Antifibrotic effect of silymarin on arecoline-induced fibrosis in primary human buccal fibroblasts: an in silico and in vitro analysis.

BACKGROUND: This study aimed to assess silymarin's anticancer and antifibrotic potential through in silico analysis and investigate its impact on in vitro arecoline-induced fibrosis in primary human buccal fibroblasts (HBF). METHODS & RESULTS: The study utilized iGEMDOCK for molecular docking, evaluating nine bioflavonoids, and identified silymarin and baicalein as the top two compounds with the highest target affinity, followed by subsequent validation through a 100ns Molecular Dynamic Simulation demonstrating silymarin's stable behavior with Transforming Growth Factor Beta. HBF cell lines were developed from tissue samples obtained from patients undergoing third molar extraction. Arecoline, a known etiological factor in oral submucous fibrosis (OSMF), was employed to induce fibrogenesis in these HBFs. The inhibitory concentration (IC50) of arecoline was determined using the MTT assay, revealing dose-dependent cytotoxicity of HBFs to arecoline, with notable cytotoxicity observed at concentrations exceeding 50µM. Subsequently, the cytotoxicity of silymarin was assessed at 24 and 72 h, spanning concentrations from 5µM to 200µM, and an IC50 value of 143µM was determined. Real-time polymerase chain reaction (qPCR) was used to analyze the significant downregulation of key markers including collagen, epithelial-mesenchymal transition (EMT), stem cell, hypoxia, angiogenesis and stress markers in silymarin-treated arecoline-induced primary buccal fibroblast cells. CONCLUSION: Silymarin effectively inhibited fibroblast proliferation and downregulated genes associated with cancer progression and EMT pathway, both of which are implicated in malignant transformation. To our knowledge, this study represents the first exploration of silymarin's potential as a novel therapeutic agent in an in vitro model of OSMF.

Benzopyrene elimination from the environment using graphitic carbon nitride-SnS nanocomposites.

Benzopyrene (BaP) stands as a potent polycyclic aromatic hydrocarbon (PAH) molecule, boasting five fused aromatic rings, making its way into the human food chain through soil contamination. The persistent environmental presence of PAHs in soil, attributed to industrial exposure, is primarily due to their low molecular weight and hydrophobic nature. To preemptively address the entry of BaP into the food chain, the application of nanocomposites was identified as an effective remediation strategy. Post-synthesis, comprehensive characterization tests employing techniques such as UV-DRS, XRD, SEM-EDX, FTIR, and DLS unveiled the distinctive features of the g-C3N4-SnS nanocomposites. These nanocomposites exhibited spherical shapes embedded on layers of nanosheets, boasting particle diameters measuring 88.9 nm. Subsequent tests were conducted to assess the efficacy of eliminating benzopyrene from a combination of PAH molecules and g-C3N4-SnS nanocomposites. Varied parameters, including PAH concentration, adsorbent dosage, and suspension pH, were systematically explored. The optimized conditions for the efficient removal of BaP utilizing the g-C3N4-SnS nanocomposite involved 2 µg/mL of benzopyrene, 10 µg/mL of the nanocomposite, and a pH of 5, considering UV light as the irradiation source. The investigation into the mechanism governing BaP elimination closely aligned with batch adsorption results involved a thorough exploration of adsorption kinetics and isotherms. Photocatalytic degradation of benzopyrene was achieved, reaching a maximum of 86 % in 4 h and 36 % in 2 h, with g-C3N4-SnS nanocomposite acting as the catalyst. Further validation through HPLC data confirmed the successful removal of BaP from the soil matrix.

Gut Microbiome and Polycystic Ovary Syndrome: Interplay of Associated Microbial-Metabolite Pathways and Therapeutic Strategies.

Polycystic ovary syndrome (PCOS) is a multifaceted disease with an intricate etiology affecting reproductive-aged women. Despite attempts to unravel the pathophysiology, the molecular mechanism of PCOS remains unknown. There are no effective or suitable therapeutic strategies available to ameliorate PCOS; however, the symptoms can be managed. In recent years, a strong association has been found between the gut microbiome and PCOS, leading to the formulation of novel ideas on the genesis and pathological processes of PCOS. Further, gut microbiome dysbiosis involving microbial metabolites may trigger PCOS symptoms via many mechanistic pathways including those associated with carbohydrates, short-chain fatty acids, lipopolysaccharides, bile acids, and gut-brain axis. We present the mechanistic pathways of PCOS-related microbial metabolites and therapeutic opportunities available to treat PCOS, such as prebiotics, probiotics, and fecal microbiota therapy. In addition, the current review highlights the emerging treatment strategies available to alleviate the symptoms of PCOS.

Current updates on metabolites and its interlinked pathways as biomarkers for diabetic kidney disease: A systematic review.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) that poses a serious risk as it can lead to end-stage renal disease (ESRD). DKD is linked to changes in the diversity, composition, and functionality of the microbiota present in the gastrointestinal tract. The interplay between the gut microbiota and the host organism is primarily facilitated by metabolites generated by microbial metabolic processes from both dietary substrates and endogenous host compounds. The production of numerous metabolites by the gut microbiota is a crucial factor in the pathogenesis of DKD. However, a comprehensive understanding of the precise mechanisms by which gut microbiota and its metabolites contribute to the onset and progression of DKD remains incomplete. This review will provide a summary of the current scenario of metabolites in DKD and the impact of these metabolites on DKD progression. We will discuss in detail the primary and gut-derived metabolites in DKD, and the mechanisms of the metabolites involved in DKD progression. Further, we will address the importance of metabolomics in helping identify potential DKD markers. Furthermore, the possible therapeutic interventions and research gaps will be highlighted.

Sleep-associated insulin resistance promotes neurodegeneration.

Lifestyle modification can lead to numerous health issues closely associated with sleep. Sleep deprivation and disturbances significantly affect inflammation, immunity, neurodegeneration, cognitive depletion, memory impairment, neuroplasticity, and insulin resistance. Sleep significantly impacts brain and memory formation, toxin excretion, hormonal function, metabolism, and motor and cognitive functions. Sleep restriction associated with insulin resistance affects these functions by interfering with the insulin signalling pathway, neurotransmission, inflammatory pathways, and plasticity of neurons. So, in this review, We discuss the evidence that suggests that neurodegeneration occurs via sleep and is associated with insulin resistance, along with the insulin signalling pathways involved in neurodegeneration and neuroplasticity, while exploring the role of hormones in these conditions.

Environmental effects and interaction of nanoparticles on beneficial soil and aquatic microorganisms.

A steadily increasing production volume of nanoparticles reflects their numerous industrial and domestic applications. These economic successes come with the potential adverse effects on natural systems that are associated with their presence in the environment. Biological activities and effects of nanoparticles are affected by their entry method together with their specificities like their size, shape, charge, area, and chemical composition. Particles can be classified as safe or dangerous depending on their specific properties. As both aquatic and terrestrial systems suffer from organic and inorganic contamination, nanoparticles remain a sink for these contaminants. Researching the sources, synthesis, fate, and toxicity of nanoparticles has advanced significantly during the last ten years. We summarise nanoparticle pathways throughout the ecosystem and their interactions with beneficial microorganisms in this research. The prevalence of nanoparticles in the ecosystem causes beneficial microorganisms to become hazardous to their cells, which prevents the synthesis of bioactive molecules from undergoing molecular modifications and diminishes the microbe population. Recently, observed concentrations in the field could support predictions of ambient concentrations based on modeling methodologies. The aim is to illustrate the beneficial and negative effects that nanoparticles have on aqueous and terrestrial ecosystems, as well as the methods utilized to reduce their toxicity.

Multi-omics insights and therapeutic implications in polycystic ovary syndrome: a review.

Polycystic ovary syndrome (PCOS) is a common gynecological disease that causes adverse effects in women in their reproductive phase. Nonetheless, the molecular mechanisms remain unclear. Over the last decade, sequencing and omics approaches have advanced at an increased pace. Omics initiatives have come to the forefront of biomedical research by presenting the significance of biological functions and processes. Thus, multi-omics profiling has yielded important insights into understanding the biology of PCOS by identifying potential biomarkers and therapeutic targets. Multi-omics platforms provide high-throughput data to leverage the molecular mechanisms and pathways involving genetic alteration, epigenetic regulation, transcriptional regulation, protein interaction, and metabolic alterations in PCOS. The purpose of this review is to outline the prospects of multi-omics technologies in PCOS research by revealing novel biomarkers and therapeutic targets. Finally, we address the knowledge gaps and emerging treatment strategies for the management of PCOS. Future PCOS research in multi-omics at the single-cell level may enhance diagnostic and treatment options.

Molecular mechanisms augmenting resistance to current therapies in clinics among cervical cancer patients.

Cervical cancer (CC) is the fourth leading cause of cancer death (~ 324,000 deaths annually) among women internationally, with 85% of these deaths reported in developing regions, particularly sub-Saharan Africa and Southeast Asia. Human papillomavirus (HPV) is considered the major driver of CC, and with the availability of the prophylactic vaccine, HPV-associated CC is expected to be eliminated soon. However, female patients with advanced-stage cervical cancer demonstrated a high recurrence rate (50-70%) within two years of completing radiochemotherapy. Currently, 90% of failures in chemotherapy are during the invasion and metastasis of cancers related to drug resistance. Although molecular target therapies have shown promising results in the lab, they have had little success in patients due to the tumor heterogeneity fueling resistance to these therapies and bypass the targeted signaling pathway. The last two decades have seen the emergence of immunotherapy, especially immune checkpoint blockade (ICB) therapies, as an effective treatment against metastatic tumors. Unfortunately, only a small subgroup of patients (< 20%) have benefited from this approach, reflecting disease heterogeneity and manifestation with primary or acquired resistance over time. Thus, understanding the mechanisms driving drug resistance in CC could significantly improve the quality of medical care for cancer patients and steer them to accurate, individualized treatment. The rise of artificial intelligence and machine learning has also been a pivotal factor in cancer drug discovery. With the advancement in such technology, cervical cancer screening and diagnosis are expected to become easier. This review will systematically discuss the different tumor-intrinsic and extrinsic mechanisms CC cells to adapt to resist current treatments and scheme novel strategies to overcome cancer drug resistance.

The impact of human papilloma virus on human reproductive health and the effect on male infertility: An updated review.

It is believed that human papilloma virus infection (HPV), which is caused by the DNA virus, is the most prominent factor contributing to sexually transmitted disease (STD) in the world, with males having a prevalence rate of 3.5%-45% while that women are 2%-44%. Infertility is a rising problem on a global basis, affecting anywhere from 10% to 30% of couples who have reached reproductive age. This study aims to investigate the existing research on HPV, its connection to male infertility, and how it could be a helpful tool for medical professionals managing HPV in the context of reproductive health care. Infection with HPV has been identified as a risk factor for several spontaneous abortions; however, there is a lack of evidence on how HPV influences individuals undergoing assisted reproductive technology (ART) in terms of live births. The significance of the immune response to HPV-infected male reproductive system cells and its effect on embryos, as well as the oxidative stress generated by high-risk HPV DNA damage and genomic instability, is discussed in this review. Further, the association between male individuals infected with HPV and asthenozoospermia should provide a compelling case for vaccinating young people against HPV.

The Implication of Mechanistic Approaches and the Role of the Microbiome in Polycystic Ovary Syndrome (PCOS): A Review.

As a complex endocrine and metabolic condition, polycystic ovarian syndrome (PCOS) affects women's reproductive health. These common symptoms include hirsutism, hyperandrogenism, ovulatory dysfunction, irregular menstruation, and infertility. No one knows what causes it or how to stop it yet. Alterations in gut microbiota composition and disruptions in secondary bile acid production appear to play a causative role in developing PCOS. PCOS pathophysiology and phenotypes are tightly related to both enteric and vaginal bacteria. Patients with PCOS exhibit changed microbiome compositions and decreased microbial diversity. Intestinal microorganisms also alter PCOS patient phenotypes by upregulating or downregulating hormone release, gut-brain mediators, and metabolite synthesis. The human body's gut microbiota, also known as the "second genome," can interact with the environment to improve metabolic and immunological function. Inflammation is connected to PCOS and may be caused by dysbiosis in the gut microbiome. This review sheds light on the recently discovered connections between gut microbiota and insulin resistance (IR) and the potential mechanisms of PCOS. This study also describes metabolomic studies to obtain a clear view of PCOS and ways to tackle it.

The pathophysiological and immunological background of the monkeypox virus infection: An update.

In addition to the COVID-19 waves, the globe is facing global monkeypox (MPX) outbreak. MPX is an uncommon zoonotic infection characterized by symptoms similar to smallpox. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus that belongs to the genus Orthopoxvirus (OPXV). MPXV, which causes human disease, has been confined to Africa for many years, with only a few isolated cases in other areas. Outside of Africa, the continuing MPXV outbreak in multiple countries in 2022 is the greatest in recorded history. The current outbreak, with over 10 000 confirmed cases in over 50 countries between May and July 2022, demonstrates that MPXV may travel rapidly among humans and pose a danger to human health worldwide. The rapid spread of such outbreaks in recent times has elevated MPX to the status of a rising zoonotic disease with significant epidemic potential. While the MPXV is not as deadly or contagious as the variola virus that causes smallpox, it poses a threat because it could evolve into a more potent human pathogen. This review assesses the potential threat to the human population and provides a brief overview of what is currently known about this reemerging virus. By analyzing the biological effects of MPXV on human health, its shifting epidemiological footprint, and currently available therapeutic options, this review has presented the most recent insights into the biology of the virus. This study also clarifies the key potential causes that could be to blame for the present MPX outbreak and draw attention to major research questions and promising new avenues for combating the current MPX epidemic.

Molecular Crosstalk between the Immunological Mechanism of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Oral Cancer.

Oral cancer is a significant non-communicable disease affecting both emergent nations and developed countries. Squamous cell carcinoma of the head and neck represent the eight major familiar cancer types worldwide, accounting for more than 350,000 established cases every year. Oral cancer is one of the most exigent tumors to control and treat. The survival rate of oral cancer is poor due to local invasion along with recurrent lymph node metastasis. The tumor microenvironment contains a different population of cells, such as fibroblasts associated with cancer, immune-infiltrating cells, and other extracellular matrix non-components. Metastasis in a primary site is mainly due to multifaceted progression known as epithelial-to-mesenchymal transition (EMT). For the period of EMT, epithelial cells acquire mesenchymal cell functional and structural characteristics, which lead to cell migration enhancement and promotion of the dissemination of tumor cells. The present review links the tumor microenvironment and the role of EMT in inflammation, transcriptional factors, receptor involvement, microRNA, and other signaling events. It would, in turn, help to better understand the mechanism behind the tumor microenvironment and EMT during oral cancer.

Role of Immune Cells and Receptors in Cancer Treatment: An Immunotherapeutic Approach.

Cancer immunotherapy moderates the immune system's ability to fight cancer. Due to its extreme complexity, scientists are working to put together all the puzzle pieces to get a clearer picture of the immune system. Shreds of available evidence show the connection between cancer and the immune system. Immune responses to tumors and lymphoid malignancies are influenced by B cells, γδT cells, NK cells, and dendritic cells (DCs). Cancer immunotherapy, which encompasses adoptive cancer therapy, monoclonal antibodies (mAbs), immune checkpoint therapy, and CART cells, has revolutionized contemporary cancer treatment. This article reviews recent developments in immune cell regulation and cancer immunotherapy. Various options are available to treat many diseases, particularly cancer, due to the progress in various immunotherapies, such as monoclonal antibodies, recombinant proteins, vaccinations (both preventative and curative), cellular immunotherapies, and cytokines.

Does serum kidney injury molecule-1 predict early diabetic nephropathy: A comparative study with microalbuminuria.

Introduction: Diabetic nephropathy (DN) is a multifactorial disease, one of the most common complications of diabetes and a major cause of chronic kidney disease. Kidney injury molecule-1 (KIM-1) is a sensitive and specific marker of kidney injury as well as a predictor of prognosis. Objective: The present study aimed to investigate the usefulness of serum KIM-1 as an early marker of DN. Patients and Methods: The present study included total 75 participants, among whom 25 nondiabetic participants were chosen as controls. The 50 diabetic participants were divided into two groups according to urine protein/creatinine ratio (UPCR) as participants with normoalbuminuria (T2DM patients without nephropathy) and microalbuminuria (T2DM patients with nephropathy). The complete blood count, blood glucose, HbA1c, serum electrolytes, and creatinine levels were measured using standard laboratory techniques, and serum KIM-1 levels were measured by sandwich enzyme-linked immunosorbent assay. Results: There was a significant difference in the mean serum KIM-1 between the control and diabetics without microalbuminuria (P = 0.0001). Patients with longer duration of diabetes had a higher serum KIM-1 values (P = 0.05 in DM without microalbuminuria; P = 0.007 for DM with microalbuminuria). Serum KIM-1 did not correlate with UPCR in controls (P = ‒0.167), in diabetics with microalbuminuria (P = 0.487). However, there was a significant correlation observed between UPCR and serum KIM-1 in diabetics without microalbuminuria (P = 0.04). Conclusion: The present study observed significantly increased levels of serum KIM-1 in both the diabetic groups compared to controls. Moreover, serum KIM-1 positively correlated with the duration of diabetes. Therefore, serum KIM-1 may be used as an early diagnostic marker to predict nephropathy among diabetes in our population.

Computational validation of ABCB1 gene polymorphism and its effect on tacrolimus dose concentration/levels in renal transplant individuals of South India.

Patients with end-stage renal failure require hemodialysis and peritoneal dialysis; however, kidney transplantation is considered a better treatment option for renal failure patients, improving their quality of life and longevity. Among several potent immunosuppressive agents, tacrolimus (TAC) has shown progressive improvement in the graft survival rates after renal transplantation. Fifty kidney transplant patients undergoing TAC immunosuppressive treatment were included. The human genomic DNA was isolated using the phenol-chloroform extraction procedure. CYP3A5*6, CYP3A5*2, and ABCB1 exon 21 G2677 T/A polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Fisher's exact test and Chi-square analysis were performed to analyze the data, where p < 0.05 was considered statistically significant. In addition, we implemented bioinformatics studies on ABCB1 protein to determine the mutation's effect sequentially and structurally. Among the genotyped single nucleotide polymorphisms (SNPs), SNPs of CYP3A5*2 and CYP3A5*6 did not vary in the studied population. The concentration/dose (C/D) ratio of TT genotype of the ABCB1 gene was higher (95% CI: 177.38-269.46) when compared to TA and AA. However, there were no substantial differences between the ABCB1 genotypes and TAC C/D ratio (p = 0.953). The TAC dose mg/kg/day (p = 0.002) and C/D ratio (p = 0.004) exhibited a statistically significant difference. However, no significant difference was found with respect to the ABCB1 gene between the non-toxicity and toxicity groups. Mutation and residue interaction analysis results showed that the S893T mutation destabilizes the ABCB1 protein, thus reducing the protein's flexibility. The present study demonstrated a substantial relationship between the TAC dose and C/D ratio, including the non-toxicity and toxicity groups. However, no possible correlation was observed between the ABCB1 gene polymorphism and renal transplant.

Comparison of potential inhibitors and targeting fat mass and obesity-associated protein causing diabesity through docking and molecular dynamics strategies.

Genome-wide association studies (GWAS) have identified an association between polymorphisms in the FTO gene and obesity. The FTO: rs9939609, an intronic variant, is considered a risk allele for developing diabesity in homozygous and heterozygous forms. This study aimed to investigate the molecular structure of the available inhibitors specific to the FTO mutations along with the rs9939609 variant. We identified the best-suited inhibitor molecules for each mutant type containing the rs9939609 risk allele. Missense mutations unique to obesity and containing the risk allele of rs9939609 were retrieved from dbSNP for this study. Further stability testing for the mutations were carried out using DynaMut and iStable tools. Three mutations (G187A, M223V, and I492V) were highly destabilizing the FTO structure. These three mutants and native FTO were docked with each of the nine-inhibitor molecules collected from literature studies with the help of PyRx and AutoDock. Further structural behavior of the mutants and native FTO were identified with molecular dynamics simulations and MM-PBSA analyses, along with the 19complex inhibitor compound. We found the compound 19complex exhibited better binding interactions and is the top candidate inhibitor for the M223V and I492V mutants. This study provided insights into the structural changes caused due to mutations in FTO, and the binding mechanism of the inhibitor molecules. It could aid in developing antiobesity drugs for treating patients with mutations and risk alleles predisposing to obesity.

Antioxidant Antagonises Chemotherapeutic Drug Effect in Lung Cancer Cell Line A549.

OBJECTIVE: This study aimed to find whether antioxidants increase or decrease the effect of chemotherapeutic drug in the in vitro model. METHODS: Small lung Cancer cell line (A549) was treated with anticancer drug 6-Thioguanine (6-TG) at different concentration viz., 1, 10, 50 and 100µM and the proliferation was measured using MTT assay. The antioxidant N-Acetyl Cysteine (NAC) in different ratios viz., 1mM, 5mM and 10mM were assayed for their effect in proliferation on the A549 cells alone and in combination with 6-TG. RESULTS: Our experiment proves that anticancer drug 6-TG decreases the proliferation and the antioxidant NAC enhances the proliferation of A549 cells. Strikingly when co-treated with 6-TG, the antioxidant NAC diminished the proliferation reduction action of 6-TG on A549 cells. CONCLUSION: Our results suggest that antioxidants in fact benefit the tumor cell growth when treated alone and when in combination with anticancer drug, it severely impair the activity of the drug. We propose that extreme care should be taken when prescribing antioxidants alone or in combination with chemotherapeutics.

Association between end-stage diabetic nephropathy and MTHFR (C677T and A1298C) gene polymorphisms.

AIM: Methylenetetrahydrofolate reductase (MTHFR) is a regulatory enzyme of homocysteine metabolism. The C677T and A1298C polymorphism of the MTHFR gene has been reported to be associated with elevated plasma homocysteine in patients with Diabetic nephropathy. This study aimed to investigate the influence of the C677T and A1298C polymorphisms on the progression chronic kidney disease in diabetic nephropathy of south Indian population. METHODS: We genotyped 145 DN cases and 100 controls for the C677T and A1298C polymorphisms using PCR-RFLP based protocols, and all diabetic nephropathy cases divided into two groups based on CKD stages: 60 DN cases were early stage (CKD1 to CKD3) and 85 DN cases were advanced stage (CKD4 and CKD5). Association χ2 and univariate analysis were performed. RESULTS: The C677T (OR = 4.2; 95% CI = 2.31-7.64 and P = 0.001) and A1298C (OR = 2.8; 95% CI = 1.05-7.57 and P = 0.033) polymorphism was shown that the significant association between the cases and control. Furthermore, the MTHFR gene polymorphism C677T (OR = 2.48; 95% CI = 1.25-4.9 and P = 0.008) was observed that the significant contribution of the progression of CKD in DN. CONCLUSION: These findings suggest that the C677T and A1298C polymorphism of MTHFR gene was associated with diabetic nephropathy in a south Indian population. Furthermore, the present study provides evidence that the C677T polymorphism was associated with CKD progression in DN.

Aldosterone synthase gene is not a major susceptibility gene for progression of chronic kidney disease in patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common heritable kidney disease and is characterized by bilateral renal cysts. Hypertension is a frequent cause of chronic kidney disease (CKD) and mortality in patients with ADPKD. The aldosterone synthase gene polymorphisms of the renin-angiotensin-aldosterone system have been extensively studied as hypertension candidate genes. The present study is aimed to investigate the potential modifier effect of CYP11B2 gene on the progression of CKD in ADPKD. One hundred and two ADPKD patients and 106 healthy controls were recruited based on Ravine inclusion and exclusion criteria. The three tag-SNPs within CYP11B2 gene (rs3802230, rs4543, and rs4544) were genotyped using FRET-based KASPar method. Cochran-Armitage trend test was used to assess the potential associations between these polymorphisms and CKD stages. Mantel- Haenszel stratified analysis was used to explore confounding and interaction effects of these polymorphisms. Of the three tag-SNPs genotyped, rs4544 polymorphism was monomorphic and rs3802230 deviated Hardy-Weinberg equilibrium. The CYP11B2 tag-SNPs did not show significant association with ADPKD or CKD. Further, these polymorphisms did not exhibit confounding effect on the relationship between CKD progression and hypertension. Our results suggest that aldosterone synthase gene is not a major susceptibility gene for progression of CKD in South Indian ADPKD patients.

Influence of angiotensin converting enzyme (ACE) gene rs4362 polymorphism on the progression of kidney failure in patients with autosomal dominant polycystic kidney disease (ADPKD).

BACKGROUND & OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disorder, characterized by the fluid filled cysts in the kidneys leading to end stage renal failure in later years of life. Hypertension is one of the major factors independently contributing to the chronic kidney disease (CKD) progression. The renin-angiotensin aldosterone system (RAAS) genes have been extensively studied as hypertension candidate genes. The aim of the present study was to investigate the role of angiotensin converting enzyme tagging - single nucleotide polymorphisms (ACE tag-SNPs) in progression of CKD in patients with ADPKD. m0 ethods: In the present study six ACE tagSNPs (angiotensin converting enzyme tag single nucleotide polymorphisms) and insertion/deletion (I/D) in 102 ADPKD patients and 106 control subjects were investigated. The tagSNPs were genotyped using FRET-based KASPar method and ACE ID by polymerase chain reaction (PCR) and electrophoresis. Genotypes and haplotypes were compared between ADPKD patients and controls. Univariate and multivariate logistic regression analyses were performed to assess the effect of genotypes and hypertension on CKD advancement. Mantel-Haenszel (M-H) stratified analysis was performed to study the relationship between different CKD stages and hypertension and their interaction. RESULTS: All loci were polymorphic and except rs4293 SNP the remaining loci followed Hardy-Weinberg equilibrium. Distribution of ACE genotypes and haplotypes in controls and ADPKD patients was not significant. A significant linkage disequilibrium (LD) was observed between SNPs forming two LD blocks. The univariate analysis revealed that the age, hypertension, family history of diabetes and ACE rs4362 contributed to the advancement of CKD. INTERPRETATION & CONCLUSIONS: The results suggest that the ACE genotypes are effect modifiers of the relationship between hypertension and CKD advancement among the ADPKD patients.