Endocrine, metabolic & immune disorders drug targets最新文献

Background: Hirschsprung disease (HD) is a congenital disorder associated with specific missense mutations in the RET proto-oncogene. This study aimed to demonstrate the incidence of Hirschsprung disease and its clinical and pathological aspects in an Iraqi pediatric cohort from a major referral hospital in Baghdad.

Methods: A retrospective analysis was conducted over a ten-year period, reviewing the clinical and surgical records of patients diagnosed with Hirschsprung disease. Pathological sections were re-evaluated, and patient medical histories, prior surgeries, and other relevant clinical data were confirmed.

Results: A total of 106 cases of Hirschsprung disease were identified. The mean age at diagnosis was 2.4 ± 3.0 years, with 40.6% of cases diagnosed within the first year of life. The male-to-female ratio was 2.6:1. The most commonly affected anatomical sites were the colon (35.8%) and rectum (23.6%). Pathological evaluation revealed the absence of ganglion cells in 57.5% of cases. Rectal biopsy was the most frequently performed diagnostic procedure (64.2%), and colon resection was required in 35.8% of cases. A significant association was found between disease presence and anatomical site involvement (P = 0.010) and surgical intervention (P = 0.046).

Conclusion: The study highlights a male predominance in Hirschsprung disease, with the majority of cases diagnosed within the first year of life. The rectum and colon were the most commonly affected sites. Significant associations were observed between disease presence and anatomical site involvement, as well as surgical interventions, emphasizing the importance of early diagnosis and appropriate management strategies.

Introduction: Sepsis is a Systemic Inflammatory Response (SIR) caused by invading pathogens. We aimed to characterize infiltrating cells in sepsis and provide novel insight for the treatment of sepsis.

Materials and methods: Whole-blood scRNA-seq samples from four septic patients and five healthy subjects were collected from the Gene Expression Omnibus (GEO) database (GSE175453). The Seurat R package was used for quality control and cell clustering by scRNA- seq analysis. Gene set enrichment analysis (GSEA) was performed using the clusterProfiler R package for pathway enrichment analysis. Then, the SCENIC analysis was used to identify key transcriptional regulons, and the CellChat R package was used for cell communication analysis.

Results: We mainly obtained 9 cell clusters, including myeloid cells, T cells, dendritic cells, NKT cells, B cells, plasma B cells, megakaryocytes, mast cells and erythrocytes. Notably, myeloid cells, erythrocytes and mast cells had a higher proportion in sepsis patients. Activated IL-17 and p53 pathways supported anti-infection response in myeloid cells, and JUNB and SPI1 mediated multiple inflammatory pathways, including TNF signaling and neutrophil activation. We also identified that the cell interaction mode of myeloid cells, such as MPZL1-MPZL1 and FASL-FAS, may serve as a potential target for an anti-inflammatory response in sepsis treatment.

Discussions: The scRNA-seq analysis revealed pro-inflammatory pathways (IL-17, p53) and key regulators (JUNB, SPI1) in septic myeloid cells. Receptor genes (MPZL1 and FAS) mediated cell communication, offering potential biomarkers and targets for sepsis therapy.

Conclusion: We characterized the pro-inflammatory immune response pathways, transcriptional regulon and cell interaction modes of myeloid cells in the development of sepsis.

Introduction: PCOS is a common endocrine disorder in women of reproductive age, with granulosa cells playing a key role in its development. This study aims to identify shared differentially expressed genes (DEG) in granulosa cells and blood from PCOS patients, offering potential biomarkers and therapeutic targets.

Methods: Transcriptomic data were obtained from the Gene Expression Omnibus (GEO) database: GSE95728 (granulosa cells; 7 PCOS, 7 controls) and two blood-based datasets, GSE85932 and GSE54248 (12 PCOS, 12 controls). In silico tools were employed to identify DEG, hub genes, and protein-protein interactions and to explore predicted drug targets.

Results: DEG analysis revealed that Vanin-2 (VNN2) and Interleukin-1 receptor type 2 (IL1R2) were consistently dysregulated in PCOS patients. Dysferlin (DYSF), Carbonic Anhydrase 4 (CA4), and Solute Carrier Family 2 Member 14 (SLC2A14) were differentially expressed between the blood datasets, while Aquaporin 9 (AQP9), C-X-C Motif Chemokine Receptor 1 (CXCR1), and Annexin A3 (ANXA3) were dysregulated in GSE95728 (granulosa cells) and GSE54248 (blood). Functional enrichment highlighted immune and metabolic pathways. Protein-protein interaction analysis identified AQP9 as a hub gene. Drug prediction analysis suggested that IL1R2 could be targeted by anakinra, while VNN2 was predicted to interact with pantothenic acid.

Discussion: The dysregulation of VNN2 and IL1R2 across tissue types suggests their involvement in immune-inflammatory processes in PCOS. The expression of AQP9 and other metabolism-related genes indicates possible immune-metabolic crosstalk, aligning with known PCOS pathophysiology.

Conclusion: VNN2 and IL1R2 show potential as biomarkers or therapeutic targets in PCOS. Further validation is needed to confirm their clinical significance and roles.

Background: Acromegaly associated with Morris syndrome has never been reported in the literature.

Case presentation: We present the case of a 49-year-old woman with Morris syndrome, diagnosed in 1992, who has undergone gonadectomy and hormone replacement therapy for about 15 years. The patient was referred to our centre for the clinical suspicion of acromegaly in June 2022, for the enlargement of the acral extremities and the development of prognathism in the last 10 years. The patient underwent mandibular reduction surgery and removal of a tubular adenoma of the colon in 2010. In June 2021, the patient performed random GH, IGF-I, and prolactin (PRL) dosages that confirmed the diagnosis of acromegaly. A contrasted pituitary MRI showed the presence of an 8 mm intrasellar pituitary adenoma. Therefore, a transsphenoidal resection of the pituitary tumor was conducted in September 2021. The histological examination proved the diagnosis of somatotropinoma. At the last follow-up at our center in June 2024, the patient presented in a fair general clinical condition, with recovery of related acromegaly symptoms, normalized IGF-I levels, and a negative pituitary MRI for signs of somatotropinoma recurrence.

Conclusion: Our clinical case describes for the first time the association between Morris syndrome and acromegaly. Due to the singularity of this case, we decided to conduct more in-depth genetic analyses through a clinical exome study and CGH Array evaluation, which, however, did not lead to the discovery of a genetic association between the two conditions. Although this condition is rare, further genetic studies are needed to demonstrate a genetic association between these two conditions.

Introduction: Autoimmune thyroiditis (AIT), a prevalent autoimmune disorder, can severely impair patients' quality of life when progressing to hypothyroidism. This investigation seeks to systematically evaluate the therapeutic efficacy of Buzhong Yiqi Decoction (BZYQ) against iodine-induced AIT while elucidating its underlying molecular mechanisms.

Methods: NOD.H-2^h4 mice received daily 0.05% sodium iodide gavage for 8 weeks to induce AIT. Thyroid histopathology was evaluated by HE staining. Serum autoantibody levels and lactate concentrations were measured. Western blotting analyzed PTEN, p-PI3K/PI3K, p-AKT/AKT, GLUT1, HK2, PKM2, and LDHA protein expression in thyroid tissues. Immunofluorescence staining localized the expression of HK2 and RORγt in thyroid sections. Flow cytometry quantified the proportion of Th17 cells within splenic lymphocytes.

Results: BZYQ reduced thyroid structural damage and lymphocytic infiltration in AIT mice, accompanied by significant reductions in serum TGAb and TPOAb levels. Notably, BZYQ modulated glycolysis to decrease lactate levels and the proportion of Th17 cells. Mechanistically, BZYQ upregulated PTEN expression to suppress downstream p-PI3K, p-AKT, GLUT1, HK2, PKM2, and LDHA expression, thereby achieving regulation of immunometabolic pathways.

Discussion: This study provides experimental evidence for broadening the modern clinical applications of this classical formula. However, the related mechanisms still require further rigorous clinical studies for validation.

Conclusion: BZYQ modulates Th17 differentiation via the PTEN/AKT-immunometabolic axis in AIT.

Introduction: Obesity, a global health crisis, necessitates innovative therapeutic strategies. Traditional Chinese Medicine (TCM), including Erchen Decoction (ECD), offers potential benefits; however, the molecular mechanisms underlying ECD's anti-obesity effects, particularly on lipid metabolism, remain unclear. This study investigates the mechanism by which ECD improves lipid metabolism through the AMPK/SIRT1/PGC-1α signaling pathway.

Methods: AML-12 hepatocytes were cultured and divided into Control, Model (palmitic acid-induced lipid deposition), and treatment groups (ECD serum: 2%, 4%, 8%; orlistat: 10 μM). Cell viability, lipid accumulation, and triglyceride (TG) content were measured. Key lipid metabolism genes (p-AMPK/AMPK, SIRT1, PPARα, PGC-1α, Nrf2, TFAM) were evaluated using RT-qPCR, Western Blot, and immunofluorescence. Network pharmacology analysis identified ECD's targets and pathways.

Results: The Model group showed increased lipid droplets and TG content, with reduced AMPK, SIRT1, PPARα, PGC-1α, Nrf2, and TFAM expression compared to Control. ECD treatment significantly decreased lipid droplets and TG content (at all doses), with the 4% dose being the most effective. ECD up-regulated all tested genes, confirmed by immunofluorescence (p-AMPK, SIRT1, PGC-1α). Network pharmacology highlighted the overlap between ECD and obesity pathways, with a particular emphasis on lipid metabolism.

Discussion: ECD improves lipid metabolism in AML-12 hepatocytes by activating the AMPK/ SIRT1/PGC-1α pathway, consistent with prior research. The upregulation of Nrf2 and TFAM indicates enhanced mitochondrial function and resistance to oxidative stress. Limitations include the use of in vitro models; future studies should focus on clinical translation and dosage optimization. Conclusion: ECD regulates lipid metabolism via the AMPK/SIRT1/PGC-1α pathway, providing a scientific basis for its clinical use in obesity-related diseases. This study highlights ECD as a promising therapeutic strategy for improving lipid metabolism and reducing obesity-associated risks.

Introduction: Pancreatic adenocarcinoma (PAAD) is characterized by aggressive progression, driven by an immunosuppressive tumor microenvironment (TME) and mitochondrial dysfunction. Alterations in mitochondrial bioenergetics and metabolic reprogramming are crucial to tumor survival, invasion, and immune evasion. The "immune dictionary" approach provides a systematic classification of immune-related genes, offering insights into immune dysfunction and its interaction with mitochondrial pathways in the context of PAAD outcomes.

Methods: To identify differentially expressed genes (DEGs) associated with immune dysfunction and mitochondrial pathways in PAAD, data from TCGA, GTEx, and three GEO datasets were integrated. Differential gene expression was analyzed using DESeq2, applying criteria of p-value < 0.05 and |log2 fold change| > 1. Using the "immune dictionary" framework, a prognostic model was developed through LASSO-Cox regression, followed by survival analysis for validation. The expression of key genes identified in the bioinformatics analysis was validated by quantitative real- time PCR (qPCR) on paired PAAD tissue and adjacent normal samples, focusing on NOG, TNFSF9, and TNFSF10.

Results: Fifty-two DEGs associated with immune and mitochondrial dysfunction were identified. Gene set enrichment analysis revealed critical pathways, including IL-4 signaling, NF-κB activation, and autophagy. The LASSO-Cox model identified 12 prognostic genes that effectively stratified patients into high- and low-risk groups with high predictive accuracy. Validation confirmed significant differential expression patterns, consistent with computational findings.

Discussion: This study, utilizing the immune dictionary framework, systematically analyzed immune- related and mitochondria-related genes in PAAD, identifying 12 DEGs for prognostic modeling. It revealed significant correlations between immune evasion and mitochondrial dysfunction, offering novel targets for personalized therapy.

Conclusion: This study presents an innovative immune dictionary approach to identify key immune- and mitochondria-related DEGs in PAAD, providing potential targets for new therapeutic strategies and personalized treatment approaches.

Diseases of the female reproductive system are prevalent. These conditions often have a high proportion of asymptomatic patients and prolonged treatment durations. Estrogen, a crucial steroid hormone, plays a central role in most diseases of the female reproductive system. It is essential for promoting the development of reproductive organs and follicular growth, maintaining regular menstrual cycles, and supporting pregnancy. The expression levels of estrogen-related receptors and circulating estrogen levels are closely linked to various female reproductive disorders. However, most diseases of the female reproductive system lack specific therapeutic drugs, and estrogen therapy is still primarily used as a monotherapy. The clinical application of hormone-targeted therapies remains immature. In light of these challenges, this review focuses on the effects of estrogen and estrogen-related receptors on common diseases of the female reproductive system. This review provides an overview of the pathogenesis and therapeutic mechanisms of four common gynecological disorders: endometriosis (EMS), abnormal uterine bleeding (AUB), polycystic ovary syndrome (PCOS), and premature ovarian insufficiency (POI). This study aims to identify novel target receptors and provide insights for estrogen-based therapies in the treatment of diseases of the female reproductive system.

Introduction: Traditional Chinese medicine, especially Bushen Huoxue decoction, has demonstrated good therapeutic effects in the treatment of intervertebral disc degeneration and osteoarthritis, but its mechanism of action in osteoporosis remains unclear. This study aimed to explore its potential mechanisms against osteoporosis.

Methods: Active components of Bushen Huoxue decoction were identified through searching the TCM databases. Osteoporosis-related genes were retrieved from three disease databases. Common targets were used to construct a PPI network. Functional enrichment analyses (GO and KEGG), molecular docking, molecular dynamics simulations, and literature validation were performed.

Results: A total of 112 active compounds and 343 potential targets were identified. Key bioactive ingredients included quercetin, luteolin, kaempferol, wogonin, and baicalein. The decoction appeared to act via multiple pathways, such as TNF, NF-κB, MAPK, PI3K/Akt, Wnt/β-catenin, HIF-1, FoxO, AMPK, mTOR, and VEGF, affecting inflammation, metabolism, cell proliferation, survival, and angiogenesis.

Discussion: Bushen Huoxue decoction likely exerted anti-osteoporotic effects through a multi-component, multi-target, and multi-pathway approach, consistent with current understanding of osteoporosis mechanisms. However, as this study was based on network pharmacology and computational analysis, experimental validation is needed.

Conclusion: Bushen Huoxue decoction showed promise as a potential treatment for osteoporosis through complex regulatory mechanisms. The findings provided a theoretical basis for further pharmacological research and TCM-based drug development.

Introduction: To evaluate the effectiveness of selective laser trabeculoplasty (SLT) in lowering intraocular pressure (IOP) in Vietnamese patients with pseudoexfoliation glaucoma (PXG).

Methods: This prospective, comparative study included a total of 64 eyes from PXG patients who had not previously received any antiglaucomatous medication. Patients were categorized into two groups: Group 1 consisted of 32 eyes treated with SLT as the initial therapy, while Group 2 comprised 32 eyes treated with Tafluprost 0.0015%.

Results: The baseline IOP before treatment ranged from 22 to 26 mmHg. There were no significant differences between the two groups in terms of mean cup/disc (C/D) ratio and retinal nerve fiber layer (RNFL) thickness. At the final visit, the mean percentage reduction of IOP was 26.73% in Group 1 and 27.15% in Group 2.

Discussion: SLT significantly reduced IOP in PXG patients, with outcomes comparable to Tafluprost. Treatment was more successful in eyes with higher trabecular pigmentation and early- stage glaucoma. Structural and functional parameters remained stable over 12 months. Side effects, including mild itchiness, IOP spikes, and anterior chamber reactions, were transient and manageable. No vision-threatening complications occurred, confirming SLT as a safe and effective first-line option for PXG in Vietnamese patients.

Conclusion: SLT can be effectively used as a primary treatment for PXG. In cases of recurrent IOP elevation, a second SLT procedure can be administered alone or in combination with other medications.