Collateral Damage in the Placenta during Viral Infection in Pregnancy: A Possible Mechanism for Vertical Transmission and an Adverse Pregnancy Outcome.

In mammals, the placenta is a connection between a mother and a new developing organism. This tissue has a protective function against some microorganisms, transports nutrients, and exchanges gases and excretory substances between the mother and the fetus. Placental tissue is mainly composed of chorionic villi functional units called trophoblasts (cytotrophoblasts, the syncytiotrophoblast, and extravillous trophoblasts). However, some viruses have developed mechanisms that help them invade the placenta, causing various conditions such as necrosis, poor perfusion, and membrane rupture which, in turn, can impact the development of the fetus and put the mother's health at risk. In this study, we collected the most relevant information about viral infection during pregnancy which can affect both the mother and the fetus, leading to an increase in the probability of vertical transmission. Knowing these mechanisms could be relevant for new research in the maternal-fetal context and may provide options for new therapeutic targets and biomarkers in fetal prognosis.

Association Study between Antioxidant Nutrient Intake and Low Bone Mineral Density with Oxidative Stress-Single Nucleotide Variants: GPX1 (rs1050450 and rs17650792), SOD2 (rs4880) and CAT (rs769217) in Mexican Women.

Oxidative stress is essential in developing multiple bone metabolism diseases, including osteoporosis. Single-nucleotide variants (SNVs) have been associated with oxidative stress, promoting an imbalance between the production of reactive oxygen species and the ability to neutralize them, and it has been reported that antioxidant nutrient intake can influence bone mineral density (BMD). This work reports the association between oxidative stress-related SNVs (GPX1-rs1050450, rs17650792, SOD2-rs4880, and CAT-rs769217), BMD, and antioxidant nutrient intake. The study included 1269 Mexican women from the Health Workers Cohort Study. Genotyping was performed using predesigned TaqMan assays. Dietary data were collected using a 116-item semi-quantitative food frequency questionnaire. A dietary antioxidant quality score (DAQS) was used to estimate antioxidant-nutrient intake. Association analysis was estimated via linear, logistic, or quantile regression models. The results showed an association of the rs1050450-A and rs17650792-A alleles with femoral neck BMD (p = 0.038 and p = 0.017, respectively) and the SNV rs4880-A allele with total hip BMD (p = 0.026) in respondents aged 45 years or older. In addition, antioxidant-nutrient intake was associated with the rs4880-GG genotype, being significant for fiber (p = 0.007), riboflavin (p = 0.005), vitamin B6 (p = 0.034), and vitamin D (p = 0.002). The study showed an association between oxidative stress-related SNVs, BMD, and antioxidant-nutrient intake in Mexican women. Therefore, treatments for low BMD could be developed based on antioxidant supplementation.

Dynamics of the Microbiota and Its Relationship with Post-COVID-19 Syndrome.

Coronavirus disease (COVID-19) is an infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can be asymptomatic or present with multiple organ dysfunction. Many infected individuals have chronic alterations associated with neuropsychiatric, endocrine, gastrointestinal, and musculoskeletal symptoms, even several months after disease onset, developing long-COVID or post-acute COVID-19 syndrome (PACS). Microbiota dysbiosis contributes to the onset and progression of many viral diseases, including COVID-19 and post-COVID-19 manifestations, which could serve as potential diagnostic and prognostic biomarkers. This review aimed to discuss the most recent findings on gut microbiota dysbiosis and its relationship with the sequelae of PACS. Elucidating these mechanisms could help develop personalized and non-invasive clinical strategies to identify individuals at a higher risk of experiencing severe disease progression or complications associated with PACS. Moreover, the review highlights the importance of targeting the gut microbiota composition to avoid dysbiosis and to develop possible prophylactic and therapeutic measures against COVID-19 and PACS in future studies.

A Review Study of the Participation of Late Domains in Sorting and Transport of Viral Factors to Exosomes.

Cellular communication depends heavily on the participation of vesicular systems generated by most cells of an organism. Exosomes play central roles in this process. Today, these vesicles have been characterized, and it has been determined that the cargo they transport is not within a random system. In fact, it depends on various molecular signals and the recruitment of proteins that participate in the biogenesis of exosomes. It has also been shown that multiple viruses can recruit these vesicles to transport viral factors such as genomes or proteins. It has been shown that the late domains present in viral proteins are critical for the exosomal selection and biogenesis systems to recognize these viral proteins and introduce them into the exosomes. In this review, the researchers discuss the evidence related to the characterization of these late domains and their role in exosome recruitment during viral infection.

Oxidative-Stress-Related Genes in Osteoporosis: A Systematic Review.

Osteoporosis is characterized by a decline in bone mineral density (BMD) and increased fracture risk. Free radicals and antioxidant systems play a central role in bone remodeling. This study was conducted to illustrate the role of oxidative-stress-related genes in BMD and osteoporosis. A systematic review was performed following the PRISMA guidelines. The search was computed in PubMed, Web of Sciences, Scopus, EBSCO, and BVS from inception to November 1st, 2022. The risk of bias was evaluated using the Joanna Briggs Institute Critical Appraisal Checklist tool. A total of 427 potentially eligible articles exploring this search question were detected. After removing duplicates (n = 112) and excluding irrelevant manuscripts based on screenings of their titles and abstracts (n = 317), 19 articles were selected for full-text review. Finally, 14 original articles were included in this systematic review after we applied the exclusion and inclusion criteria. Data analyzed in this systematic review indicated that oxidative-stress-related genetic polymorphisms are associated with BMD at different skeletal sites in diverse populations, influencing the risk of osteoporosis or osteoporotic fracture. However, it is necessary to look deep into their association with bone metabolism to determine if the findings can be translated into the clinical management of osteoporosis and its progression.

Interaction between SIDT2 and ABCA1 Variants with Nutrients on HDL-c Levels in Mexican Adults.

Previous studies have reported that the SIDT2 and ABCA1 genes are involved in lipid metabolism. We aimed to analyze the association-the gene x gene interaction between rs17120425 and rs1784042 on SIDT2 and rs9282541 on ABCA1 and their diet interaction on the HDL-c serum levels-in a cohort of 1982 Mexican adults from the Health Workers Cohort Study. Demographic and clinical data were collected through a structured questionnaire and standardized procedures. Genotyping was performed using a predesigned TaqMan assay. The associations and interactions of interest were estimated using linear and logistic regression. Carriers of the rs17120425-A and rs1784042-A alleles had slightly higher blood HDL-c levels compared to the non-carriers. In contrast, rs9282541-A was associated with low blood HDL-c levels (OR = 1.34, p = 0.013). The rs1784042 x rs9282541 interaction was associated with high blood HDL-c levels (p = 3.4 × 10-4). Premenopausal women who carried at least one rs17120425-A allele and consumed high dietary fat, protein, monounsaturated, or polyunsaturated fatty acids levels had higher HDL-c levels than the non-carriers. These results support the association between the genetic variants on SIDT2 and ABCA1 with HDL-c levels and suggest gene-gene and gene-diet interactions over HDL-c concentrations in Mexican adults. Our findings could be a platform for developing clinical and dietary strategies for improving the health of the Mexican population.

Association of MARC1, ADCY5, and BCO1 Variants with the Lipid Profile, Suggests an Additive Effect for Hypertriglyceridemia in Mexican Adult Men.

Epidemiological studies have reported that the Mexican population is highly susceptible to dyslipidemia. The MARC1, ADCY5, and BCO1 genes have recently been involved in lipidic abnormalities. This study aimed to analyze the association of single nucleotide polymorphisms (SNPs) rs2642438, rs56371916, and rs6564851 on MARC1, ADCY5, and BCO1 genes, respectively, with the lipid profile in a cohort of Mexican adults. We included 1900 Mexican adults from the Health Workers Cohort Study. Demographic and clinical data were collected through a structured questionnaire and standardized procedures. Genotyping was performed using a predesigned TaqMan assay. A genetic risk score (GRS) was created on the basis of the three genetic variants. Associations analysis was estimated using linear and logistic regression. Our results showed that rs2642438-A and rs6564851-A alleles had a risk association for hypertriglyceridemia (OR = 1.57, p = 0.013; and OR = 1.33, p = 0.031, respectively), and rs56371916-C allele a trend for low HDL-c (OR = 1.27, p = 0.060) only in men. The GRS revealed a significant association for hypertriglyceridemia (OR = 2.23, p = 0.022). These findings provide evidence of an aggregate effect of the MARC1, ADCY5, and BCO1 variants on the risk of hypertriglyceridemia in Mexican men. This knowledge could represent a tool for identifying at-risk males who might benefit from early interventions and avoid secondary metabolic traits.

Effect of Hypoxia in the Transcriptomic Profile of Lung Fibroblasts from Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by exacerbated extracellular matrix deposition that disrupts oxygen exchange. Hypoxia and its transcription factors (HIF-1α and 2α) influence numerous circuits that could perpetuate fibrosis by increasing myofibroblasts differentiation and by promoting extracellular matrix accumulation. Therefore, this work aimed to elucidate the signature of hypoxia in the transcriptomic circuitry of IPF-derived fibroblasts. To determine this transcriptomic signature, a gene expression analysis with six lines of lung fibroblasts under normoxia or hypoxia was performed: three cell lines were derived from patients with IPF, and three were from healthy donors, a total of 36 replicates. We used the Clariom D platform, which allows us to evaluate a huge number of transcripts, to analyze the response to hypoxia in both controls and IPF. The control's response is greater by the number of genes and complexity. In the search for specific genes responsible for the IPF fibroblast phenotype, nineteen dysregulated genes were found in lung fibroblasts from IPF patients in hypoxia (nine upregulated and ten downregulated). In this sense, the signaling pathways revealed to be affected in the pulmonary fibroblasts of patients with IPF may represent an adaptation to chronic hypoxia.

Uric Acid Levels Are Associated with Bone Mineral Density in Mexican Populations: A Longitudinal Study.

Background: Inconsistent epidemiological evidence between uric acid (UA) and bone mineral density (BMD) has been observed. Therefore, we evaluated the association between UA and BMD in Mexican adults. Methods: This analysis was conducted on 1423 participants from the Health Workers Cohort Study. We explored cross-sectional associations using linear regression and longitudinal associations using fixed-effects linear regression by sex and age groups (<45 and ≥45 years). Results: In females <45 years old, the cross-sectional analysis showed that UA levels were positively associated with total hip BMD. However, in the longitudinal analysis, we observed a negative association with the femoral neck and lumbar spine BMD. In contrast, in males <45 years old, we found an increase in total hip and femoral neck BMD in the groups with high levels of UA in the longitudinal association. On the other hand, in females ≥45 years old, we observed a longitudinal association between UA and loss of BMD at different sites. We did not observe an association between UA levels and BMD in males ≥45 years old. Conclusions: Our results suggest higher serum UA levels are associated with low BMD at different skeletal sites in Mexican females. Further studies are needed to delineate the underlying mechanisms behind this observation.

Unravelling the Contribution of the rs7041 and rs4588 Polymorphisms of the GC Gene and Serum VDBP Levels for Developing Metabolic Syndrome in the Mexican Population.

Metabolic syndrome (MetS) is a multifactorial disorder integrated by a constellation of cardiovascular risk factors. The genetic and environmental determinants of MetS are not fully elucidated. This study investigated the association of two common single nucleotide polymorphisms (SNPs) on GC, rs7041 and rs4588, derived haplotypes, and serum vitamin D binding protein (VDBP) levels with the susceptibility to suffer MetS in Mexican adults. We included 1924 individuals; clinical and biochemical data were obtained through standard methods. Genotyping was performed through predesigned TaqMan assays. Logistic regression models were used to assess the associations of interest. Prevalence of MetS was 52.9% in the whole population, being more frequent in women. We observed that some association results differed between sexes. The GG genotype of the rs7041 was associated with increased odds of MetS in women. For the rs4588, the CA genotype had a protective effect against MetS in women. The haplotype GC2 was associated with reduced odds for MetS and some of its components in women. Our data suggest that VDBP serum levels were influenced by genotypes/haplotypes and this interplay seems to influence the risk of MetS. Our data provide reliable evidence regarding the association of GC polymorphisms with MetS risk in Mexican women.

Targeted Metabolomics Revealed a Sex-Dependent Signature for Metabolic Syndrome in the Mexican Population.

Metabolic syndrome (MetS) is a group of several metabolic conditions predisposing to chronic diseases. Individuals diagnosed with MetS are physiologically heterogeneous, with significant sex-specific differences. Therefore, we aimed to investigate the potential sex-specific serum modifications of amino acids and acylcarnitines (ACs) and their relationship with MetS in the Mexican population. This study included 602 participants from the Health Workers Cohort Study. Forty serum metabolites were analyzed using a targeted metabolomics approach. Multivariate regression models were used to test associations of clinical and biochemical parameters with metabolomic profiles. Our findings showed a serum amino acid signature (citrulline and glycine) and medium-chain ACs (AC14:1, AC10, and AC18:10H) associated with MetS. Glycine and AC10 were specific metabolites representative of discrimination according to sex-dependent MetS. In addition, we found that glycine and short-chain ACs (AC2, AC3, and AC8:1) are associated with age-dependent MetS. We also reported a significant correlation between body fat and metabolites associated with sex-age-dependent MetS. In conclusion, the metabolic profile varies by MetS status, and these differences are sex-age-dependent in the Mexican population.

Dietary inflammatory index and bone mineral density in Mexican population.

Dietary inflammatory index has been associated with bone loss. In this longitudinal study, we reported that changes in dietary inflammatory index were associated with a reduction in bone mineral density of the total hip and femoral neck in males and females ≥ 45 years, but not in individuals < 45 years. PURPOSE: Previous studies have suggested that an inflammatory environment can affect bone mineral density (BMD). However, most of the studies have been done in postmenopausal women. Thus, longitudinal studies in different age groups and sex are necessary to evaluate the longitudinal association between dietary inflammatory index (DII) and BMD in Mexican adults. METHODS: A total of 1,486 participants of the Health Workers Cohort Study were included in this study. The DII was estimated with data retrieved through a semi-quantitative food frequency questionnaire. Total hip, femoral neck, and lumbar spine BMD were measured by dual-energy X-ray absorptiometry. Linear regression models for cross-sectional associations and fixed effects linear regression models for longitudinal association were estimated, and both models were stratified by sex and age groups (< 45 and ≥ 45 years). RESULTS: We did not observe cross-sectional associations between DII and the different BMD sites at baseline. In contrast, women and men ≥ 45 years in the 25th quartile of changes in DII were associated with a gain of 0.067 g/cm2 and 0.062 g/cm2 of total hip BMD, while those in the 75th quartile of DII was associated with a reduction of - 0.108 g/cm2 and - 0.100 g/cm2, respectively. These results were similar for femoral neck BMD in women. In contrast, we did not observe association with femoral neck BMD in men. We did not observe statistically significant changes for lumbar spine BMD. CONCLUSION: Our data suggest that changes in the DII score are associated with changes in total hip and femoral neck BMD among Mexican population.

Common variant rs6564851 near the beta-carotene oxygenase 1 gene is associated with plasma triglycerides levels in middle-aged Mexican men adults.

Dyslipidemias have been linked to an increased risk of adverse health outcomes, including cardiovascular disease, type 2 diabetes, and the metabolic syndrome. Recent reports have associated the beta-carotene oxygenase 1 (BCO1) gene with lipid metabolism, mainly reducing total cholesterol and increasing high-density lipoprotein-cholesterol (HDL-C) concentrations. The hypothesis of this study was that the variant rs6564851 near the BCO1 gene is associated positively with the lipid profile in middle-aged Mexican adults. This study included 1441 Mexicans older than 40 years of age from the Health Workers Cohort Study (HWCS). Genotyping was conducted using a predesigned TaqMan assay. Lipid profile was measured with standardized procedures. Our results showed that the men carrying at least 1 T allele had higher serum triglyceride concentrations than GG homozygous (GG: 146.5 mg/dL; GT: 175 mg/dL; and TT: 184 mg/dL; P = .008). The variant rs6564851 showed a risk associated with the serum triglyceride concentrations(odds ratio [OR], 2.77; P = .002) only in the male group. However, we did not observe significant differences in the serum total cholesterol, HDL-C, and low-density lipoprotein-cholesterol concentrations in both sexes. Our study provides evidence that the variant rs6564851 is negatively associated with the triglyceride concentrations in middle-aged Mexican male adults in the HWCS. This knowledge can be the basis for developing effective nutritional strategies according to sex and the genetic variants present in an individual. Further studies in independent populations are required to validate these findings and determine the mechanism of the association sex dependent.

Total, Bioavailable, and Free 25-Hydroxyvitamin D Equally Associate with Adiposity Markers and Metabolic Traits in Mexican Adults.

Epidemiological studies suggest a relationship between total 25-hydroxyvitamin D [25(OH)D], adiposity, and metabolic traits. The bioavailability of 25(OH)D is regulated by the albumin, vitamin D binding protein (VDBP), and variants of the GC gene. Therefore, it is not clear if bioavailable or free 25(OH)D offer additional benefits compared to total 25(OH)D when estimating the magnitude of these associations. Our aim was to evaluate the association between 25(OH)D (total, free and bioavailable) with adiposity and metabolic traits. This was a cross-sectional study of 1904 subjects from the Health Workers Cohort Study from Mexico. Free and bioavailable 25(OH)D were calculated based on VDBP and albumin determinations, using a formula adjusted for the GC gene diplotypes. Adiposity and metabolic traits were measured with standardized procedures. Free and bioavailable 25(OH)D levels correlated with total 25(OH)D, r = 0.71 and 0.70, respectively (p < 0.001). Total, bioavailable and free 25(OH)D levels were negatively associated with the adiposity marker (visceral adiposity index) and metabolic traits (metabolic syndrome, type 2 diabetes, triglycerides, triglycerides/HDL-c ratio, and triglycerides/glucose index) in multivariate regression models (ORs = 0.73 to 0.96). Our findings suggest that free and bioavailable 25(OH)D do not offer additional advantages over total 25(OH)D regarding its association with adiposity and several metabolic traits in Mexican adults.

The genomic landscape of Mexican Indigenous populations brings insights into the peopling of the Americas.

The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15-30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4-9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far.

Serum Metabolite Profile Associated with Sex-Dependent Visceral Adiposity Index and Low Bone Mineral Density in a Mexican Population.

Recent evidence shows that obesity correlates negatively with bone mass. However, traditional anthropometric measures such as body mass index could not discriminate visceral adipose tissue from subcutaneous adipose tissue. The visceral adiposity index (VAI) is a reliable sex-specified indicator of visceral adipose distribution and function. Thus, we aimed to identify metabolomic profiles associated with VAI and low bone mineral density (BMD). A total of 602 individuals from the Health Workers Cohort Study were included. Forty serum metabolites were measured using the targeted metabolomics approach, and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical, and biochemical parameters. The analysis showed a serum amino acid signature composed of glycine, leucine, arginine, valine, and acylcarnitines associated with high VAI and low BMD. In addition, we found a sex-dependent VAI in pathways related to primary bile acid biosynthesis, branched-chain amino acids, and the biosynthesis of pantothenate and coenzyme A (CoA). In conclusion, a metabolic profile differs by VAI and BMD status, and these changes are gender-dependent.

Association of GC Variants with Bone Mineral Density and Serum VDBP Concentrations in Mexican Population.

Vitamin D-binding protein (VDBP) is encoded by the GC gene and is an active participant in the control of bone metabolism. However, the effect of its major variants on VDBP concentration and bone mineral density (BMD) remains unclear. Our aim was to analyze the effect of major GC variants on serum VDBP concentration and BMD. We recruited individuals from the Health Workers Cohort Study, which includes employees of the Mexican Institute of Social Security (IMSS). A total of 1853 adults were included. The single nucleotide polymorphisms (SNPs) rs7041 and rs4588 were genotyped to identify the three best characterized haplotypes of GC. Serum VBDP, 25(OH)D and BMD were also measured. Among women, the G allele of rs7041 was associated with higher VDBP and BMD compared to homozygous TT. The A allele of rs4588 was associated with lower VDBP and BMD compared to CC homozygous. In men, GC variants were only associated with VDBP levels. We did not observe an association between free/bioavailable 25(OH)D and BMD in men and women. Our results support an association of VDBP in bone health. The G and C alleles, from rs7041 and rs4588, respectively, are associated with high concentrations of VDBP and BMD in this sample of Mexican postmenopausal women.

Inhibition of AMP-activated protein kinase in respiratory syncytial virus infection activates lipid metabolism.

Respiratory syncytial virus (RSV) is most commonly associated with upper respiratory tract infections during childhood. The lipid composition of cells and lipogenic enzymes play an important role in RSV infection. There are controversial data about whether lipid biosynthesis regulators such as AMP-activated protein kinase (AMPK) are deregulated by RSV. Hence, we examined whether the activation state of AMPK is altered in RSV-infected HEp-2 cells. Our data show that RSV infection inhibits AMPK activity, favoring the activation of downstream lipogenic effectors and cellular lipid anabolism in HEp-2 cells.

The Variant rs1784042 of the SIDT2 Gene is Associated with Metabolic Syndrome through Low HDL-c Levels in a Mexican Population.

The Mexican population has one of the highest prevalences of metabolic syndrome (MetS) worldwide. The aim of this study was to investigate the association of single-nucleotide polymorphisms (SNPs) with MetS and its components. First, we performed a pilot Genome-wide association study (GWAS) scan on a sub-sample derived from the Health Workers Cohort Study (HWCS) (n = 411). Based on GWAS results, we selected the rs1784042 and rs17120425 SNPs in the SIDT1 transmembrane family member 2 (SIDT2) gene for replication in the entire cohort (n = 1963), using predesigned TaqMan assays. We observed a prevalence of MetS in the HWCS of 52.6%. The minor allele frequency for the variant rs17120425 was 10% and 29% for the rs1784042. The SNP rs1784042 showed an overall association with MetS (OR = 0.82, p = 0.01) and with low levels of high-density lipoprotein (HDL-c) (odds ratio (OR) = 0.77, p = 0.001). The SNP rs17120425 had a significant association with type 2 diabetes (T2D) risk in the overall population (OR = 1.39, p = 0.033). Our results suggest an association of the rs1784042 and rs17120425 variants with MetS, through different mechanisms in the Mexican population. Further studies in larger samples and other populations are required to validate these findings and the relevance of these SNPs in MetS.

Lysosomal dysfunction induced by changes in albumin's tertiary structure: Potential key factor in protein toxicity during diabetic nephropathy.

AIMS: Increased amounts of protein, in particular albumin within renal tubular cells (TBCs), induce the expression of inflammatory and fibrogenic mediators, which are adverse prognostic factors in tubulointerstitial fibrosis and diabetic nephropathy (DN). We sought to assess the participation of the thiol-linked tertiary structure of albumin in the mechanism of protein toxicity in a model of TBCs. MATERIALS AND METHODS: Cultured human renal proximal tubular cells, HK-2, were exposed to isolated albumin from patients with and without DN (Stages 0, 1 and 4). The magnitude of change of the albumin tertiary structure, cell viability (LDH leakage), apoptosis (Annexin V), transdifferentiation and reticulum endoplasmic stress (Western blot and flow cytometry) and lysosomal enzyme activity were assessed. KEY FINDINGS: We found that albumin from Stage 4 patients presented >50% higher thiol-dependent changes of tertiary structure compared to Stages 0 and 1. Cells incubated with Stage 4 albumin displayed 5 times less viability, accompanied by an increased number of apoptotic cells; evidence of profibrogenic markers E-cadherin and vimentin and higher expression of epithelial-to-mesenchymal transition markers α-SMA and E-cadherin and of endoplasmic reticulum stress protein GRP78 were likewise observed. Moreover, we found that cathepsin B activity in isolated lysosomes showed a significant inhibitory effect on albumin from patients in advanced stages of DN and on albumin that was intentionally modified. SIGNIFICANCE: Overall, this study showed that thiol-dependent changes in albumin's tertiary structure interfere with the lysosomal proteolysis of renal TBCs, inducing molecular changes associated with interstitial fibrosis and DN progression.