumorigenesis [26]. In recent years, the mitochondrial ND1 (mtND1) gene has received considerable interest from the scientific community. Recently identified mutations in the mtND1 gene have been shown to disrupt normal complex I activity and affect oxidative phosphorylation, thus leading to increased ROS production. Based on these elements, a study was conducted to determine the alterations in the mtND1 gene and evaluate their association with the development of precancerous lesions and cervical cancer. Warowicka et al. [27] showed that mutations in the mtND1 gene were detected in patients with precancerous stage and cervical cancer. The lowest mRNA expression of ND1 was detected in cervical cancer cases and in all samples in which mtND1 mutations were identified. The analysis also revealed that the level of ROS production was higher in cervical cancer tissues and in all cases characterized by mtND1 mutations.

From the clinical point of view, vaginal space is rich in all chemical resources for oxygen activation and its transformation through reduction to water. The complete reduction of oxygen to water requires four electrons and four protons to be added to oxygen in a stepwise chemical path, better known as a univalent pathway. It requires the production of intermediate compounds such as superoxide (O2 •–), hydrogen peroxide (H2O2), the hydroxyl radical (˙OH), and hydroxide ions (OH−). These compounds are the main part of ROS. These intermediate compounds can damage all cell structures, including DNA, and may play a significant role in cervical cancer pathogenesis, as described in the next section.

4 Potential vaginal lactic acid role for cervical cancer pathogenesis

The lactic acid inside the vaginal space has two different metabolic pathways. The first is a well-known physiological path built in biological collaboration between Lactobacillus species and women. The woman as the host provides glycogen to anaerobe bacteria. Lactobacillus species use it as a life nutrient for their own growth and in turn convert glycogen from exfoliated superficial vaginal and uterine ectocervix cells to lactic acid.

Hydronium ion [H3O+] or proton [H+] concentrations are indicators of the health status in the lower part of the woman’s reproductive tract. During fertile age, the average pH of the cervico-vaginal fluid samples is 3.5, with a range of 2.8–4.2 [28].

Lactobacillus exhibits a mutualistic relationship with the woman’s body, as it protects the host against potential invasions by pathogens, and in turn, the host provides a source of nutrients to support bacterial growth [29,30].

Lactobacillus species convert glycogen from exfoliated superficial vaginal and exocervix cells to lactic acid. The cervicovaginal partial pressure of O2 is in the range of 4–14 mmHg (0.5–1.8%), with only transient increase during vaginal intercourse and some gynecological diagnostic activities [28]. In the air environment, the partial pressure of oxygen (O2) is 160 mmHg or 21%. Lactobacilli use exfoliated cells rich in glucose as a metabolic ingredient and energetic supply. During reproductive age, this process continues because the vaginal epithelium, under ovarian estrogen influence, is regenerated every 4–5 days. At the end of this physiological pathway, the vaginal environment is supplied with a high concentration of lactic acid (CH3CHOHCOOH). After lactic acid dissociation, the vaginal space has the same concentrations of hydronium ions [H3O+] and lactate [CH3CH(OH)COO−].

The lactic acid needs water for dissociation: CH3CHOHCOOH + H2O = [CH3CHOHCOO−] + [H3O+].

High concentration of [H3O+] in vaginal space creates physiological pH level at 3.5. In such physiological condition, vaginal ecosystem has effective defense network against external microorganisms.

During reproductive years the vaginal pH should be 3.5 and the pOH 10.5, respectively, because the sum of pH and pOH in all solutions has the same numerical indicator of 14. In the first step, from the Henderson–Hasselbalch equation, it is necessary to determine the concentration of hydronium ions [H3O+] and hydroxide ions [OH−] in aqueous solution at physiological pH level:

pH = 3.5

pOH = 10.5

[H3O+] = 10−3.5 = 3.1623 × 10−4 mol/L

N[H3O+] = Na·m = 6.022141 × 1023 × 3.1623 × 10−4 = 1.90436 × 1020

[OH−] = 10−10.5 = 3.16227 × 10−11 mol/L

N[OH−] = Na·m = 6.022141 × 1023 × 3.16227 × 10−11 = 1.90436 × 1013

Based on the Henderson–Hasselbalch equation and biochemistry relationships, the concentration of hydronium ions [H3O+] or protons [H+] is 1.9 × 107 or 19 million times higher than the concentration of hydroxide ions [OH−] at physiological vaginal pH value of 3.5. The lactic acid and lactate concentration is calculated by the same equation as follows:

pH = 3.5

pKa (CH3CH(OH)COOH) = 3.86

Ka = 10−3.86 = 1.3804 × 10−4 mol/L

(CH3CH(OH)COOH) = 7.2444 × 10−4 mol/L (initial concentration)

CH3CH(OH)COOH + H2O = CH3CH(OH)COO− + H3O+

Ka = [H3O+] [CH3CH(OH)COO−]/(CH3CH(OH)COOH)

[H3O+] = [CH3CH(OH)COO−] = 10−pH = 10−3.5 = 3.16227 × 10−4 mol/L

Further analysis follows calculation of lactate CH3CH(OH)COO− and lactic acid CH3CH(OH)COOH concentrations.

Na(CH3CH(OH)COO−) = Na·m = 6.022141 × 1023 × 3.1623 × 10−4 = 1.90436 × 1020

Na(CH3CH(OH)COOH) = Na·m = 7.2444 × 10−4 × 6.022141 × 1023 = 4.36268 × 1020

From a biological point of view, the architecture of vaginal physiology is quite relativistic. The vaginal space is hypoxic. The oxygen molecules in the triplet ground state have no toxic effect on their environment. For toxic transformations, the oxygen needs energy activation. The lactic acid dissociation to hydronium ions [H3O+] and lactate [CH3CH(OH)COO−] is the energetic fuel for potential toxic oxygen turn over. The oxygen needs four protons [H+] and four electrons [e−] for its reduction to water. The protons have origin from hydronium ions [H3O+], but the electrons have origin from lactate [CH3CH(OH)COO−].

A high lactate concentration is the source for extensive electron donation in the Lewis concept of acids and bases. Reduction is the gain of hydrogen, gain of electrons, and loss of oxygen. Reduction of ground state triplet oxygen is the basic process of oxidative stress and ROS production. ROS are classically defined as partially reduced metabolites of oxygen that possess strong oxidizing capabilities. They are deleterious to cells at high concentrations, but at low concentrations, they serve as complex signaling functions at the physiological level [31].

ROS oxidizes protein and lipid cellular constituents and may also damage the DNA. At low physiological concentrations, ROS functions as signaling molecule and regulate cell growth, adhesion of cells toward other cells, differentiation, senescence, and apoptosis [32,33].

The intermediate compounds of oxygen reduction on the univalent pathway are superoxide ( O 2 ˙ − ), hydrogen peroxide (H2O2), the hydroxyl radical (˙OH), and hydroxide ions (OH−) [34].

The additional problem of this complexity is the life expectancy of free radicals. It depends on two main factors. The former is more chemical than biological in nature. A measure of life expectancy in chemistry is the half-life. In general, free radicals are short-lived, especially in biological milieu. The half-life of free radicals, including the vaginal cornerstone compound superoxide anion ( O 2 ˙ − ), is an important factor in determining and assessing the biological activity of radical species.

In biological systems, the half-life of superoxide is estimated to be in the range of 10−6–10−5 s. Sometimes something that seems short-lived is unusually long-lived, especially if we add new possibilities for ROS development from superoxide anion ground level, in chemistry better known as Haber–Weiss and Fenton reactions.

5 Oxidative stress, CIN, and cancer

Molecular dioxygen (O2) is an essential element of aerobic life, yet incomplete reduction or excitation of O2 during aerobic metabolism generates diverse oxygen-containing free radicals and related reactive species, commonly known as ROS.

On the one hand, these compounds are a serious threat to aerobic organisms by inducing oxidative damage to cellular constituents. On the other hand, these reactive species, when their generation is under homeostatic control, also play important physiological roles through participation in redox signaling and as an important part of immunity [33].

Oxidative stress conditions can be caused by either increased ROS formation, decreased activity of antioxidants, or both in a biological system. Oxidative stress accompanied by chronic inflammation can produce all kinds of cell damage, including cancer initiation/development.

Extensive research during the last two decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases, including cancer, diabetes, cardiovascular, neurological, and pulmonary diseases [35]. From this perspective, extensive production of ROS inside the vaginal space throughout life may be a trigger for the development of diverse cervical intraepithelial abnormalities.

The electronic structure for ground state oxygen, which is essential for the life of all aerobic organisms, makes it potentially dangerous for those organisms. The atmospheric oxygen in its triplet ground state is biradical (i.e., it has two unpaired electrons). This feature makes oxygen paramagnetic, but the two unpaired electrons in oxygen occupy a separate orbital. These two unpaired electrons have the same spin or spin state. According to Pauli’s exclusion principle such paired electrons with same parallel rotation produce the spin restriction. This means that the triplet ground state of oxygen makes it very unlikely to participate in reactions with organic molecules unless it is “activated.” In different microenvironment, the activation of oxygen may occur by two different mechanisms:

  1. Absorption of sufficient energy to reverse the spin on one of the unpaired electrons.

  2. Through mono- or univalent reduction.

The vaginal space is rich with all chemical resources for oxygen activation and its transformation through reduction to water. The complete reduction of oxygen to water requires four electrons and four protons to be added to oxygen in a stepwise chemical fashion producing intermediate compounds as follows:

  1. O2 (oxygen molecule) + e− (electron) = O 2 ˙ − (superoxide ion)

  2. O 2 ˙ − (superoxide ion) + 2H+ (protons) + e− = H2O2 (hydrogen peroxide)

  3. H2O2 + e− = OH* (hydroxyl radical) + OH− (hydroxide ion)

  4. OH* + OH− + e− + 2H + = 2H2O (water)

For complete reduction of an oxygen molecule to two molecules of water requires four electrons and four protons to be added to the oxygen molecule. The biological pathway shown through four stepwise reactions is also known and as “the univalent pathway.” The path described is not the end of ROS production. Since 1933 when Linus Pauling proposed superoxide existence based on the theory of quantum mechanics, this has gradually taken the center stage in the research field of free radical biology and medicine. Indeed, superoxide is considered as the primary ROS that gives rise to secondary ROS in biological system. Due to its low reductional potential, superoxide often acts as reducing agent, rather than oxidizing species. Superoxide is produced from one electron reduction of molecular dioxygen (oxygen for simplicity) [36]: O2 + e− = O 2 ˙ − . In biological systems, superoxide is generated from various metabolic processes. Molecular oxygen (O2) is in fact biradical because it contains two unpaired electrons. The same spin direction of two unpaired electrons in O2 causes spin restriction, making O2 less reactive. On the other hand, superoxide ( O 2 ˙ − ) contains one unpaired electron and has one more electron other than O2, so it means that superoxide is negatively charged. In such environmental circumstances, a superoxide anion radical can donate one electron to molecule of hydrogen peroxide leading to the formation of one molecule of molecular oxygen, a hydroxyl radical, and a hydroxide ion as follows: O 2 ˙ − + H2O2 = O2 + OH* + OH−.

This is also known as Heber–Weiss reaction or Heber–Weiss cycle [37]. In the absence of iron ion (Fe3+) the above-mentioned reaction proceeds very slowly. However, the presence of iron ion (Fe3+) markedly accelerates the reaction to produced hydroxyl radical (OH*), the most potent ROS capable of damaging the entire spectrum of biomolecules. The presence of iron ions markedly accelerates the reaction to produce hydroxyl radical. The iron-ion catalyzed Heber–Weiss reaction can be written in two sequential sub-reactions:

  1. O 2 ˙ − + Fe3+ = O2 + Fe2+

  2. Fe2+ + H2O2 = Fe3+ + OH* + OH−

The second reaction is commonly referred to as the Fenton reaction. It represents the oxidation of organic substrates by Fe2+ and H2O2. In 1894, Henry Fenton first observed the oxidation of tartaric acid by H2O2 in the presence of Fe2+, indicating that potent oxidant(s) are formed by the reaction between H2O2 and Fe2+, which are also known as the Fenton reagent.

Later, in the 1930s, Fritz Haber and Joseph Weiss proposed the formation of hydroxyl radicals from the Fenton reagent, which is today known to be a major ultimate free radical species responsible for the oxidative damage of a wide range of biomolecules. In general, free radicals are short-lived in biological milieu.

The half-life of superoxide is an important factor in determining the biological activity of radical species. The half-life of superoxide is estimated to be in the range of 10−6–10−5 s. For these reasons, increasing concentrations of superoxide anions in vaginal space have time for hydroxyl radical production through Haber–Weiss and Fenton reactions.

In addition, any increase in exposure to iron ions, as it occurs during the menstrual period, supports oxidative stress, and markedly accelerates superoxide anion transformation to hydroxyl radicals (OH*), the most potent oxidizing ROS formed in biological systems. According to recent data, it is also known that ROS can induce DNA double-strand breaks in both host DNA and the viral circular episome; this could facilitate virus integration, promoting HPV carcinogenesis [38]. Therefore, in HPV-infected women, it might be beneficial to reduce additional ROS resources by improving the lifestyle. In this regard, it seems worth noting that modulation of the vaginal/cervical microbiome by exogenous administration of Lactobacillus crispatus has been associated with a high rate of HPV clearance. Indeed, recent studies have found a higher rate of clearance of PAP smear abnormalities in patients who took Lactobacillus crispatus M247 orally for a long time compared with the control group who had a simple follow-up [3]. Specifically, after a median follow-up of 12 months, a higher likelihood of resolution of HPV-related cytological abnormalities was found in patients on long-term oral probiotic treatment compared with the group who only did follow-up (60.5 vs 41.3%) [3]. Complete HPV clearance was evidenced in only 9.3% of patients on follow-up as compared to 15.3% of patients taking long-term oral Lactobacillus crispatus M247[3].

6 Consequences of the hypothesis and future research priorities

There are several different protocols for diagnostic approaches and treatments for CIN and cervical cancer worldwide.

The Bethesda system (TBS) was modified in 1991 and 2001 [39]. The last TBS classification subdivides atypical squamous cells into two subdivisions.

Atypical squamous cells of undetermined significance refer to samples in which the cytological changes are suggestive of LSIL, but atypical squamous cells cannot exclude HSIL [40].

The vaginal space, as the origin of ROS and free radicals, is not yet fully recognized as an adjuvant trigger for cervical intraepithelial abnormality development. Increasing oxygen concentrations accompanied by lactic acid dissociation are the source for the activation of the triplet ground state of molecular oxygen.

Oxygen activation in the vaginal space led to its reduction via a univalent pathway in a stepwise fashion, enriched with an additional four protons [H+] and an additional four electrons [e−] as well as superoxide ( O 2 ˙ − ), hydrogen peroxide (H2O2), the hydroxyl radical (˙OH), and hydroxide ion (OH−) production. These intermediate compounds may influence the vulnerable metaplastic cervical epithelium.

From this perspective, it is possible that oxidative stress within the vaginal space may increase the risk that metaplastic cervical epithelium, caused by HPV infection, progresses to CIN and overt cervical cancer. Overall, this hypothesis needs to be evaluated by rigorous biochemical evaluation with future clinical trials. Future studies should therefore ascertain the actual applicability of the hypothesis to clarify its potential role in clinical practice. Should this be confirmed, the preventive focus of cervical cancer could extend from the microbiological and immunological realm to the biochemical field.

In addition, the possible confirmation of the hypothesis could open possible explanatory scenarios to understand how even in women in whom prevention of HPV infection, and thus screening for cervical cancer, is optimally performed, neoplasia can still develop.

Acknowledgement

Not applicable.

  1. Funding information: This study was not funded.

  2. Author contributions: A.E., A.D., and A.S.L.: project development; R.F., A.M.D., M.M., and G.Z.: evidence collection; A.D’A., V.C., and P.S.: evidence discussion; A.S.L. and A.E.: manuscript writing; A.E., M.M., and A.D.: manuscript editing and final approval. All the authors conform to the International Committee of Medical Journal Editors criteria for authorship, contributed to the intellectual content of the study and gave approval for the final version of the article. The authors alone are responsible for the content and writing of the article.

  3. Conflict of interest: Dr Antonio Simone Laganà serves as Editor in Open Medicine, but it did not affect peer-review process. The authors have no proprietary, financial, professional, or other personal interest of any nature in any product, service or company.

  4. Data availability statement: All data generated or analyzed during this study are included in this published article.

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Received: 2023-05-19
Revised: 2023-09-13
Accepted: 2023-09-25
Published Online: 2023-10-21

© 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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  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-2023-0826
Keywords for this article
cervical cancer; cervical intraepithelial neoplasia; oxygen reduction; oxidative stress; vaginal microbiota
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
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  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
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  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
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  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
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  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
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  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
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  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
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  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
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  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
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  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
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  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
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  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
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  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
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  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
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  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
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  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
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  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
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  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
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  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
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  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
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  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
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  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
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  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
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  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
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  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
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  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
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  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
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  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
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  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
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  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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