Endocrine, metabolic & immune disorders drug targets最新文献

Introduction: Accumulating evidence has multilaterally proved the indispensable contribution of inflammation in mediating various diseases over the last decade, including sepsis, obesity, diabetes, and neurological disorders. This established correlation between inflammation and disease progression has positioned anti-inflammatory intervention as a promising therapeutic strategy for disease prevention and treatment. Naturally occurring flavonoids have emerged as a subject of extensive investigation due to their well-documented anti-inflammatory properties and molecular mechanisms. The current review provides a comprehensive analysis of isoliquiritigenin (ISL), a bioactive flavonoid compound isolated from Glycyrrhiza glabra (licorice), with particular emphasis on its pharmacological activities and molecular mechanisms in modulating inflammation- associated disorders.

Methods: A systematic literature review was executed across the PubMed and Google Scholar electronic databases spanning the period from January 2000 to December 2024, employing the following keyword combination: "isoliquiritigenin" (MeSH) AND "inflammation" (MeSH).

Results: ISL was found to exhibit significant therapeutic potential in mitigating both acute and chronic inflammatory responses. Particular attention was devoted to elucidating ISL's multi-target regulatory mechanisms in acute organ injury models, including neurological, pulmonary, hepatic, and renal systems. Furthermore, the compound's therapeutic effects were found to extend to chronic inflammatory pathologies associated with metabolic and neurodegenerative disorders, notably diabetes mellitus, obesity-related complications, and Alzheimer's disease-associated tissue damage, particularly manifesting in ocular, pulmonary, and cardiovascular systems. Systematic characterization of ISL's molecular targets and associated signalling cascades, like MAPK, JAK/STAT3, Nrf2, and SIRT1 pathways, substantially enhanced our mechanistic understanding of its anti-inflammatory properties.

Discussion: ISL demonstrated extensive protection in many inflammatory models. Its multi-target action implied broad therapeutic applicability. However, despite its excellent anti-inflammatory efficacy and safety profile, further study is required to investigate its effectiveness for clinical translation.

Conclusion: This comprehensive analysis has provided a pharmacological foundation for developing ISL-based therapeutic interventions against inflammation-driven human pathologies.

Introduction: CircRNAs are implicated in various autoimmune diseases, such as Myasthenia Gravis (MG), yet their regulatory mechanisms remain poorly understood. This research investigated the regulatory network of circRNAs, miRNAs, and mRNAs in modulating MG progression.

Materials and methods: Three MG patients (male: female = 1:2) and three healthy controls were enrolled for microarray analysis. The "Limma" package was employed to identify the differentially expressed circRNAs (DECs). Target miRNAs of DECs were predicted via the CircInteractome database, while target genes of miRNAs were predicted utilizing miRWalk, miRTarbase, and TargetScan databases. Cytoscape software was applied to establish the circRNAs-miRNAs-mRNAs network. Thereafter, a dual-luciferase reporter assay was conducted to validate the targeted regulatory relationship between hsa_circ_0062400, hsa_circ_0002397, and miR-338-3p. The expression of NRP1 was measured by qRT-PCR and Western blotting, and the cell viability of Jurkat cells was evaluated via CCK-8 assay. The levels of cytokines (IL-2, IL-6, IFN-γ, TNF-α) after NRP1 knockout were detected by ELISA.

Results: 4 circRNAs, 2 miRNAs, and 11 target genes associated with MG pathogenesis were identified to construct a ceRNA regulatory network. In-vitro assays validated the targeted interactions between hsa_circ_0062400, hsa_circ_0002397, and miR-338-3p. miR-338-3p negatively regulated both protein and mRNA levels of NRP1. Further, silencing hsa_circ_0062400 or hsa_circ_ 0002397 markedly suppressed NRP1 expression and Jurkat cell proliferation, which was reversed by miR-338-3p inhibitor. Moreover, NRP1 affected the levels of cytokines in Jurkat cells.

Discussion: The circRNAs were demonstrated to be closely associated with MG etiology, which was also supported by our current discovery that hsa_circ_0062400 and hsa_circ_0002397 regulated the level of NRP1 by sponging miR-338-3p in MG. However, the roles of hsa_circ_0062400 and hsa_circ_0002397 in MG have been rarely reported, which requires further validation. Limitations of this study included a small, gender-imbalanced sample size for microarray analysis and incomplete verification of the ceRNA network. In addition, functional experiments were limited to Jurkat cells, and more in-vivo validation assays were lacking.

Conclusion: Collectively, the present study revealed MG pathogenesis and also provided potential treatment targets for the disease.

Introduction: Hyperandrogenism in Polycystic ovary syndrome (PCOS) negatively affects health-related quality of life (HRQOL). Anti-androgens may improve both biochemical and patient-related outcomes.

Objectives: To evaluate the impact of combined finasteride and spironolactone on HRQOL in married and unmarried women with PCOS using PCOSQOL-47 and PCOSQOL-42, respectively.

Methods: A total of 263 married and 236 unmarried women with PCOS were enrolled from two tertiary centers. All received finasteride (5mg) and spironolactone (100mg) daily and were followed every four months over a year. HRQOL was assessed using PCOSQOL-47 for married and PCOSQOL-42 for unmarried women, alongside evaluating their biochemical and clinical hyperandrogenism.

Results: After one year, significant reductions were observed in total and free testosterone, dehydroepiandrosterone sulfate, body mass index (BMI), and a decrease in modified Ferriman-Gallwey (mFG) scores. Both groups showed marked HRQOL improvement, greater in unmarried women. In PCOSQOL-47, psychological and emotional domains improved most, while fertility and sexual domains improved least. In PCOSQOL-42, menstrual and fertility domains had the highest gains, while coping improved least. Both groups had a 25% reduction in mFG score and 5% reduction in BMI.

Discussion: This is the first study to evaluate combined finasteride and spironolactone on HRQOL domains in PCOS using PCOSQOL-47 and PCOSQOL-42. Prior studies assessing anti- androgens used other tools, without distinction between married and unmarried women.

Conclusions: Combined finasteride and spironolactone significantly improved all HRQOL scales and reduced hyperandrogenism within the first four months in women with PCOS, supporting its role alongside lifestyle measures.

Introduction: This study aimed to investigate whether Guipi Decoction ameliorates Diabetic Erectile Dysfunction (DMED) in rats by regulating the RhoA/ROCK signaling pathway.

Methods: 36 SD rats were utilized: 6 served as controls, and 30 were induced into DMED models using STZ, confirmed by blood glucose >16.7 mmol/L and a failed erection test. Successfully modeled DMED rats were divided into five groups (n=6/group): Model (saline), Sildenafil (5 mg/kg), and GD Low (0.5 g/mL), Medium (1 g/mL), and High (2 g/mL) dose groups. All groups received corresponding treatments for 4 weeks. Assessments included: body weight, FBG, lipids (TC, TG), erectile function (ICP/MAP ratio), penile NO levels, renal function (BUN, SCr), oxidative stress markers (SOD activity, MDA content), penile histopathology (HE and Masson staining), and mRNA/protein expression levels of RhoA, ROCK1, ROCK2, Caspase-3, p-LIMK2, and p-MYPT1, analyzed via qPCR, Western blot, and IHC.

Results: Compared with controls, DMED model rats showed significantly elevated FBG, TG, TC, BUN, SCr, and MDA levels, as well as upregulated expression of RhoA/ROCK pathway-related proteins and Caspase-3 (all P<0.01). In contrast, their body weight, ICP/MAP ratio, NO levels, SOD activity, and penile smooth muscle/collagen ratio were significantly reduced (all P<0.01). GD treatment exerted significant dose-dependent effects: relative to the Model group, GD increased the ICP/MAP ratio, NO levels, and SOD activity (all P<0.01); decreased FBG, weight loss, TC, TG, BUN, SCr, and MDA levels (P<0.05 or P<0.01); improved erectile function; alleviated penile fibrosis and pathological damage; and downregulated the mRNA and protein expression of RhoA, ROCK1, ROCK2, Caspase-3, p-LIMK2, and p-MYPT1 (P<0.05 or P<0.01). Higher GD doses showed stronger therapeutic efficacy.

Discussion: The therapeutic effects of GD on DMED may be attributed to its ability to inhibit the RhoA/ROCK signaling pathway, which in turn enhances NO bioavailability, mitigates oxidative stress (as reflected by increased SOD activity and decreased MDA content), and suppresses apoptosis (via reduced Caspase-3 expression).

Conclusion: Guipi Decoction effectively improves erectile function and ameliorates penile histopathological lesions in DMED rats, suggesting its potential as a therapeutic agent for DMED through modulation of the RhoA/ROCK signaling pathway.

Introduction: Activity-Based Protein Profiling (ABPP) has been widely applied in the field of drug target identification by virtue of its unique technical advantages. To gain insights into the global research status of this field, this study outlines the research content and progress and predicts future development trends through bibliometric analysis.

Methods: This study adopted a dual-platform data retrieval strategy and conducted visual analysis by combining multidimensional metrics with the use of CiteSpace and VOSviewer.

Results: This study included a total of 5,326 relevant pieces of literature published between 2006 and 2025. The global number of publications showed an overall upward trend, particularly since 2019. The United States and China were the major contributing countries, while the Chinese Academy of Sciences and Benjamin Cravatt were the most active institutions and authors in this field, respectively. Analysis indicated that the Journal of Biological Chemistry made significant contributions to this field, and the keywords "protein" and "expression" had the highest frequency of occurrence.

Discussion: Research in this field focuses on technological innovation and clinical translation and exhibits a trend of interdisciplinary integration with artificial intelligence, spatial omics, and other disciplines. Future priorities will focus on the optimization of probe design, deepening international cooperation, and promoting the application of clinical translation.

Conclusions: This study identifies that the current research focus lies in the development of key pathogenic protein inhibitors, the exploration of drug repurposing strategies, and the target validation of Chinese medicine monomers and natural products. This study provides valuable references for scholars in this field.

Introduction: Acute kidney injury caused by cisplatin (Cis-AKI) is a major limitation in its clinical use, primarily due to the lack of effective therapeutic targets to mitigate nephrotoxicity. Although several molecular pathways are involved in Cis-AKI, identifying reliable and actionable therapeutic targets has been challenging. Through a CRISPR-based genome-wide screening approach, UBE2M was identified as a novel gene involved in cellular survival during cisplatin-induced stress. However, its expression, biological function, and underlying mechanism in Cis-AKI have not been thoroughly investigated. This study aims to identify key therapeutic targets for Cis- AKI and investigate the role of UBE2M in this condition.

Methods: A CRISPR-Cas9 genome-wide screening approach was employed to identify key genes involved in cisplatin-induced renal tubular epithelial cell injury. UBE2M, identified as a critical survival factor, was further investigated using both gain- and loss-of-function strategies to explore its biological function and underlying regulatory mechanisms in the Cis-AKI model.

Results: CRISPR screening identified UBE2M as a key regulator of cellular survival in Cis-AKI, and subsequent validation experiments confirmed its suppression in cisplatin-induced renal injury models. UBE2M overexpression alleviated apoptosis and renal injury by reducing p53 activation. In contrast, UBE2M knockdown exacerbated these effects, leading to increased apoptosis and renal injury.

Discussion: This study reveals that UBE2M is a critical regulator of cisplatin-induced renal tubular epithelial cell injury. By regulating the p53-mediated apoptotic pathway, UBE2M protects against Cis-AKI.

Conclusion: UBE2M could serve as a novel therapeutic target for the prevention and treatment of cisplatin-induced nephrotoxicity.

Introduction: This study aimed to investigate the effects of vitamin D on serological, etiological, and imaging indicators in patients with Coronavirus Disease 2019 (COVID-19), exploring new strategies for its prevention and treatment.

Methods: In this retrospective observational study, 300 COVID-19 patients admitted between January 2022 and March 2023 were enrolled from a public health center and our hospital. Participants were stratified into standard treatment (n=150) and vitamin D supplementation (n=150) groups. Outcomes included clinical recovery and improvements in laboratory, etiological, and imaging findings.

Results: No significant intergroup differences were observed at baseline in demographic or laboratory parameters, including white blood cell (WBC), neutrophil (NEUT), lymphocyte (LYM), interleukin (IL)-6, c-reactive protein (CRP), procalcitonin (PCT), and serum calcium (P > 0.05). Both groups exhibited subnormal 25(OH)D levels initially. After adjusting for age, sex, hypertension, diabetes, and cardiovascular and cerebrovascular diseases, multivariable linear regression analyses indicated that the vitamin D group showed significant increases in 25(OH)D and serum calcium, while the standard treatment group exhibited only a mild increase in 25(OH)D with no significant change in serum calcium after treatment. Both groups showed decreases in WBC, NEUT, IL-6, CRP, and PCT, and increases in LYM after treatment. Compared with the standard group, the vitamin D group had greater improvements in NEUT, LYM, 25(OH)D, and serum calcium (P < 0.05), and more pronounced reductions in IL-6 and CRP (P < 0.05). Symptom resolution and viral clearance times were significantly shorter in the vitamin D group (P < 0.05), and imaging improvements were more evident (P < 0.05).

Conclusion: Supplementation with vitamin D, in addition to standard treatment, improves inflammatory markers, shortens the disease course, and is associated with radiographic improvement in COVID-19 patients.

Introduction: In this study, we examined the clinical relevance of serum Matrix Metalloproteinase- 9 (MMP-9) in patients with Type 2 Diabetes Mellitus (T2DM) presenting with Pulmonary Nodules (PNs) and its association with different nodule densities.

Methods: In total, 240 participants were recruited, including 60 individuals each with T2DM and Ground-Glass Nodules (GGNs; group A), T2DM and Solid Nodules (SNs; group B), T2DM without PNs (group C), and healthy controls (group D). Serum MMP-9 levels were measured using an enzyme-linked immunosorbent assay and analysed for correlations with clinical parameters.

Results: Serum MMP-9 levels were significantly higher in group A than in groups B, C, and D (P < 0.01). MMP-9 levels were higher in group B than in groups C (P < 0.05) and D (P < 0.01), and higher in group C than in group D (P < 0.01). MMP-9 levels were positively correlated with fasting blood glucose (r = 0.277, P < 0.01) and glycated haemoglobin levels (r = 0.344, P < 0.01). Logistic regression analysis identified that MMP-9, HbA1c, and total cholesterol were independently associated with the presence of PNs in T2DM. The area under the receiver operating characteristic curve of MMP-9 was 0.722 for diagnosing PNs and 0.822 for diagnosing GGNs.

Conclusions: Serum MMP-9 levels were significantly elevated in patients with T2DM and PNs, particularly in those with GGNs, suggesting that MMP-9 may have clinical relevance in characterizing PNs in diabetic populations.

Introduction: Osteoporosis (OP) is a major public health burden; however, the role of SERPIN family proteins remains incompletely understood. This study aimed to investigate genetically inferred associations between SERPINs and OP and to explore potential regulatory relationships.

Methods: Genome-wide association study (GWAS) summary statistics were used to perform two sample Mendelian randomization (MR) and summary-data-based Mendelian randomization (SMR) analyses. Primary MR estimates were derived using inverse-variance-weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. Cancellous bone tissue from the greater trochanter of the femur was collected from three patients with OP and three non-osteoporotic controls. qPCR and WB were used to analyze the whole bone homogenate, IHC was used to detect decalcified bone sections, and mediation analysis was used to explore potential regulatory associations.

Results: Among the proteins of the SERPIN family, only SERPING1 had an obvious positive correlation with the risk of osteoporosis (OR = 1.06, P = 0.0012). qPCR, WB, and IHC analyses demonstrated increased SERPING1 mRNA and protein expression in bone tissue from OP patients. Mediation analyses suggested that cg15918732 DNA methylation may serve as an upstream regulatory factor for SERPING1 expression. In addition, the downstream associations also consist of the alteration of immune cell conditions, like the decrease in the quantity of natural killer cells and T cells, and the rise in the level of mononuclear cells, and so forth.

Discussion: These findings provide genetic evidence for the possible role of SERPING1 in OP, which may be achieved through epigenetic regulation and immune pathways. Due to the corresponding characteristics of genetic inference and the small sample size, these results are hypothetical and generative.

Conclusion: This study shows that DNA methylation of cg15918732 may be associated with SERPING1 expression in osteoporosis and immune-related traits. These findings provide new insights into potential epigenetic and immunological pathways in osteoporosis, which may contribute to future mechanistic and translational research.

Introduction: The Objective is to explore the mechanism by which Buzhong Yiqi decoction improves inflammatory damage in autoimmune thyroiditis (AIT) mice based on the Wnt5a/ β-catenin signaling pathway.

Methods: Sixty 8-week-old NOD.H-2h4 mice of SPF grade were selected and randomly divided into six groups: control group, model group, Buzhong Yiqi decoction low, middle, and high-dose groups (4.78, 9.56, 19.12 g·kg-1), and Western medicine group (selenium yeast tablets, 3.033×10-5 g·kg-1), with ten mice in each group. All groups of AIT model mice were allowed to drink a 0.05% sodium iodide solution freely for 8 weeks to establish the AIT model, while the control group drank distilled water freely. ELISA, HE staining, Real-time PCR, and Western Blot were used to assess serum antibodies, thyroid pathology, and expression levels of Wnt5a, β-catenin, PPAR, GSK-3β, IL-1β, and IL-6.

Results: The model group showed increased TgAb and TPOAb levels (P<0.01), lymphocyte infiltration, and altered expression of Wnt5a, β-catenin, PPAR, GSK-3β, IL-1β, and IL-6 (P<0.01). Buzhong Yiqi decoction groups and Western medicine groups significantly reduced these effects, indicating improved thyroid function and inflammation reduction.

Discussion: Buzhong Yiqi decoction modulates the Wnt5a/β-catenin pathway, suggesting a potential therapeutic approach for AIT by reducing inflammation and restoring thyroid function.

Conclusion: Buzhong Yiqi decoction can effectively improve AIT inflammatory damage, and the modulation of the Wnt/β-catenin signaling pathway may be one of its intervention mechanisms.