Human papillomavirus type 16 E6 promotes cervical cancer proliferation by upregulating transketolase enzymatic activity through the activation of protein kinase B.

Over 99% of precancerous cervical lesions are associated with human papillomavirus (HPV) infection, with HPV types 16 and 18 (especially type 16) found in over 70% of cervical cancer cases globally. E6, a critical HPV gene, triggers malignant proliferation by degrading p53; however, this mechanism alone cannot fully explain the oncogenic effects of HPV16 E6. Therefore, we aimed to investigate new targets of HPV oncogenic mechanisms. Our results revealed significant changes in nonoxidative pentose phosphate pathway (PPP) metabolites in HPV16-positive cells. However, the role of nonoxidative PPP in HPV-associated cell transformation and tumor development remained unexplored. In this study, we investigated the impact and mechanisms of HPV16 E6 on cervical cancer proliferation using the HPV-negative cervical cancer cell line (C33A). HPV16 E6 was found to promote cervical cancer cell proliferation both in vitro and in vivo, activating the nonoxidative PPP. Transketolase (TKT), a key enzyme in the nonoxidative PPP, is highly expressed in cervical cancer tissues and associated with poor prognosis. HPV16 E6 promotes cervical cancer cell proliferation by upregulating TKT activity through the activation of AKT. In addition, oxythiamine (OT), a TKT inhibitor, hindered tumor growth, with enhanced effects when combined with cisplatin (DDP). In conclusion, HPV16 E6 promotes cervical cancer proliferation by upregulating TKT activity through the activation of AKT. OT demonstrates the potential to inhibit HPV16-positive cervical cancer growth, and when combined with DDP, could further enhance the tumor-suppressive effect of DDP.

Unveiling the enigmatic role of MYH9 in tumor biology: a comprehensive review.

Non-muscle myosin heavy chain IIA (MYH9), a member of the non-muscle myosin II (NM II) family, is widely expressed in cells. The interaction of MYH9 with actin in the cytoplasm can hydrolyze ATP, completing the conversion of chemical energy to mechanical motion. MYH9 participates in various cellular processes, such as cell adhesion, migration, movement, and even signal transduction. Mutations in MYH9 are often associated with autosomal dominant platelet disorders and kidney diseases. Over the past decade, tumor-related research has gradually revealed a close relationship between MYH9 and the occurrence and development of tumors. This article provides a review of the research progress on the role of MYH9 in cancer regulation. We also discussed the anti-cancer effects of MYH9 under special circumstances, as well as its regulation of T cell function. In addition, given the importance of MYH9 as a key hub in oncogenic signal transduction, we summarize the current therapeutic strategies targeting MYH9 as well as the ongoing challenges.

ACOX1 deficiency-induced lipid metabolic disorder facilitates chronic interstitial fibrosis development in renal allografts.

Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid ß-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.

Short-chain fatty acids in diseases.

Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract.

Targeted changes in blood lipids improves fibrosis in renal allografts.

BACKGROUND: Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear. METHODS: Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson's trichrome staining were used to determine the degree of fibrosis. RESULTS: Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation. CONCLUSIONS: This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet.

Lactobacillus plantarum alleviates irradiation-induced intestinal injury by activation of FXR-FGF15 signaling in intestinal epithelia.

Abdominal irradiation (IR) may destroy the intestinal mucosal barrier, leading to severe intestinal infection and multiple organ dysfunction syndromes. The role of intestinal microbiota in the development of IR-induced intestinal injury remains largely unknown. Herein, we reported that abdominal IR altered the composition of the microbiota and reduced the abundance and diversity of the gut microbiome. Alterations of bacteria, in particular reduction of Lactobacillus, played a critical role in IR-induced intestinal injury. Fecal microbiota transplant (FMT) from normal mice or administration of Lactobacillus plantarum to intestinal microbiota-eliminated mice substantially reduced IR-induced intestinal damage and prevented mice from IR-induced death. We further characterized that L. plantarum activated the farnesoid X receptor (FXR) - fibroblast growth factor 15 (FGF15) signaling in intestinal epithelial cells and hence promoted DNA-damage repair. Application of GW4064, an activator of FXR, to microbiota eliminated mice markedly mitigated IR-induced intestinal damage, reduced intestinal epithelial cell death and promoted the survival of IR mice. In contrast, suppression of FXR with Gly-ß-MCA, a bile acid and an intestine-selective and high-affinity FXR inhibitor, abrogated L. Plantarum-mediated protection on the ileum of IR mice. Taken together, our findings not only provide new insights into the role of intestinal flora in radiation-induced intestinal injury but also shed new light on the application of probiotics for the protection of radiation-damaged individuals.

Role of regulatory T cells in CD47/donor-specific transfusion-induced immune tolerance in skin-heart transplantation mice.

OBJECTIVES: To explore the role of regulatory T (Treg ) cells in the establishment of immune tolerance induced by donor-specific transfusion (DST) in mice with skin-heart transplantation. METHODS: C57BL/6 mice received DST of splenocytes from CD47+/+ or CD47-/- H-2bm1 mice or no DST 7 days before skin-heart transplantation from major histocompatibility complex class I-mismatched H-2bm1 donors. The number and proportion of Treg cells in graft and lymphoid organs were measured by flow cytometry (FACS) and immunohistochemistry (IHC). The inhibitory function of Treg cells and anti-donor T-cell responses were assessed by mixed lymphocyte reaction. RESULTS: We observed that mean survival time (MST) of skin or heart graft was significantly longer in C57BL/6 mice which received DST from CD47+/+ H-2bm1 mice than from CD47-/- H-2bm1 mice. By FACS, we found that the number of Treg cells in spleen was increased significantly in mice which received CD47-/- DST compared to mice which received CD47+/+ DST. However, the percentages of Treg cells in total splenocytes and lymph node cells were significantly higher in mice that received CD47+/+ DST than mice which received CD47-/- DST. Immunohistochemistry showed an increased heart grafts infiltration of Treg cells in the recipients with CD47-/- DST, but not CD47+/+ DST. Supporting this, we found that donor T-cell proliferation was significantly suppressed in mice which received CD47+/+ DST compared to mice which received CD47-/- DST. There was no difference of inhibitory function of Treg cells between these two groups. CONCLUSION: Our results indicated that CD47 expression on DST cells plays an important role in the induction of immune tolerance in mice with skin-heart transplantation. Increased percentage of Treg cells may contribute to immune tolerance induced by CD47+/+ DST.

New Factors Predicting Delayed Graft Function: a Multi-Center Cohort Study of Kidney Donation After Brain Death Followed by Circulatory Death.

BACKGROUND/AIMS: Delayed graft function (DGF) is a common complication following kidney transplantation adversely affecting graft outcomes. Donation after brain death followed by circulatory death (DBCD), a novel donation pattern, is expected to correlate with high incidence of DGF. However, little information is available about factors associated with DGF in DBCD. METHODS: A total of 383 kidney transplants from DBCD donation in three institutions were enrolled. Associations of DGF with the clinical characteristics of recipients and donors were quantified. RESULTS: In this retrospective multi-center study, the incidence of DGF was 19.3%. Lower incidence of DGF was found in recipients for whom antithymocyte globulin was used for induction (p < 0.05), which was an independent protective factor against DGF (odds ratio [OR] = 0.48; 95% CI 0.27-0.86). Two novel explicative variables were recognized as independent risk factors, including use of vasoactive drugs (OR = 3.15; 95% CI 1.39-7.14) and cardiopulmonary resuscitation (OR = 2.51; 95% CI 1.05-6.00), which contributed significantly to increased risk of DGF (p < 0.05). Prolonged warm ischemia time (> 18 min; OR = 2.42; 95% CI 1.36-4.32), was also predictive of DGF in DBCD. A prediction model was developed and achieved an area under the curve of 0.89 in predicting DGF when combined with reported parameters. CONCLUSION: The novel factors, confirmed for the first time in our study, will help to improve risk prediction of DGF and to determine optimal interventions to prevent DGF in clinical practice.

Donation after brain death followed by circulatory death, a novel donation pattern, confers comparable renal allograft outcomes with donation after brain death.

BACKGROUND: Organ donation after brain death (DBD) is the standard strategy for organ transplantation; however, the concept of brain death is not universally accepted due to cultural beliefs and barriers amongst billions of people worldwide. Hence, a novel donation pattern has been established in China which outlines the concept of donation after brain death followed by circulatory death (DBCD). Differently from any current donation classification, this new concept is formulated based on combination of recognizing brain death and circulatory death. Should approval be gained for this definition and approach, DBCD will pave a novel donation option for billions of people who cannot accept DBD due to their cultural beliefs. METHODS: A multi-center, cohort study was conducted from February 2012 to December 2015. 523 kidney transplant recipients from four kidney transplant institutions were enrolled into the study, of which, 383 received kidneys from DBCD, and 140 from DBD. Graft and recipient survivals following transplantation were retrospectively analyzed. Postoperative complications including delayed graft function,, and acute rejection, were also analyzed for both groups. RESULTS: DBCD could achieve comparable graft and recipient survivals in comparison with DBD (Log-rank P = 0.32 and 0.86,respectively). One-year graft and recipient survivals were equal between DBCD and DBD groups (97.4% versus 97.9%, P = 0.10;98.4% versus 98.6%, P = 1.0, respectively). Furthermore, DBCD did not increase incidences of postoperative complications compared with DBD, including delayed graft function (19.3% versus 22.1%, P = 0.46) and acute rejection (9.1% versus 8.6%, P = 1.0). Additionally, antithymocyte globulin as induction therapy and shorter warm ischemia time decreased incidence of delayed graft function in DBCD group (16.8% on antithymocyte globulin versus 27.2% on basiliximab, P = 0.03; 16.7% on ≤18 min versus 26.7% on > 18 min group, P = 0.03). CONCLUSIONS: Kidney donation through DBCD achieves equally successful outcomes as DBD, and could provide a feasible path to graft availability for billions of people who face barriers to organ donation from DBD.

Hypothermic Machine Perfusion in DCD Kidney Transplantation: A Single Center Experience.

INTRODUCTION: Donation after cardiac death (DCD) began in 2011 after the program hosted by the First Affiliated Hospital of Sun Yat-sen University in China. The aim of this study is to report on our experience regarding the method of preserving donated kidneys for DCD kidney transplantation. MATERIAL AND METHODS: A total of 37 donors and 73 primary kidney transplant recipients during the period 2011-2014 in the Urology Center of the First Hospital of Jilin University were enrolled in the study. Recipients were assigned to traditional static cold storage (SCS) group and hypothermic machine perfusion (HMP) group based on the preservation environment of donated kidneys after organ harvest. Clinical data were collected for each group. RESULT: The HMP group had a lower rate of delayed graft function (DGF), better postoperative recovery and kidney function compared with that of SCS group. There is no significant difference in postoperative rejection incidence between the 2 groups. CONCLUSIONS: DCD kidneys stored by hypothermic machine contribute to a lower rate of DGF and promoted the rehabilitation progress.

Analgetic Efficacy of Flurbiprofen Axcetil in Rigid Cystoscopy for Men: a Prospective Study.

Objective: To evaluate the analgesic effect of preprocedural flurbiprofen axetil on rigid cystoscopy-associated pain for men. Methods: Fifty-two men scheduled for cystoscopy were recruited in this study. The effects of oxybuprocaine jelly alone or in combination with preprocedural flurbiprofen axetil, were compared. The pain intensity was assessed using visual analogue scale (VAS) scores during injecting oxybuprocaine jelly into the urethra, during inserting rigid cystoscope into the urethra, during viewing inside the urinary bladder, at the first urination after cystoscopy and at the first urination on the following morning at home. Results: VAS scores with preprocedural flurbiprofen axetil were significantly lower as compared with the control group at the time periods of inserting rigid cystoscope into the urethra, viewing inside the urinary bladder, the first urination after cystoscopy and at the first urination on the following morning at home. No side effects associated with flurbiprofen axetil were observed. Conclusion: Preprocedural flurbiprofen axetil can decrease cystoscopy-associated pain.

Imbalance of different types of CD4(+)Foxp3(+) T cells in renal transplant recipients.

AIMS: To determine the number of CD4(+)CD25(-)Foxp3(+), CD4(+)CD25(+)Foxp3(+) and CD4(+)CXCR5(+)Foxp3(+) T cells in renal transplant recipients that are transplanted stable (TS), or experiencing accelerated rejection (ALR), or acute rejection (AR). METHODS: Renal transplantation was conducted in 28 patients with end-stage renal failure (ESRF). The number of peripheral CD4(+)CD25(-)Foxp3(+), CD4(+)CD25(+)Foxp3(+), or CD4(+)CXCR5(+)Foxp3(+) T cells and the serum levels of interleukin-10 (IL-10) were measured in pre- and post-transplant patients and these results were compared to 10 healthy controls (HC). Correlation between CD4(+)CD25(+)Foxp3(+) and estimated glomerular filtration rate (eGFR), CD4(+)CD25(-)Foxp3(+) and serum creatinine (Cr) levels, or Cr and IL-10 levels in TS patients was also determined. RESULTS: The number of CD4(+)CD25(-)Foxp3(+) T cells was significantly increased in patients with ESRF, as compared to HC. Stratification analysis demonstrated that TS patients contained greater numbers of CD4(+)CD25(+)Foxp3(+) and CD4(+)CXCR5(+)Foxp3(+) T cells, higher levels of serum IL-10, and fewer numbers of CD4(+)CD25(-)Foxp3(+) T cells than ESRF patients. In contrast, ALR and AR patients contained fewer numbers of CD4(+)CD25(+)Foxp3(+) and CD4(+)CXCR5(+)Foxp3(+) T cells, greater numbers of CD4(+)CD25(-)Foxp3(+) T cells, and lower levels of serum IL-10 than ESRF patients. In TS patients, the numbers of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3(+) T cells were positively correlated with eGFR and serum Cr levels, respectively. CONCLUSION: An imbalance of different types of CD4(+)Foxp3(+) T cells might be involved in renal transplant rejection.

The effect of erectile dysfunction on quality of life in male kidney transplant recipients.

UNLABELLED: Objective : To assess how erectile dysfunction (ED) affects the quality of life in male kidney transplant recipients. METHODS: We randomly selected 150 cases of married male kidney transplant recipients. Using the International Index of Erectile Function (IIEF-5) Questionnaire, we divided our research subjects into ED group (n=63) and non-ED group (n = 87). The Short-Form health survey (SF-36) was used to evaluate the quality of life of the recipients. Hamilton Anxiety Rating Scale was used to compare the mental health status of the two groups. RESULTS: No significant differences (P > 0.05) were observed between the ED and non-ED groups in physical functioning (PF), role-physical (RP), or bodily pain (BP). However, the ED group exhibited a lower score (P < 0.05) than the non-ED group in general health (GH), vitality, social functioning (SF), role emotional (RE) and mental health (MH). There were 13 cases in the ED group with anxiety disorders (20.6%), which was clearly more than in the non-ED group (3.4%, P < 0.05). CONCLUSION: Erectile dysfunction is an important factor in the quality of life of male kidney transplant recipients.

Hemorrhagic events associated with tacrolimus: a real-world pharmacovigilance study.

BACKGROUND: Tacrolimus is a potent macrolide immunosuppressant frequently used to prevent graft rejection in organ transplantation. Despite the known side effect of hemorrhage, there are no extensive descriptive series of patients who experience hemorrhage events associated with tacrolimus. We sought to review and describe tacrolimus-related hemorrhage events reported by healthcare professionals to the United States Food and Drug Association Adverse Event Reporting System (FAERS) database. METHODS: The FAERS database (2004q1-2022q4) was retrospectively analyzed to characterize reporting of hemorrhage adverse events (AEs) with tacrolimus. Subgroup analysis was completed on the hemorrhage. RESULTS: A total of 75,310 tacrolimus-associated AEs were identified, of which 1,511 cases met specific inclusion/exclusion criteria with most occurring in the gastrointestinal tract (422 cases, 27.93% of all included cases). Death was reported in 558 patients (36.93% of hemorrhage cases), the most of which occurred in cases of brain hemorrhage (219 cases, 39.25% of death cases). Among definitive organ transplants, renal transplant was the most common indication for tacrolimus (62 cases, 4.10%) followed by bone marrow transplant (44 cases, 2.91%) and liver transplant (30 cases, 1.99%). CONCLUSIONS: This study presents the largest collective description of tacrolimus-related hemorrhage events. We additionally described a number of previously unreported tacrolimus-related hemorrhage events.

Corrigendum: Comprehensive transcriptomic analysis of critical RNA regulation associated with metabolism and prognosis in clear cell renal carcinoma.

[This corrects the article DOI: 10.3389/fcell.2021.709490.].

Identification and validation of the TRHDE-AS1/hsa-miR-449a/ADAMTS5 axis as a novel prognostic biomarker in prostate cancer.

Despite advancements in cancer research, the prognostic implications of competing endogenous RNA (ceRNA) networks in prostate cancer (PCa) remain incompletely understood. This study aimed to elucidate the prognostic relevance of ceRNA networks in PCa, utilizing a comprehensive bioinformatics approach alongside experimental validation. After searching The Cancer Genome Atlas (TCGA) database, RNA sequencing (RNA-Seq) data were extracted to identify differentially expressed RNAs (DERs) between 491 PCa samples and 51 normal prostate tissues, following which a comprehensive bioinformatics strategy was implemented to construct a ceRNA network. An optimal prognostic signature comprising these DERs was then established and validated using TCGA data. In addition, functional validation was performed through RNA pull-down, dual-luciferase reporter assays, quantitative real-time PCR, and western blot analysis conducted in PC-3 and DU145 cell lines, thereby complementing the bioinformatics analysis. A total of 613 DERs, comprising 103 long noncoding RNAs (lncRNAs), 60 microRNAs (miRNAs), and 450 messenger RNAs (mRNAs), were identified and utilized in constructing a ceRNA network, which encompassed 23 lncRNAs, 9 miRNAs, and 52 mRNAs. An optimal prognostic signature was established, including VPS9D1 antisense RNA 1 (VPS9D1-AS1), miR-449a, cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1), targeting protein for Xklp2 (TPX2), solute carrier family 7 member 11 (SLC7A11), copine7 (CPNE7), and maternal embryonic leucine zipper kinase (MELK), yielding area under the curve (AUC) values exceeding 0.8 across training, validation, and entire datasets. Our experiments results revealed an interaction between lncRNA TRHDE antisense RNA 1 (TRHDE-AS1) and miR-449a and that miR-449a could target the ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) mRNA. Knockdown of miR-449a significantly impeded cell proliferation, G1/S transition, migration and invasion, and promoted apoptosis in PC-3 and DU145 cells. Furthermore, knockdown of miR-449a notably downregulated protein expression of CDK4, cyclin D1, N-cadherin and vimentin, while upregulating protein expression of cleaved caspase-3 and E-cadherin. This study contributes to a deeper understanding of the prognostic-linked ceRNA network in PCa, providing fundamental insights that could improve diagnostic and therapeutic approaches for PCa management.

The impact of JC viruria on renal transplant recovery and prognosis.

Postoperative JC viruria is common in kidney transplant recipients, however there remains a dearth of research on perioperative JCV infection in this population. The clinical significance of JCV monitoring in kidney transplant recipients remains unclear. Based on JCV urine monitoring during the perioperative phase, renal transplant recipients who underwent perioperative and postoperative monitoring at our center were categorized into two groups: the perioperative JC virus infection group and the control group consisting of recipients without detectable JCV DNA in plasma or urine during the two-year follow-up period. A comparative analysis of baseline data was initially performed, followed by a 1:1 propensity score matching of 80 cases from each group. Within the first month after transplantation, the JC viruria group exhibited a significant decrease in the incidence of delayed graft function compared to the control group (P = 0.031).Over the two-year postoperative period, the JC viruria group displayed a significantly lower rate of acute rejection (P = 0.027). Notably, the JC viruria group demonstrated higher estimated glomerular filtration rate levels compared to the control group, particularly within the first year post-transplantation. Moreover, recipient and transplant kidney survival rates did not significantly differ between the two groups (P = 0.642). Perioperative JC viruria in kidney transplant recipients may persist beyond the initial two postoperative years. The presence of JCV is associated with lower rates of DGF and acute rejection, indicating a favorable post-transplant recovery. These findings provide novel insights into the importance of postoperative JCV monitoring.

Association between GATM gene polymorphism and progression of chronic kidney disease: a mitochondrial related genome-wide Mendelian randomization study.

Chronic Kidney Disease (CKD) stands as a substantial challenge within the global health landscape. The elevated metabolic demands essential for sustaining normal kidney function have propelled an increasing interest in unraveling the intricate relationship between mitochondrial dysfunction and CKD. However, the authentic causal relationship between these two factors remains to be conclusively elucidated. This study endeavors to address this knowledge gap through the Mendelian Randomization (MR) method. We utilized large-scale QTL datasets (including 31,684 eQTLs samples, 1980 mQTLs samples, and 35,559 pQTLs samples) to precisely identify key genes related to mitochondrial function as exposure factors. Subsequently, we employed GWAS datasets (comprising 480,698 CKD samples and 1,004,040 eGFRcrea samples) as outcome factors. Through a comprehensive multi-level analysis (encompassing expression, methylation, and protein quantification loci), we evaluated the causal impact of these genes on CKD and estimated glomerular filtration rate (eGFR). The integration and validation of diverse genetic data, complemented by the application of co-localization analysis, bi-directional MR analysis, and various MR methods, notably including inverse variance weighted, have collectively strengthened our confidence in the robustness of these findings. Lastly, we validate the outcomes through examination in human RNA sequencing datasets encompassing various subtypes of CKD. This study unveils significant associations between the glycine amidinotransferase (GATM) and CKD, as well as eGFR. Notably, an augmentation in GATM gene and protein expression corresponds to a diminished risk of CKD, whereas distinct methylation patterns imply an increased risk. Furthermore, a discernible reduction in GATM expression is observed across diverse pathological subtypes of CKD, exhibiting a noteworthy positive correlation with GFR. These findings establish a causal relationship between GATM and CKD, thereby highlighting its potential as a therapeutic target. This insight lays the foundation for the development of potential therapeutic interventions for CKD, presenting substantial clinical promise.

LAMB3: Central role and clinical significance in neoplastic and non-neoplastic diseases.

Recently, topics related to targeted gene therapy and diagnosis have become increasingly important in disease research. The progression of many diseases is associated with specific gene signaling pathways. Therefore, the identification of precise gene targets in various diseases is crucial for the development of effective treatments. Laminin subunit beta 3 (LAMB3), a component of laminin 5, functions as an adhesive protein in the extracellular matrix and plays a vital role in regulating cell proliferation, migration, and cell cycle in certain diseases. Previous studies have indicated that LAMB3 is highly expressed in numerous tumorous and non-tumorous conditions, including renal fibrosis; squamous cell carcinoma of the skin, thyroid, lung, pancreatic, ovarian, colorectalr, gastric, breast, cervical, nasopharyngeal, bladder, prostate cancers; and cholangiocarcinoma. Conversely, it is underexpressed in other conditions, such as hepatocellular carcinoma, epidermolysis bullosa, and amelogenesis imperfecta. Consequently, LAMB3 may serve as a molecular diagnostic and therapeutic target for various diseases through its involvement in critical gene signaling pathways. This paper reviews the research status of LAMB3 and its role in related diseases.