Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis.

Trichomoniasis, a prevalent sexually transmitted infection (STI) caused by the protozoan Trichomonas vaginalis, has gained increased significance globally. Its relevance has grown in recent years due to its association with a heightened risk of acquiring and transmitting the human immunodeficiency virus (HIV) and other STIs. In addition, many publications have revealed a potential link between trichomoniasis and certain cancers. Metronidazole (MTZ), a nitroimidazole compound developed over 50 years ago, remains the first-choice drug for treatment. However, reports of genotoxicity and side effects underscore the necessity for new compounds to address this pressing global health concern. In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 µM and ≤ 41 µM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 µM), 1e (IC50 4.8 µM), and 1i (IC50 5.2 µM) exhibited potencies equivalent to MTZ (IC50 4.9 µM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 µM) and 48 h (IC50 2.1 µM). Additionally, all compounds demonstrated either non-cytotoxic to HeLa cells (CC50 > 100 µM) or low cytotoxicity (CC50 between 69 and 100 µM). These findings suggest that pyrazole-nitroimidazole derivatives represent a promising heterocyclic system, serving as a potential lead for further optimization in trichomoniasis chemotherapy.

Antiparasitic activity of chalcones analogue against Trichomonas vaginalis: biochemical, molecular and in silico aspects.

Trichomonas vaginalis is the etiologic agent of trichomoniasis, a worldwide distributed sexually transmitted infection (STI) that affects the genitourinary tract. Even though this disease already has a treatment in the prescription of drugs of the 5-nitroimidazole class, described low treatments adhesion, adverse side effects and cases of resistant isolates demonstrate the need for new formulations. With this in mind, chalcones emerge as a potential alternative to be tested, being compounds widely distributed in nature, easy to chemically synthesize and presenting several biological activities already reported. In this experiment, we evaluated the antiparasitic activity of 10 chalcone at a concentration of 100 µM against ATCC 30236 T. vaginalis isolates, considering negative (live trophozoites), positive (Metronidazole 100 µM) and vehicle (DMSO 0.6%) controls. Compounds 3a, 3c, 3g and 3i showed promising results, with MICs set at 70 µM, 80 µM, 90 µM and 90 µM, respectively (p<0,05). Cytotoxicity assays were performed on VERO and HMVII cell lines and revealed low inhibition rates at concentrations bellow 20 µM. To elucidate a possible mechanism of action for these molecules, the DPPH, ABTS and FRAP assays were performed, in which none of the four compounds presented antioxidant activity. Assays to verify ROS and lipid peroxidation in the parasite membrane were performed. None of the tested compounds identified ROS accumulation after incubation with trophozoites. 3g molecule promoted an increase in MDA production after incubation. Results presented in this paper demonstrate the promising trichomonicidal profile, although further tests are still needed to optimize their performance and better elucidate the mechanisms of action involved.

Stimulation of microvesicle secretion in Trichomonas vaginalis.

Trichomonas vaginalis is an extracellular flagellate protozoan and the etiological agent of human trichomoniasis, a sexually transmitted infection (STI) with a high incidence. Several reports have shown that this protozoan releases microvesicles into the culture medium, which show high potential in modulating cell-to-cell communication and the host response to infections. However, the biogenesis of these vesicles has not been analyzed in detail. In the present study, high-resolution ion scanning microscopy (SEM) and transmission electron microscopy (TEM) were used to analyze the surface of control cells and cells incubated in the presence of Ca2+ alone or with A 23187 calcium ionophore. Two different strains of T. vaginalis were analyzed. Most control cells displayed relatively smooth surfaces, whereas cells incubated with Ca2+ had many surface projections of variable shape and size (from 40 nm to around 1 µm). Quantitative analyses were performed directly in the scanning electron microscope and showed a significant increase in the number of cells with surface projections after incubation in the presence of calcium. TEM showed that treated cells presented several cytoplasmic multivesicular structures, suggesting membrane fusion and exosomes in the extracellular medium. The amount and size of the released vesicles were quantitatively analyzed using light scattering and TEM on negatively stained samples. The observations show that incubation of both parasite strains in the presence of Ca2+ significantly increased the release of microvesicles into the extracellular medium in a time-dependent process. Sequential incubation in the presence of Ca2+ and the calcium ionophore A23187 increases the presence of vesicles on the parasite surface only at a short incubation time (5 min). Transmission electron microscopy showed that at least part of the vesicles are originated from cytoplasmic multivesicular structures. This information contributes to a better understanding of the biogenesis of extracellular vesicles secreted by T. vaginalis.

Effect of Trichomonacide 6-Nitro-1H-benzimidazole Derivative Compounds on Expression Level of Metabolic Genes in Trichomonas vaginalis.

The parasite Trichomonas vaginalis is the etiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease worldwide. This infection often remains asymptomatic and is related to several health complications. The traditional treatment for trichomoniasis is the use of drugs of the 5-nitroimidazole family, such as metronidazole; however, scientific reports indicate an increasing number of drug-resistant strains. Benzimidazole derivatives could offer an alternative in the search for new anti-trichomonas drugs. In this sense, two attractive candidates are the compounds O2N-BZM7 and O2N-BZM9 (1H-benzimidazole derivatives), since, through in vitro tests, they have shown a higher trichomonacide activity. In this study, we determined the effect on the expression level of metabolic genes in T. vaginalis. The results show that genes involved in redox balance (NADHOX, G6PD::6PGL) are overexpressed, as well as the gene that participates in the first reaction of glycolysis (CK); on the other hand, structural genes such as ACT and TUB are decreased in expression in trophozoites treated with the compound O2N-BZM9, which would probably affect its morphology, motility and virulence. These results align with the trichomonacidal activity of the compounds, with benzimidazole O2N-BZM9 being the most potent, with an IC50 value of 4.8 µM. These results are promising for potential future therapeutic applications.

Imidazole Carbamates as a Promising Alternative for Treating Trichomoniasis: In Vitro Effects on the Growth and Gene Expression of Trichomonas vaginalis.

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC50 value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC50 values in the nanomolar range and AGR-2 being the most potent (IC50 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis.

Positive cases of bovine genital campylobacteriosis and bovine trichomonosis in the eradication program of La Pampa, Argentina: 2008-2021.

Bovine genital campylobacteriosis, caused by the gram-negative bacteria Campylobacter fetus venerealis, and bovine trichomonosis, caused by the parasite protozoan Tritrichomonas foetus, are venereal diseases that occur with long intercalving periods and abortion. The control of both diseases relies on microbiological testing and culling infected bulls. Vaccination and antibiotic treatment may help in controlling campylobacteriosis but are not recommended for trichomonosis control. Several regions of the world have active control programs for trichomonosis, not campylobacteriosis. In Argentina, the state of La Pampa aims to eradicate trichomonosis and campylobacteriosis by imposing annual diagnostic testing of every bull and slaughtering positive animals. Prior studies indicated a declining trend in the prevalence of campylobacteriosis and trichomonosis in La Pampa. It was also proposed that the prevalence of one disease could be estimated from the prevalence of the other. The purpose of this retrospective analysis of data gathered from 2008 to 2021 was to determine the La Pampa program's efficacy. Descriptive statistics were employed to determine the reason behind the correlation between tricomonosis and campylobacteriosis diagnostic results. The outcomes refute the notion that this program of venereal eradication was a success. Furthermore, an excess of false positives in both diagnoses may have contributed to the correlation between the prevalences of campylobactriosis and trichomonosis. The practice of killing animals without verifying positive results hinders the determination of disease prevalence and results in the death of numerous healthy animals.

The Estimated Lifetime Quality-Adjusted Life-Years Lost Due to Chlamydia, Gonorrhea, and Trichomoniasis in the United States in 2018.

BACKGROUND: Comprehensive evaluation of the quality-adjusted life-years (QALYs) lost attributable to chlamydia, gonorrhea, andtrichomoniasis in the United States is lacking. METHODS: We adapted a previous probability-tree model to estimate the average number of lifetime QALYs lost due to genital chlamydia, gonorrhea, and trichomoniasis, per incident infection and at the population level, by sex and age group. We conducted multivariate sensitivity analyses to address uncertainty around key parameter values. RESULTS: The estimated total discounted lifetime QALYs lost for men and women, respectively, due to infections acquired in 2018, were 1541 (95% uncertainty interval [UI], 186-6358) and 111 872 (95% UI, 29 777-267 404) for chlamydia, 989 (95% UI, 127-3720) and 12 112 (95% UI, 2 410-33 895) for gonorrhea, and 386 (95% UI, 30-1851) and 4576 (95% UI, 13-30 355) for trichomoniasis. Total QALYs lost were highest among women aged 15-24 years with chlamydia. QALYs lost estimates were highly sensitive to disutilities (health losses) of infections and sequelae, and to duration of infections and chronic sequelae for chlamydia and gonorrhea in women. CONCLUSIONS: The 3 sexually transmitted infections cause substantial health losses in the United States, particularly gonorrhea and chlamydia among women. The estimates of lifetime QALYs lost per infection help to prioritize prevention policies and inform cost-effectiveness analyses of sexually transmitted infection interventions.

Inflammatory responses during trichomoniasis: The role of Toll-like receptors and inflammasomes.

Toll-like receptors (TLRs) and inflammasomes belong to the pattern recognition receptors (PRRs) of innate immunity identifying conserved compounds produced by pathogens or discharged by injured cells. Different cell subsets in the human urogenital system, such as epithelial cells and infiltrating leukocytes, express different kinds of TLRs (such as TLR2, TLR3, TLR4, TLR5 and TLR9) as well as inflammasomes (such as NLRP3, NLRC4 and AIM2). Various types of the Trichomonas vaginalis-derived components such as glycosyl-phosphatidylinositol (GPI), T. vaginalis virus (TVV), Lipophosphoglycan (LPG) and flagellin can be recognized by TLR2, TLR3, TLR4 and TLR5, respectively, leading to the production of proinflammatory cytokines and chemokines in the cervicovaginal mucosa. The T. vaginalis-induced inflammasomes can lead to pyroptosis as well as the release of IL-1ß and IL-18 promoting innate and adaptive immune responses. The PRR-mediated responses to T. vaginalis may contribute to the induction of protective immune responses, local inflammation, promotion of co-infections, or even the development of malignancies, for example, prostate cancer. The protective or pathogenic roles of the TLRs and inflammasomes during trichomoniasis are highlighted in this review. A better understanding of PRR-mediated responses provides invaluable insights to develop effective immunotherapeutic strategies against T. vaginalis infection.

Phenolic chalcones as agents against Trichomonas vaginalis.

Trichomonas vaginalis, a flagellated and anaerobic protozoan, is a causative agent of trichomoniasis. This disease is among the world's most common non-viral sexually transmitted infection. A single class drug, nitroimidazoles, is currently available for the trichomoniasis treatment. However, resistant isolates have been identified from unsuccessfully treated patients. Thus, there is a great challenge for a discovery of innovative anti-T. vaginalis agents. As part of our ongoing search for antiprotozoal chalcones, we designed and synthesized a series of 21 phenolic chalcones, which were evaluated against T. vaginalis trophozoites. Structure-activity relationship indicated hydroxyl group plays a role key in antiprotozoal activity. 4'-Hydroxychalcone (4HC) was the most active compound (IC50 = 27.5 µM) and selected for detailed bioassays. In vitro and in vivo evaluations demonstrated 4HC was not toxic against human erythrocytes and Galleria mellonella larvae. Trophozoites of T. vaginalis were treated with 4HC and did not present significant reactive oxygen species (ROS) accumulation. However, compound 4HC was able to increase ROS accumulation in neutrophils coincubated with T. vaginalis. qRT-PCR Experiments indicated that 4HC did not affect the expression of pyruvate:ferredoxin oxidoreductase (PFOR) and ß-tubulin genes. In silico simulations, using purine nucleoside phosphorylase of T. vaginalis (TvPNP), corroborated 4HC as a promising ligand. Compound 4HC was able to establish interactions with residues D21, G20, M180, R28, R87 and T90 through hydrophobic interactions, π-donor hydrogen bond and hydrogen bonds. Altogether, these results open new avenues for phenolic chalcones to combat trichomoniasis, a parasitic neglected infection.

Identification of volatile biomarkers of Trichomonas vaginalis infection in vaginal discharge and urine.

Trichomoniasis, a disease caused by Trichomonas vaginalis, is the most common non-viral sexually transmitted infection worldwide. The importance of its diagnosis lies in its ease of transmission and the absence of symptoms in most cases, as occurs in men, which have a significant role as asymptomatic carriers. The most widely used diagnostic methods are the fresh examination of vaginal or urethral secretions and molecular techniques. However, as they have some disadvantages and, sometimes, low sensitivity, new trichomoniasis diagnostic methods are necessary. Volatile organic compounds in clinical samples are effective in the diagnosis of different diseases. This work aimed to study, for the first time, those present in vaginal discharge and urine of patients with Trichomonas vaginalis infection to look for volatile biomarkers. The results showed that volatile compounds such as 2-methyl-1-propanol and cyclohexanone could serve as biomarkers in vaginal discharge samples, as well as 2-octen-1-ol and 3-nonanone in urine. Moreover, 3-hydroxy-2,4,4-trimethylpentyl 2-methylpropanoate found in vaginal discharge, highly correlated to positive patients, is also highly related to urines of patients with trichomoniasis. The biomarkers described in this study might be a promising diagnostic tool. KEY POINTS: • The incidence of Trichomonas vaginalis infection is increasing • Trichomonas vaginalis VOC study in vaginal discharge and urine was performed • The identification of volatile biomarkers could allow a new diagnostic method.

Molecular diagnosis of Trichomonas vaginalis in liquid-based Papanicolaou samples in Shiraz, southern Iran.

BACKGROUND: Trichomoniasis is a parasitic infection of the urinary and genital tract, caused by Trichomonas vaginalis. This study aimed to investigate the molecular diagnosis of T. vaginalis infection in liquid-based Papanicolaou samples in Shiraz, southern Iran. MATERIALS AND METHODS: In this cross-sectional study, 534 liquid-based Papanicolaou samples were collected from women referring to the laboratory of Motahari Clinic of Shiraz University of Medical Sciences in 2021. Genomic DNA were extracted from the samples and examined for evidence of T. vaginalis using polymerase chain reaction (PCR) using TVK3 and TVK7 specific primers. RESULTS: The mean age of participants was 39.28 ± 9.89 with a maximum age of 65 and a minimum age of 19 years. T. vaginalis DNA fragments were detected in 4.86% (26/534) of the cases. There was significantly higher prevalence in the age groups of 21 to 30 and 41 to 50 years (46.15%, p = 0.001 and 38.46%, p = 0.015, respectively). Furthermore, the results showed an association between a history of foamy discharge and Trichomonas positivity (p = 0.001). CONCLUSION: T. vaginalis infection is common in liquid-based Papanicolaou samples of women who attended regular health check-ups in the study area. Screening for trichomoniasis in populations, particularly if using highly sensitive methods such as PCR, may lead to increased detection and treatment.

Infectious vaginitis among women seeking reproductive health services at a sexual and reproductive health facility in Kampala, Uganda.

BACKGROUND: Infectious vaginitis is one of the most prevalent conditions affecting women of reproductive age with significant clinical consequences. Bacterial vaginosis (BV), vulvo-vaginal candidiasis (VVC), and trichomoniasis (TV) are the main etiologies. Unfortunately, there is limited data on the prevalence and associated risk factors, especially in sub-saharan Africa. This study, thus, determined the prevalence and risk factors of infectious vaginitis among women seeking reproductive health services at a Marie-stopes health facility in urban areas of Kampala, Uganda. METHODS: A cross-sectional study with 361 participants was conducted from July to October 2021. Data on risk factors and infection were collected via a structured questionnaire and laboratory analysis of vaginal swabs, respectively, with data analysis performed using Stata version 14.0 college station, Texas 77,845 US. RESULTS: The ages of participants ranged from 18 to 49 years, with a mean age of 29.53 years. Overall, 58.45% were infected, of whom 33.24% had VVC, 24.93% had BV, and 0.28% had TV. Bivariate analysis revealed that women with pruritus (COR: 3.057, 95% CI: 1.940-4.819), pregnancy (COR: 4.914, 95% CI: 1.248-19.36), antibiotic use (COR: 1.592, 95% CI: 1.016-2.494), douching (COR: 1.719, 95% CI: 1.079-2.740), and multiple partners (COR: 1.844, 95% CI: 1.079-2.904) were more likely to have VVC, whereas having higher education status (University; Vocational) (COR: 0.325, 95% CI: 0.134-0.890; COR: 0.345, 95% CI: 0.116-0.905) reduced the risk. On the other hand, women with a smelly discharge (COR: 1.796, 95% CI: 1.036-3.110), IUD use (COR: 1.868, 95% CI: 1.039-3.358), and antibiotic use (COR: 1.731, 95% CI: 1.066-2.811) were more likely to have BV. Multivariable analysis identified pruritus (AOR: 2.861, 95% CI: 1.684-4.863) as the only independent predictor for VVC. CONCLUSION: Results indicate a high prevalence of infection among these women; therefore regular screening and treatment is recommended to curb the high rate of infection. More studies on risk factors of infection are recommended.

Effects of SQ109 on Trichomonas vaginalis.

Trichomonas vaginalis is a protozoan that causes human trichomoniasis, a sexually transmitted infection (STI) that affects approximately 278 million people worldwide. The current treatment for human trichomoniasis is based on 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, known as Metronidazole (MTZ). Although effective in eliminating parasitic infection, MTZ is related to serious adverse effects and is not recommended during pregnancy. In addition, some strains are resistant to 5'-nitroimidazoles, prompting the development of alternative drugs for trichomoniasis. Here we show that SQ109 [N-adamantan-2-yl-N'-((E)-3,7-dimethyl-octa- 2,6-dienyl)-ethane-1,2-diamine], a drug under development (antitubercular drug candidate that completed Phase IIb/III) for the treatment of tuberculosis, and previously tested in Trypanosoma cruzi and Leishmania. SQ109 inhibited T.vaginalis growth with an IC50 of 3.15 µM. We used scanning and transmission electron microscopy to visualize the ultrastructural alterations induced by SQ109. The microscopy analysis showed morphological changes on the protozoan surface, where the cells became rounded with increasing surface projections. In addition, the hydrogenosomes increased their size and area occupied in the cell. Furthermore, the volume and a significant association of glycogen particles with the organelle were seen to be altered. A bioinformatics search was done about the compound to find its possible targets and mechanisms of action. Our observations identify SQ109 as a promising compound against T. vaginalis in vitro, suggesting its potential utility as an alternative chemotherapy for trichomoniasis.

Activity of compounds derived from benzofuroxan in Trichomonasvaginalis.

Trichomoniasis is a sexually transmitted infection caused by the protozoan Trichomonas vaginalis. Currently, trichomoniasis is treated with the class of nitroimidazoles, namely, metronidazole; however, resistant isolates and strains have been reported. The compounds derived from benzofuroxan are biologically active heterocycles. This study evaluated the in vitro antiparasitic activity of these compounds in trophozoites of T. vaginalis and determined the mean inhibitory concentration (IC50), minimum inhibitory concentration (MIC), mortality curve, and cytotoxicity. The compounds were named EH1, EH2, EH3, and EA2 and tested in various concentrations: 100 to 15 µM (EH1 and EH2); 100 to 5 µM (EH3); and 100 to 25 µM (EA2), respectively. The greatest efficacy was observed in the highest concentrations in 24 h, with inhibition of approximately 100% of trophozoites. Compounds EH2 and EH3 had the lowest MIC: EH2 (35 µM) and EH3 (45 µM), with IC50 of 11.33 µM and 6.83 µM, respectively. Compound EA2 was effective at the highest concentrations. The activity of the compounds in T. vaginalis started in the first hour of incubation with 90% inhibition; after 12 h, inhibition >95% was observed. Compound EH1 showed the lowest activity, with the highest activity between 12 and 24 h after incubation. These results demonstrate that benzofuroxan derivatives are promising compounds for the in vitro treatment of T. vaginalis.

Diagnosis and Management of Trichomonas vaginalis: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines.

Trichomonas vaginalis is likely the most prevalent nonviral sexually transmitted infection, affecting an estimated 3.7 million women and men in the United States. Health disparities are prominent in the epidemiology of trichomoniasis, as African Americans are >4 times more likely to be infected than persons of other races. Since publication of the 2015 Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines, additional data have bolstered the importance of T. vaginalis infection sequelae in women, including increased risk of human immunodeficiency virus (HIV) acquisition, cervical cancer, preterm birth, and other adverse pregnancy outcomes. Less is known about the clinical significance of infection in men. Newly available diagnostic methods, including point-of-care assays and multiple nucleic acid amplification tests, can be performed on a variety of genital specimens in women and men, including urine, allowing more accurate and convenient testing and screening of those at risk for infection. Repeat and persistent infections are common in women; thus, rescreening at 3 months after treatment is recommended. In vitro antibiotic resistance to 5-nitroimidazole in T. vaginalis remains low (4.3%) but should be monitored. High rates of T. vaginalis among sexual partners of infected persons suggest a role for expedited partner treatment. A randomized controlled trial in HIV-uninfected women demonstrated that multidose metronidazole 500 mg twice daily for 7 days reduced the proportion of women with Trichomonas infection at 1 month test of cure compared with women receiving single-dose therapy (2 g). The 2-g single-dose oral metronidazole regimen remains the preferred treatment in men.

Latent Upregulation of Nlrp3, Nlrc4 and Aim2 Differentiates between Asymptomatic and Symptomatic Trichomonas vaginalis Infection.

Trichomonas vaginalis is a parasitic protozoan that causes trichomoniasis. The involvement of NLRP3 inflammasome in trichomoniasis has been discussed in recent studies. The present study aimed to find out the involvement of Nlrp3, Nlrc4, and Aim2 in the BALB/c mouse model infected with symptomatic and asymptomatic isolates of T. vaginalis by quantitative real-time PCR and immunohistochemistry. Our results showed a significantly increased expression of Nlrp3 in the vaginal tissue of the symptomatic group on the 2nd dpi and 14th dpi in the asymptomatic group, respectively. The cervical tissue of asymptomatic groups expressed higher Nlrp3 on 14th dpi than the symptomatic group. The Nlrc4 was expressed on 14th dpi in the vaginal and cervical tissues of mice infected with asymptomatic group as compared to the symptomatic group. Aim2 expression in vaginal tissue was highest at early time points in both the infected groups as compared to controls. However, in cervical tissues, a significant increase of Aim2 expression was observed on 14th dpi in asymptomatic as compared to the symptomatic group. The significantly higher expression of caspase-1 and caspase-4 was observed in cervical tissues of the asymptomatic group on 14th dpi as compared to the symptomatic group, respectively. All NLRs together resulted in higher IL-1ß expression in the vaginal tissues of the symptomatic and asymptomatic groups. We conclude from this study that early expression of Nlrp3, Nlrc4, and Aim2 was seen in the symptomatic group as compared to the late-onset asymptomatic in the vaginal and cervical tissues.

Increasing incidence rates of sexually transmitted infections from 2010 to 2019: an analysis of temporal trends by geographical regions and age groups from the 2019 Global Burden of Disease Study.

BACKGROUND: World Health Organization announced its goal of ending sexually transmitted infection (STI) epidemics by 2030. To provide a reference for tailored prevention strategies, we analyzed trends and differences in STIs by geographical regions and age groups from 1990 to 2019. METHODS: Annual number of new infections and age-standardized incidence rates (ASRs) of syphilis, chlamydia, gonorrhea, trichomoniasis, and genital herpes were recorded from the 2019 Global Burden of Disease study. We quantified the temporal trends of STIs by calculating changes in new infections and estimated annual percentage changes (EAPCs) of ASR. RESULTS: The ASRs of syphilis, chlamydia, trichomoniasis, and genital herpes increased by 1.70% (95% confidence interval [CI], 1.62-1.78%), 0.29% (95% CI 0.04-0.54%), 0.27% (95% CI 0.03-0.52%), and 0.40% (95% CI 0.36-0.44%) per year from 2010 to 2019 worldwide, respectively, while that of gonorrhea did not. The American regions had the greatest increase in ASR for syphilis (tropical Latin America: EAPC, 5.72; 95% CI 5.11-6.33), chlamydia (high-income North America: EAPC, 1.23; 95% CI 0.73-1.73), and gonorrhea (high-income North America: EAPC, 0.77; 95% CI 0.12-1.41). Additionally, southern sub-Saharan Africa and East Asia had the greatest increase in ASR for trichomoniasis (EAPC, 0.88; 95% CI 0.57-1.20) and genital herpes (EAPC, 1.44; 95% CI 0.83-2.06), respectively. In the most recent years, the population with the greatest incidence of syphilis tended to be younger globally (25-29 years in 2010 vs. 20-24 years in 2019) but older in North Africa and Middle East (20-24 year vs. 25-29 years); with chlamydia tended to be older in southern sub-Saharan Africa (25-29 years vs. 30-34 years) but younger in Australasia (40-44 years vs. 25-29 years); with genital herpes tended to be older in high-income North America (20-24 years vs. 25-29 years) and South Asia (25-29 years vs. 30-34 years). CONCLUSIONS: Syphilis, chlamydia, trichomoniasis, and genital herpes showed a trend of increasing ASR from 2010 to 2019. The differences in trends by geographical regions and age groups point to the need for more targeted prevention strategies in key regions and populations.

Local cytokine/chemokine profiles in BALB/c and C57BL/6 mice in response to T. vaginalis infection.

Trichomonas vaginalis is the causative agent of Trichomoniasis (a sexually transmitted infection). Recent reports have shown that stimulation of cellular immunity can reduce trichomoniasis infection. Animal studies are essential to understanding the pathogenesis of infection and developing new potential drugs and vaccines to treat the infection. Therefore, we have tried to understand the pathogenesis of T. vaginalis infection by investigating the differences in the expression of chemokine/cytokine levels in vaginal and cervical tissues of BALB/c and C57BL/6 mice. Different pathological symptoms, like desquamation, neutrophil infiltration, and hemorrhage, were recorded in BALB/c and C57BL/6 in response to T. vaginalis infection. Vaginal and cervical tissues of BALB/c showed these symptoms on 2nd dpi, which became severe on 7th dpi and turned to mild or normal till 14th dpi compared to C57BL/6 strain. Immunohistochemistry in the vagina and cervical tissues of BALB/c and C57BL/6 mice was done to assess cytokines at different time intervals post-infection. Significant expression of Interleukin-1ß (IL-1ß) (a pro-inflammatory cytokine) was found in BALB/c compared to the C57BL/6 mice, on 7th dpi and 2nd dpi in vaginal and cervical tissues, respectively. Higher expression of MIP-2 (neutrophil chemoattractant) was observed in the vaginal tissues of BALB/c mice on 7th dpi compared to the C57BL/6 group. In addition, higher expression of TGF-ß (immune-suppressor) was observed on 7th dpi in the vaginal tissue of BALB/c mice. The present study demonstrates that more pathological signs of T. vaginalis infection developed in BALB/c mice than C57BL/6 mice. Also, significant levels of IL-1ß and MIP-2 were measured in BALB/c mice in response to T. vaginalis compared to C57BL/6.

Effects of amiodarone, amioder, and dronedarone on Trichomonas vaginalis.

Trichomonas vaginalis is a protozoan that causes human trichomoniasis, the most common non-viral sexually transmitted infection (STI) affecting approximately 278 million people worldwide. The current treatment for trichomoniasis is based on 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, known as metronidazole (MTZ). Although effective in clearing the parasite infection, MTZ is related to provoking severe side effects, and it is not recommended during pregnancy. In addition, some strains present resistance to 5'-nitroimidazoles, making urgent the development of alternative drugs for trichomoniasis. Amiodarone, an antiarrhythmic drug, exerts a significant anti-parasite effect, mainly due to its interference with calcium homeostasis and the biosynthesis of sterols. Therefore, we decided to test the effect of amiodarone and two other related compounds (amioder and dronedarone) on T. vaginalis. Our observations show that amiodarone stimulated, rather than inhibited, parasite growth, induced cell aggregation, and glycogen accumulation. Furthermore, the other two compounds displayed anti-parasite activity with IC50 of 3.15 and 11 µM, respectively, and the apoptosis-like process killed the cells. In addition, cells exhibited morphological changes, including an effect on hydrogenosomes structure.

In vitro activity of amixicile against T. vaginalis from clinical isolates.

Trichomoniasis is a sexually transmitted infection in humans caused by the protozoan Trichomonas vaginalis, the leading causative agent of vaginitis in women and urethritis in men worldwide. Metronidazole is the standard treatment for trichomoniasis, with tinidazole as the second line. There are currently no FDA-approved non-nitroimidazole alternative treatments for resistant strains. This study compares the efficacy of a newly synthesized non-nitroimidazole oral drug, amixicile, to that of both metronidazole and the synthetic precursor of amixicile, nitazoxanide with in vitro sensitivity testing. One standard strain from ATCC and three patient-isolated strains of T. vaginalis were used to compare treatments under anaerobic conditions. The minimum inhibitory concentration for metronidazole, nitazoxanide, and amixicile were 12.5 µM, 100 µM, and 6.25 µM, respectively. These results suggest that amixicile may be highly active against T. vaginalis and warrants further investigation as a potential alternative to metronidazole in the treatment of trichomoniasis.