Identifying novel potential drug targets for endometriosis via plasma proteome screening.

Background: Endometriosis (EM) is a chronic painful condition that predominantly affects women of reproductive age. Currently, surgery or medication can only provide limited symptom relief. This study used a comprehensive genetic analytical approach to explore potential drug targets for EM in the plasma proteome. Methods: In this study, 2,923 plasma proteins were selected as exposure and EM as outcome for two-sample Mendelian randomization (MR) analyses. The plasma proteomic data were derived from the UK Biobank Pharmaceutical Proteomics Project (UKB-PPP), while the EM dataset from the FinnGen consortium R10 release data. Several sensitivity analyses were performed, including summary-data-based MR (SMR) analyses, heterogeneity in dependent instruments (HEIDI) test, reverse MR analyses, steiger detection test, and bayesian co-localization analyses. Furthermore, proteome-wide association study (PWAS) and single-cell transcriptomic analyses were also conducted to validate the findings. Results: Six significant (p < 3.06 × 10-5) plasma protein-EM pairs were identified by MR analyses. These included EPHB4 (OR = 1.40, 95% CI: 1.20 - 1.63), FSHB (OR = 3.91, 95% CI: 3.13 - 4.87), RSPO3 (OR = 1.60, 95% CI: 1.38 - 1.86), SEZ6L2 (OR = 1.44, 95% CI: 1.23 - 1.68) and WASHC3 (OR = 2.00, 95% CI: 1.54 - 2.59) were identified as risk factors, whereas KDR (OR = 0.80, 95% CI: 0.75 - 0.90) was found to be a protective factor. All six plasma proteins passed the SMR test (P < 8.33 × 10-3), but only four plasma proteins passed the HEIDI heterogeneity test (PHEIDI > 0.05), namely FSHB, RSPO3, SEZ6L2 and EPHB4. These four proteins showed strong evidence of co-localization (PPH4 > 0.7). In particular, RSPO3 and EPHB4 were replicated in the validated PWAS. Single-cell analyses revealed high expression of SEZ6L2 and EPHB4 in stromal and epithelial cells within EM lesions, while RSPO3 exhibited elevated expression in stromal cells and fibroblasts. Conclusion: Our study identified FSHB, RSPO3, SEZ6L2, and EPHB4 as potential drug targets for EM and highlighted the critical role of stromal and epithelial cells in disease development. These findings provide new insights into the diagnosis and treatment of EM.

Investigating the causal relationship and potential shared diagnostic genes between primary biliary cholangitis and systemic lupus erythematosus using bidirectional Mendelian randomization and transcriptomic analyses.

Background: The co-occurrence of primary biliary cholangitis (PBC) and systemic lupus erythematosus (SLE) has been consistently reported in observational studies. Nevertheless, the underlying causal correlation between these two conditions still needs to be established. Methods: We performed a bidirectional two-sample Mendelian randomization (MR) study to assess their causal association. Five MR analysis methods were utilized for causal inference, with inverse-variance weighted (IVW) selected as the primary method. The Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and the IVW Radial method were applied to exclude outlying SNPs. To assess the robustness of the MR results, five sensitivity analyses were carried out. Multivariable MR (MVMR) analysis was also employed to evaluate the effect of possible confounders. In addition, we integrated transcriptomic data from PBC and SLE, employing Weighted Gene Co-expression Network Analysis (WGCNA) to explore shared genes between the two diseases. Then, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment methods to perform on the shared genes. The Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm was utilized to identify potential shared diagnostic genes. Finally, we verified the potential shared diagnostic genes in peripheral blood mononuclear cells (PBMCs)-specific cell populations of SLE patients by single-cell analysis. Results: Our MR study provided evidence that PBC had a causal relationship with SLE (IVW, OR: 1.347, 95% CI: 1.276 - 1.422, P < 0.001) after removing outliers (MR-PRESSO, rs35464393, rs3771317; IVW Radial, rs11065987, rs12924729, rs3745516). Conversely, SLE also had a causal association with PBC (IVW, OR: 1.225, 95% CI: 1.141 - 1.315, P < 0.001) after outlier correction (MR-PRESSO, rs11065987, rs3763295, rs7774434; IVW Radial, rs2297067). Sensitivity analyses confirmed the robustness of the MR findings. MVMR analysis indicated that body mass index (BMI), smoking and drinking were not confounding factors. Moreover, bioinformatic analysis identified PARP9, ABCA1, CEACAM1, and DDX60L as promising diagnostic biomarkers for PBC and SLE. These four genes are highly expressed in CD14+ monocytes in PBMCs of SLE patients and potentially associated with innate immune responses and immune activation. Conclusion: Our study confirmed the bidirectional causal relationship between PBC and SLE and identified PARP9, ABCA1, CEACAM1, and DDX60L genes as the most potentially shared diagnostic genes between the two diseases, providing insights for the exploration of the underlying mechanisms of these disorders.

TRPA1 promotes cisplatin-induced acute kidney injury via regulating the endoplasmic reticulum stress-mitochondrial damage.

BACKGROUND: Cisplatin is a widely used and effective chemotherapeutic agent against cancer. However, nephrotoxicity is one of the most common side effects of cisplatin, and it can proceed to acute kidney injury (AKI). Studies have reported that activation of transient receptor potential ankyrin-1 (TRPA1) mediates cisplatin-induced renal tubular cytotoxic injury. The aim of this study was to investigate the mechanism of TRPA1 in promoting cisplatin-induced AKI through modulation of the endoplasmic reticulum stress (ERS)-mitochondrial damage. METHODS: A cisplatin-induced HK-2 cell model in vitro and mouse model in vivo were established. The mechanism of TRPA1 promotes AKI was elucidated by H&E staining, TUNEL staining, transmission electron microscope (TEM), immunofluorescence, CCK-8 viability assays, flow cytometry, Western blotting, JC-1 assay, and enzyme linked immunosorbent assay (ELISA). RESULT: In vivo and in vitro, HC-030031 reduced cisplatin-induced Scr and BUN level elevations; improved cisplatin-induced renal tissue injury, apoptosis, and mitochondrial dysfunction; elevated the reduced ERS-associated proteins glucose-regulated protein 78 (GRP78), glucose-regulated protein 75 (GRP75), and C/EBP homologous protein (CHOP) levels induced by cisplatin; reduced the elevated optic atrophy 1 (OPA1), mito-fusion 1 (MFN1), and mito-fusion 2 (MFN2) protein levels, and elevated phospho-dynamin-related protein 1 (p-DRP1) and mitochondrial fission factor (MFF) protein levels. HC-030031 also reduced the mitochondria-associated endoplasmic reticulum membrane (MAM) structure. In addition, TRPA1 agonists also decreased cell proliferation, increased apoptosis, and triggered mitochondrial dysfunction and calcium overload in HK-2 cells via modulation of MAM. ERS inhibitors and GRP75 inhibitors reversed these changes caused by TRPA1 agonists. CONCLUSION: Our findings suggest that TRPA1 enhances cisplatin-induced AKI via modulation of ERS and mitochondrial damage.

Dipeptidyl-peptidase-4 inhibitors have anti-inflammatory effects in patients with type 2 diabetes.

AIMS: Systematic low-grade inflammation is considered to be an important factor leading to the development of T2DM and the progression of its complications. Dipeptidyl-peptidase-4 (DPP-4) inhibitors show potential anti-inflammatory effects in patients with T2DM. This meta-analysis aimed to evaluate the anti-inflammatory effects of DPP-4 inhibitors in patients with T2DM. METHODS: A comprehensive search was performed in PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials to identify randomized controlled trials that assess the anti-inflammatory effects of DPP-4 inhibitors. Quantitative data analysis was conducted by a random-effects model. Sensitivity analyses were conducted to determine the robustness of the pooled results. RESULTS: Twenty-two studies with 1595 patients with T2DM were included. Pooled results showed that DPP-4 inhibitor therapy was significantly associated with the reduction of C-reactive protein (CRP) (SMD, - 0.56, p < 0.01), TNF-α (SMD, - 1.69, p < 0.01), IL-6 (SMD, - 0.67, p < 0.01), and IL-1ß (WMD, - 8.21 pg/ml, p < 0.01). Leave-one-out meta-analysis showed no significant change in the pooled results of CRP and TNF-α. CONCLUSION: This meta-analysis demonstrated that DPP-4 inhibitors can significantly attenuate low-grade inflammatory state in patients with T2DM. In addition to improving glycemic control, DDP-4 inhibitors might offer extra therapeutic value by controlling inflammation.

Biopsy-proven granulomatous interstitial nephritis associated with vancomycin in an adult patient: a case report.

Acute kidney injury (AKI) caused by vancomycin mainly manifests as acute interstitial nephritis or acute tubular necrosis. Here, the rare case of a 71-year-old female patient with no history of kidney disease, who was diagnosed with granulomatous interstitial nephritis associated with vancomycin, is reported. The patient had been treated with vancomycin for over a month for an abscess in her right thigh. She presented to the emergency department with a history of fever, scattered rash, oliguria and elevated serum creatinine for >10 days. After hospitalization, the vancomycin trough concentration was confirmed to be >50 µg/ml. The patient received furosemide and continuous renal replacement therapy for AKI, teicoplanin and piperacillin/tazobactam for pulmonary infection, and urapidil, sodium nitroprusside and nifedipine for elevated blood pressure. Percutaneous ultrasound-guided kidney biopsy was performed. Light microscopy revealed granuloma formation, and diffuse infiltration of lymphocytes, monocytes, eosinophils, and some multinucleated giant cells. Finally, the patient was diagnosed with vancomycin-induced granulomatous interstitial nephritis and was treated with high-flux haemodialysis and 16 mg oral methylprednisolone, daily, for 3 weeks, which contributed to a significant recovery of renal function. This case suggests the need for regular vancomycin concentration testing during treatment. When AKI due to vancomycin occurs, a renal biopsy may be performed to help diagnose and treat the condition.

A case report: Catatonic symptoms secondary to systemic lupus erythematosus with multiple infections: neuropsychiatric or "mimickers?"

RATIONALE: Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) manifestations. However, typical symptoms of catatonia are uncommon. Neuropsychiatric SLE or its "mimickers" may cause NP symptoms, making differential diagnosis a significant challenge in clinical practice. PATIENT CONCERNS: A 68-year-old female with SLE was hospitalized for edema, lung infection, and recurrent fungal mouth ulcers after multiple courses of cortisol and immunosuppressive therapy. Five days after admission, stupor, immobility, mutism, and rigidity were observed. DIAGNOSIS: "Mimickers": catatonic disorder due to a general medical condition. INTERVENTION: Initially, relevant laboratory tests, imaging studies, and the disease activity index score were performed. A survey of the causes of the disease was conducted among the patient's relatives. Subsequently, we discontinued moxifloxacin, corticosteroids, fluconazole, and other medications and inserted a gastric tube for nutritional support. During this process, traditional Chinese medicine and acupuncture have been utilized. OUTCOMES: After 3 days, the patient recovered and only complained of fatigue. CONCLUSION: When SLE presents with NP symptoms, it is essential to make a correct diagnosis in order to guide appropriate treatment by actively searching for inducers and clinical, laboratory, and neuroradiological characteristics that can aid in the differential diagnosis. When treatment options are limited, it can be beneficial to try a variety of combination strategies, such as traditional Chinese medicine and acupuncture.

Effects of vitamin D on inflammatory state in patients with chronic kidney disease: A controversial issue.

BACKGROUND: The anti-inflammatory effect of vitamin D in patients with chronic kidney disease (CKD) remains controversial. This study aimed to conduct a meta-analysis of randomized controlled trials to assess the anti-inflammatory effects of vitamin D in patients with CKD. METHODS: We searched Embase, Science Citation Index, Medline, Cochrane Central Register of Controlled Trials, and Clinical Trial Registries for randomized controlled trials that comparing vitamin D with control groups for inflammatory markers in patients with CKD. Subgroup analysis was performed based on treatment duration (short-term treatment, long-term treatment), type of patients (predialysis CKD, dialysis, kidney transplant), 25(OH)D levels (25(OH)D deficiency or normal 25(OH)D), and methods of C-reactive protein (CRP) test (standard CRP test or high-sensitivity CRP [hs-CRP] test). RESULTS: Eighteen trials with 1834 patients were included in the present study. There were no significant differences between the vitamin D group and control group for CRP (WMD, -0.3 mg/L; 95% CI, -0.81 to 0.22, p = 0.26, I2  = 62%), interleukin-6 (IL-6) (WMD, -1.07 pg/ml; 95% CI, -2.44 to 0.30, p = 0.12, I2  = 52%), and tumor necrosis factor-α (TNF-α) (WMD, -0.00 pg/ml; 95% CI, -0.36 to 0.35, p = 0.99, I2  = 0%) in patients with CKD. Subgroup analysis showed vitamin D can improve hs-CRP, but not CRP. The rest of subgroups showed that no significant differences were observed between the vitamin D group and control group based on 25(OH)D levels, treatment duration, and predialysis CKD or dialysis patients. CONCLUSION: This meta-analysis demonstrates that vitamin D supplementation does not have anti-inflammatory effects in CKD patients. Well-designed randomized controlled trials with large samples are required to confirm this conclusion. It is still needed to find an effective treatment for inflammatory state in CKD.

Emodin-Mediated Treatment of Acute Kidney Injury.

Acute kidney injury (AKI), a common condition associated with a high mortality rate, is characterized by declined glomerular filtration rate, retention of nitrogen products, and disturbances in balance of water, electrolyte, and acid-base. Up to date, there is no effective treatment for AKI. Despite the continuous improvement in blood purification techniques, a considerable proportion of patients with AKI still progress to end-stage renal disease. These patients with advanced stage of end-stage renal disease will require long-term renal replacement therapy, which places a heavy burden on the family and the society. In recent years, the use of traditional Chinese medicine (TCM) in AKI management has been gradually increasing. Clinical evidence has demonstrated that three-month treatment with TCM produced better clinical outcomes in terms of clinical effectiveness rate and improvement in renal function (serum creatinine, neutrophil gelatinase-associated lipocalin, and cystatin C) compared with Western medicine. Rhubarb is a commonly used herb in TCM for the treatment of AKI. The main active component of rhubarb is emodin, which was first recorded in Shennong's Classic of Materia Medica. It has been shown that emodin has a variety of pharmacological activities including antibacterial, anti-inflammatory, antiulcer, and immunosuppressive effects. Emodin has been found to be effective against renal fibrosis and has been widely studied for its effects on kidney diseases such as diabetic nephropathy, renal fibrosis, and AKI. Moreover, promising results have been obtained from these studies. In this study, the results obtained from research on the use of emodin for AKI treatment has been reviewed.

TRPA1 promotes cisplatin-induced nephrotoxicity through inflammation mediated by the MAPK/NF-κB signaling pathway.

BACKGROUND: The nephrotoxicity induced by cisplatin (DDP) has been a severe obstacle for its clinical use in anticancer treatment. The apoptosis and inflammation induced by DDP are the main causes of the nephrotoxicity. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation ligand-gated channel that is involved in the inflammation progress. METHODS: The apoptosis, inflammation, MAPK/NF-κB signaling pathway, and TRPA1 expression were assessed after HEK293 cells had been induced by DDP, and the role of TRPA1 in apoptosis and inflammation of DDP-induced HEK293 cells treated with TRPA1 antagonist HC-030031 was also evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), flow cytometry, and western blot assays. RESULTS: The cell viability was reduced by DDP in both a time-dependent and dose-dependent manner with a minimal cytotoxic concentration of 10 µM. Moreover, DDP induced an enhancement of the apoptosis and inflammation in a dose-dependent manner, as indicated by the increase of the relative protein level of cleaved-caspase3 (cleaved-cas3), the cleavage product of caspase-3 substrate poly-ADP-ribose polymerase (cleaved-PARP) and inducible nitric oxide synthase (iNOS), and the messenger RNA (mRNA) expression level of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ). Additionally, DDP treatment increased the protein phosphorylation expression of IKKß, JNK, ERK, and p38 in a dose-dependent manner, which was antagonized by the treatment of NF-κB-specific inhibitor BAY 11-7082 and pan-MAPK inhibitor U0126. It was also found that DDP upregulated the expression of TRPA1 at both the mRNA and protein levels in a dose-dependent manner. Besides, block of TRPA1 with HC-030031 relieved the apoptosis, diminished the level of IL-1ß, IL-6, TNF-α, and INF-γ, reduced the level of cleaved-cas3, cleaved-PARP, and iNOS, decreased the p-IKKß, p-JNK, p-ERK, and p-p38 expression, and enhanced the expression of IκBα. CONCLUSIONS: Taken together, these results indicate that TRPA1 regulates DDP-induced nephrotoxicity via inflammation mediated by the MAPK/NF-κB signaling pathway in HEK293 cells.

Madelung's disease with alcoholic liver disease and acute kidney injury: A case report.

BACKGROUND: Madelung's disease (MD) is a rare disorder of lipid metabolism, characterized by the growth of unencapsulated masses of adipose tissue symmetrically deposited around the neck, shoulders, or other sites around the body. Its pathological mechanism is not yet known. One of the most common comorbidities in MD patients is liver disease, especially chronic alcoholic liver disease (CALD); however, no reports exist of acute kidney injury (AKI) with MD. CASE SUMMARY: We report a 60-year-old man who presented with complaint of edema in the lower limbs that had persisted for 3 d. Physical examination showed subcutaneous masses around the neck, and history-taking revealed the masses to have been present for 2 years and long-term heavy drinking. Considering the clinical symptoms, along with various laboratory test results and imaging characteristics, a diagnosis was made of MD with acute exacerbation of CALD and AKI. The patient was treated with liver function protection and traditional Chinese medicine, without surgical intervention. He was advised to quit drinking. After 10 d, the edema had subsided, renal function indicators returned to normal, liver function significantly improved, and size of subcutaneous masses remained stable. CONCLUSION: In MD, concomitant liver or kidney complications are possible and monitoring of liver and kidney functions can be beneficial.