Cathepsin S (CTSS) in IgA nephropathy: an exploratory study on its role as a potential diagnostic biomarker and therapeutic target.

Introduction: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear. Methods: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning. Results: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS. Conclusion: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.

Renal amyloidogenic leukocyte chemotactic factor 2 combined with IgA nephropathy: A case report.

RATIONALE: Amyloidogenic leukocyte chemotactic factor 2 (ALECT2) was recently considered as a new clinicopathologic type of amyloid, which frequently affects kidney in adults and results in different degrees of renal insufficiency and failure with or without proteinuria. Here, we present a case of combining LECT2-associated renal amyloidosis with immunoglobulin (Ig)A nephropathy. PATIENT CONCERNS: A 71-year-old Chinese man presented with edema of both lower extremities. DIAGNOSES: There was pale eosinophilic material strongly positive for the Congo red stain in interstitium with demonstrated apple green birefringence under polarized light. Immunofluorescent stain was positive for IgA deposits (4+), IgG deposits (2+), C3 deposits (3+) within the mesangium and capillary wall. Immunohistochemistry was positive for κ (+), λ (2+) in mesangial area, and LECT2 (2+) in the interstitium. On electron microscopy, there were electron-dense deposits within mesangial area and subendothelial and randomly orientated and nonbranching fibrils 10 nm in size found in the interstitium areas. Liquid chromatography tandem mass spectrometry was performed on peptides extracted from Congo red-positive, microdissected areas of the paraffin-embedded kidney specimen. LECT 2-associated renal amyloidosis with IgA nephropathy was pathologically confirmed by renal biopsy. INTERVENTIONS: Steroids (60 mg/d) were used to treat IgA nephropathy daily. Antihypertensive treatment was switched to an angiotensin-converting enzyme inhibitor. OUTCOMES: One year after diagnosis, creatine remained stable in the normal range, and 24-hour proteinuria decreased to 2.9 g. LESSONS: To date, ALECT2 has still not been comprehensively investigated. The findings of this research provide insights for concurrent IgA nephropathy with ALECT2.

The Effects of Resistant Starch on Biomarkers of Inflammation and Oxidative Stress: A Systematic Review and Meta-Analysis.

The aim of this systematic review and meta-analysis was to investigate the effects of resistant starch (RS) on inflammation and oxidative stress related indicators. PubMed, Embase and The Cochrane library were systematically searched to find randomized controlled trials (RCTs) of RS intervention up to February 2020. We used from the effect size, as estimated by the standardized mean difference (SMD) with 95% confidence intervals (95%CI) to perform the random method meta-analysis, with P value ≦0.05 as statistically significant. The 16 included trials with 17 effect sizes included a total of 739 participants in this paper. The intervention duration was from 2 weeks to 3 months. The analysis indicated that RS decreases the levels of tumor necrosis factor-α (TNF-α) (SMD = -0.711; 95%CI: -1.227, -0.194; P = 0.007) and interleukin 6 (IL-6) (SMD = -0.609; 95%CI: -0.924, -0.294; P < 0.001), increases total antioxidant capacity (TAC) (SMD = 2.543, 95% CI: 0.069: 5.017, P = 0.044). No significant effects on C-reactive protein (CRP) (SMD = -0.583; 95%CI: -1.270, 0.104; P = 0.096), superoxide dismutase (SOD) (SMD = 0.091; 95%CI: -0.156, 0.338; P = 0.471), and malondialdehyde (MDA) (SMD = -0.320; 95%CI: -0.907, 0.266; P = 0.285). Subgroup analysis shown that CRP level significant reduced in subjects from the east (SMD = -1.501; 95%CI: -2.662, -0.340; P = 0.011) or suffering from diseases (SMD: -1.057; 95%CI: -1.999, -0.115; P = 0.028).Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.2019284.

miR-155-5p upregulation ameliorates myocardial insulin resistance via mTOR signaling in chronic alcohol drinking rats.

BACKGROUND: Chronic alcohol intake is associated with an increased risk of alcoholic cardiomyopathy, which may present with pathological changes such as myocardial insulin resistance, leading to ventricular dilation and cardiac dysfunction. Although a correlation between microRNA-155 (miR-155) and insulin signaling has been identified, the underlying mechanism has not been elucidated to date. The purpose of the study was to determine whether overexpression of miR-155-5p in vivo could ameliorate chronic alcohol-induced myocardial insulin resistance and cardiac dysfunction. MATERIAL AND METHODS: Wistar rats were fed with either alcohol or water for 20 weeks to establish chronic alcohol intakes model. Then the alcohol group were divided into three groups: model group, miRNA-155 group and AAV-NC group. Rats undergoing alcohol treatment were injected with AAV-miRNA-155 (adeno-associated virus 9) or its negative control AAV-NC, respectively. Gene expression was determined by real-time PCR, and protein expression was determined by western blot. Echocardiography was performed to assess terminal cardiac function. Insulin responsiveness was determined through the quantification of phosphorylated insulin receptor substrate 1 (ser 307) and phosphorylated insulin receptor (Tyr 1185) levels. RESULTS: We found that cardiac function was attenuated in chronic alcohol intake rats, with an activated mammalian target of rapamycin (mTOR) signaling pathway, accompanied by an increase in p-IRS1(ser 307) and a decrease in p-IR (Tyr 1185) level in myocardial tissue. Also, alcohol drinking significantly up-regulated miR-155-5p level and its overexpression decreased p-IRS1 (ser 307) and increased p-IR (Tyr 1185) levels, and meanwhile inhibited the mTOR signaling pathway. CONCLUSION: miR-155-5p upregulation ameliorates myocardial insulin resistance via the mTOR signaling in chronic alcohol drinking rats. We propose that miR-155 may serve as a novel potential therapeutic target for alcoholic heart disease.

Morphological structure of the infraorbital canal using three-dimensional reconstruction.

Our study aim was to evaluate the initial position accurately and the direction of infraorbital canal approximately by analyzing the parameters of infraorbital canal. This study was based on 64-slice computed tomographic multiple planar reconstruction technique and can improve the success rate of infraorbital nerve blockade. The following observations and measurements were carried out in 224 normal infraorbital canals (112 people): the length, angle, and adjoined relations of initial infraorbital canal, to reveal the anatomic characteristics of the canals and to compare the difference between left and right or male and female. Six indicators were measured: (1) the length of initial infraorbital canal; (2) the distance between skin and the first obvious turn of infraorbital canal along the direction of initial infraorbital canal (the depth of puncture); (3) the vertical distance between infraorbital canal and nasal septum; (4) the vertical distance between infraorbital canal and infraorbital rim; (5) the angle between the infraorbital canal and the Frankfort plane; and (6) the angle between the infraorbital canal and the sagittal plane. The difference was statistically significant between 2 sides on the depth of puncture. For other values, the differences between left and right and between women and men were of no statistical significance.

Measurement of jugular foramen to the adjacent structures with thin-section computed tomographic image.

This study aimed to measure the bilateral internal aperture of the jugular foramen to internal acoustic pore, bilateral external aperture of the jugular foramen to occipital condyle, and atlas transverse process, so as to provide imaging evidence for different ways of clinical operation and smoothen the operation by protecting important nerves and blood vessels in this area. We scan 120 volunteers' skulls on computed tomography who had no skull base lesions. High-resolution spiral computed tomography multiplane reformation is used to rebuild the three-dimensional reconstruction of the brain. The difference of our study from others is that we select some specific sections to make the measurement more accurately.