Familial schwannomatosis carrying LZTR1 variant p.R340X with brain tumor: A case report.

Schwannomatosis (SWN) is a rare genetic condition characterized by the risk of developing multiple benign peripheral nerve sheath tumors; however, the risk of developing malignant tumors in patients with SWN remains unclear. This study described the case of a 57-year-old Japanese man diagnosed with SWN whose older brother also had SWN. Whole-exome sequencing identified a heterozygous mutation [c.1018C > T (p.Arg340X)] in the LZTR1 gene, linked to the RAS/MAPK pathway, in the patient and his brother. Moreover, the patient had aphasia and right-sided paralysis because of a brain tumor. RNA sequencing revealed the remarkable upregulation of several genes associated with oxidative stress, such as the reactive oxygen species pathway and oxidative phosphorylation, a downstream effector of the RAS/MAPK pathway, in the the patient and his brother compared with healthy volunteers. The final diagnosis was LZTR1-related familial SWN, and the dysregulated RAS/MAPK pathway in this patient might be associated with brain tumorigenesis.

Mucin 1 expression is regulated by hsa_circ_0055054/microRNA­122­5p and promotes hepatocellular carcinoma development.

The abnormal expression of mucin 1 (MUC1) is a major cause of poor prognosis in patients with hepatocellular carcinoma (HCC). Competitive endogenous RNA demonstrates a novel regulatory mechanism that can affect the biological behavior of tumors. In the present study, the regulatory functions of hsa_circ_0055054 as well as those of microRNA (miR/miRNA) 122-5p on MUC1 expression and its role in HCC cell proliferation, migration and invasion, were evaluated. MUC1 expression was assessed using western blotting and reverse transcription-quantitative PCR. The phenotypic functions of the HCC cell lines were evaluated following MUC1 knockdown using Cell Counting Kit-8, wound healing and Transwell assays. Bioinformatics tools were used to identify specific miRNAs and circular (circ)RNAs that interact with and can regulate MUC1. The stability of circRNAs was assessed using a Ribonuclease R assay. The binding of circRNA/miRNA/MUC1 was assessed using dual-luciferase reporter assays and cellular function tests. Finally, in vivo experiments were performed using animal models. The results demonstrated that in MHCC97L cells, MUC1 and hsa_circ_0055054 were expressed at high levels while miR-122-5p was downregulated. The proliferation, migration and invasion of MHCC97L cells were suppressed by low MUC1 expression. hsa_circ_0055054 knockdown or miR-122-5p overexpression both led to a decrease in MUC1 expression. In MHCC97L cells with a low MUC1 expression caused by hsa_circ_0055054 knockdown, miR-122-5p inhibition resulted in the increased proliferation, migration and invasion of MHCC97L cells. In combination, the results of the present study indicate that hsa_circ_0055054 knockdown in MHCC97L cells leads to an increased expression of miR-122-5p and decreased expression of MUC1, which results in the inhibition of MHCC97L cell proliferation, migration and invasion.

KLRB1 expression is associated with lung adenocarcinoma prognosis and immune infiltration and regulates lung adenocarcinoma cell proliferation and metastasis through the MAPK/ERK pathway.

Background: Lung cancer is the most common primary malignant tumor of the lung, and as one of the malignant tumors that pose the greatest threat to the health of the population, the incidence rate has remained high in recent years. Previous studies have shown that KLRB1 is transcriptionally repressed in lung adenocarcinoma and correlates with lung adenocarcinoma prognosis. The objective of this study is to investigate the intrinsic mechanisms by which KLRB1 affects the malignant phenotypes of lung adenocarcinoma such as immune infiltration, proliferation, growth and metastasis. Methods: We assessed the expression levels of KLRB1 in publicly available databases and investigated its associations with clinical and pathological variables. Enrichment analysis was subsequently conducted to investigate possible signaling pathways and their associated biological functions. Statistical analysis, including Spearman correlation and the application of multigene prediction models, was utilized to assess the relationship between the expression of KLRB1 and the infiltration of immune cells. The diagnostic and prognostic value of KLRB1 was evaluated using Kaplan-Meier survival curves, diagnostic receptor operating characteristic (ROC) curves, histogram models, and Cox regression analysis. Specimens from lung adenocarcinoma (LUAD) patients were collected, the expression level of KLRB1 was detected by protein blotting analysis, and the expression level of KLRB1 was detected at the mRNA level by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Small interfering RNA (siRNA) was used to silence gene expression, and Transwell, Cell Counting Kit-8 (CCK-8) and colony formation assays were subsequently performed to analyze the effects of KLRB1 on LUAD cell migration, invasion and proliferation. Results: KLRB1 expression was lower in lung cancer tissue than in surrounding healthy tissue. Genes differentially expressed in the low and high KLRB1 expression groups were found to be significantly enriched in pathways related to immunity. KLRB1 exerted an impact on the MAPK/ERK signaling pathway, thereby modulating the growth and proliferation of LUAD cells. KLRB1 expression is linked to prognosis, immune infiltration, and cell migration and proliferation in LUAD. Conclusions: The evidence revealed a correlation between KLRB1 and both prognosis and immune infiltration in LUAD patients.

Prognostic significance of immunotherapy in postoperative recurrent non-small cell lung cancer without EGFR mutations or ALK rearrangements.

Background: Limited reports exist regarding postoperative recurrent non-small cell lung cancer (NSCLC) without major driver mutations [epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements] treated with immune checkpoint inhibitors (ICIs) when programmed cell death ligand 1 (PD-L1) is expressed in a real-world setting. The aim of this study was to evaluate the effect of ICIs for those NSCLC. Methods: We enrolled 255 patients with postoperative recurrent NSCLC lacking EGFR mutations or ALK rearrangements who underwent lobectomy or more extensive resection between 2012 and 2021. Factors associated with post-recurrence survival (PRS) were determined using the Cox proportional hazards model. PRS was analyzed using Kaplan-Meier curves and compared using the log-rank test. Results: Multivariable analysis demonstrated that squamous cell carcinoma, pathological stage III, and an Eastern Cooperative Oncology Group (ECOG) performance status ≥2 were significantly associated with worse PRS. Conversely, ICI use at first line was associated with improved PRS. Patients who used ICIs during the first line and subsequent therapies had better PRS than those who received chemotherapy alone. Among patients who used ICIs, there was no significant difference in response rate at the first line, nor in PRS among those with PD-L1 expression ≥50%, 1-49%, and <1% in surgically resected specimens. Conclusions: ICI use at any treatment line improved the PRS of NSCLC patients without major driver mutations, irrespective of PD-L1 expression, in a real-world setting.

Tumor immune microenvironment remodeling and prognosis of patients with esophageal squamous cell carcinoma after neoadjuvant chemotherapy with and without immunotherapy: a retrospective cohort study.

Background: Immunochemotherapy was an emerging neoadjuvant treatment mode that can potentially benefit patients with esophageal carcinoma, but its synergistic mechanism and impact on the tumor immune microenvironment were still unclear. The purpose of this study was to investigate the outcomes of neoadjuvant chemotherapy (nCT) and neoadjuvant immunochemotherapy (nICT) in tumor microenvironment (TME) remodeling among patients with esophageal squamous cell carcinoma (ESCC) and to evaluate the prognostic value of immune-related biomarkers and clinicopathological characteristics. Methods: Patients with locally advanced ESCC who underwent neoadjuvant therapy followed by esophagectomy at the Fourth Hospital of Hebei Medical University between December 2019 and March 2022 were enrolled in this retrospective study. We examined TME features and immune antigen-related biomarkers before and after neoadjuvant therapy. Logistic and Cox regression model were used to evaluate the correlation between these factors and other clinical features and outcomes. Results: A total of 50 eligible participants were analyzed, including 31 males (62%), 25 patients of ≥65 years old, 4/28/18 of upper/middle/lower thoracic cancer, 25/17/8 of poor/moderate/high tumor differentiation, 8/42 of cT1+2/T3+4 stages and 30/20 of cN0/N+ stages. In the entire cohort, the rates of pathological complete response (pCR) and major pathological response (MPR) were 18% and 30%, respectively. pCR rates were 7.1% and 22.2% (χ2=0.699; P=0.40) MPR rates were 7.1% and 38.9% (χ2=4.837; P=0.03) in the nCT and nICT groups, respectively. Compared with the non-pCR patients, the pCR patients had a higher baseline programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) positive expression rate (16.7% vs. 77.8%, χ2=13.089; P<0.001). Following neoadjuvant therapy, the expression rates of PD-L1, CD3+ T cells, and CD8+ T cells in the tumor tissue was higher in the nICT group compared to the nCT group (P<0.05). Deficient expression of mismatch repair (MMR) genes was only observed in one patient (2%). Among patient-related biomarkers, lymphocyte and neutrophil counts decreased after treatment, with no significant changes in the neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio (PLR). Cox regression analysis showed that pretreatment, well-differentiated tumors and positive PD-L1 status were positive predictors of MPR (P<0.05). MPR was an independent predictor of disease-free survival (DFS) (P=0.03). Conclusions: Compared to nCT, nICT could more significantly upregulates PD-L1 TPS, PD-L1 combined positive score (CPS), CD3+ T cells, and CD8+ T cells. Pretreatment tumor differentiation and PD-L1 TPS level could be predictive of MPR. Our findings suggested that the combination of chemotherapy and immunotherapy may be more beneficial for activating anti-tumor immunity in the TME.

FLMatchQA: a recursive neural network-based question answering with customized federated learning model.

More sophisticated data access is possible with artificial intelligence (AI) techniques such as question answering (QA), but regulations and privacy concerns have limited their use. Federated learning (FL) deals with these problems, and QA is a viable substitute for AI. The utilization of hierarchical FL systems is examined in this research, along with an ideal method for developing client-specific adapters. The User Modified Hierarchical Federated Learning Model (UMHFLM) selects local models for users' tasks. The article suggests employing recurrent neural network (RNN) as a neural network (NN) technique for learning automatically and categorizing questions based on natural language into the appropriate templates. Together, local and global models are developed, with the worldwide model influencing local models, which are, in turn, combined for personalization. The method is applied in natural language processing pipelines for phrase matching employing template exact match, segmentation, and answer type detection. The (SQuAD-2.0), a DL-based QA method for acquiring knowledge of complicated SPARQL test questions and their accompanying SPARQL queries across the DBpedia dataset, was used to train and assess the model. The SQuAD2.0 datasets evaluate the model, which identifies 38 distinct templates. Considering the top two most likely templates, the RNN model achieves template classification accuracy of 92.8% and 61.8% on the SQuAD2.0 and QALD-7 datasets. A study on data scarcity among participants found that FL Match outperformed BERT significantly. A MAP margin of 2.60% exists between BERT and FL Match at a 100% data ratio and an MRR margin of 7.23% at a 20% data ratio.

Getting the diagnostic clue, role of MRI in the diagnosis of type 1 Glutaric aciduria in resource-limited settings.

Glutaric aciduria type 1 is a rare autosomal recessive disorder caused by a deficiency of glutaryl-CoA dehydrogenase, which is the key mitochondrial enzyme involved in the final degradation of lysine, L-hydroxylysine, and L-tryptophan. It is an inherited organic acidemia characterized by macrocephaly and dystonia, which results in high morbidity and mortality. In resource-limited countries like Nepal, where enzyme assays are not available, MRI has a great role to play in supporting diagnosis in such situations. Here, we present 2 cases of glutaric aciduria type 1 in brothers from the same parent that were diagnosed by MRI, and subsequent diet modification and L-carnitine therapy led to improvement of clinical symptoms.

FDX1 as a novel biomarker and treatment target for stomach adenocarcinoma.

BACKGROUND: Stomach adenocarcinoma (STAD) is one of the main reasons for cancer-related deaths worldwide. This investigation aimed to define the connection between STAD and Cuproptosis-related genes (CRGs). Cuproptosis is a newly identified form of mitochondrial cell death triggered by copper. AIM: To explore the identification of potential biomarkers for STAD disease based on cuproptosis. METHODS: A predictive model using Gene Ontology (GO), Least Absolute Shrinkage and Selection Operator (LASSO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Variation Analysis (GSVA), and Gene Set Enrichment Analysis analyzed gene interconnections, focusing on 3 copper-related genes and their expression in The Cancer Genome Atlas-STAD. Networks for mRNA-miRNA and mRNA-transcription factor interactions were constructed. The prognostic significance of CRG scores was evaluated using time-receiver operating characteristic, Kaplan-Meier curves, and COX regression analysis. Validation was conducted with datasets GSE26942, GSE54129, and GSE66229. Expression of copper-related differentially expressed genes was also analyzed in various human tissues and gastric cancer subpopulations using the human protein atlas. RESULTS: Three significant genes (FDX1, LIAS, MTF1) were identified and selected via LASSO analysis to predict and classify individuals with STAD into high and low CRG score subgroups. These genes were down-regulated in both risk categories. GO and KEGG analyses highlighted their involvement mainly in the electron transport chain. After validating their differential expression, FDX1 emerged as the most accurate diagnostic marker for gastric cancer. Additionally, the RCircos package localized FDX1 on chromosome 11. CONCLUSION: Our study revealed that FDX1 could be a potential biomarker and treatment target for gastric malignancy, providing new ideas for further scientific research.

Complex heterozygous mutations in hereditary spherocytosis: A case report.

BACKGROUND: The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis (HS) in children. We also hope to promote the application of gene detection technology in children with HS, with the goals of identifying more related gene mutations, supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children, and providing important guidance for the diagnosis, treatment, and prevention of HS in children. CASE SUMMARY: A 1-year and 5-month-old patient presented jaundice during the neonatal period, mild anemia 8 months later, splenic enlargement at 1 year and 5 months, and brittle red blood cell permeability. Genetic testing was performed on the patient, their parents, and sister. Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1. Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother. Combined with the clinical symptoms of the children, it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause, providing important guidance for revealing the pathogenesis, diagnosis, treatment, and promotion of gene detection technology in children with HS. CONCLUSION: This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1, which provides a reference for exploring HS.

Cytokine release syndrome triggered by programmed death 1 blockade (sintilimab) therapy in a psoriasis patient: A case report.

BACKGROUND: In recent years, immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy across diverse malignancies. Notably, in patients with advanced gastric cancer, the use of programmed death 1 (PD-1) blockade has significantly prolonged overall survival, marking a pivotal advancement comparable to the impact of Herceptin over the past two decades. While the therapeutic benefits of ICIs are evident, the increasing use of immunotherapy has led to an increase in immune-related adverse events. CASE SUMMARY: This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis. Following sintilimab therapy, the patient developed severe rashes accompanied by cytokine release syndrome (CRS). Fortunately, effective management was achieved through the administration of glucocorticoid, tocilizumab, and acitretin, which resulted in favorable outcomes. CONCLUSION: Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.

25-hydroxyvitamin D and parathyroid hormone in new onset sepsis: A prospective study in critically ill patients.

Hypovitaminosis D is highly prevalent in critically ill patients, and it has been suggested to be a risk factor for infections, sepsis and higher mortality. We sought to investigate whether serum 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) in critically ill patients with new onset sepsis are associated with severity and outcome. We prospectively included 50 consecutive critically ill adult cases with new onset sepsis and 50 healthy controls matched for age and sex. PTH and 25(OH)D were determined in serum via electrochemiluminescence immunoassays at inclusion in the study in all cases and controls, and one week after sepsis onset in cases. Patients had reduced 25(OH)D compared to controls at sepsis onset (7.9 ± 3 vs 24.6 ± 6.7 ng/mL, p < 0.001), whilst PTH was similar (median (range): 34.5 (5.7-218.5) vs 44.2 (14.2-98.1) pg/mL, p = 0.35). In patients, 25(OH)D upon enrollment and one week after did not differ significantly (7.9 ± 3 vs 7 ± 4.3 ng/mL, p = 0.19). All patients presented with hypovitaminosis D (25(OH)D < 20 ng/mL), while 40 patients (80 %) had vitamin D deficiency (25(OH)D < 12 ng/mL) at sepsis onset, including all ten (20 %) nonsurvivors, who died within 28 days from sepsis onset. Patients with sepsis (N = 28) and septic shock (N = 22) as well as survivors (N = 40) and nonsurvivors (N = 10) had similar 25(OH)D at enrollment (p > 0.05). 25(OH)D was positively correlated with ionized calcium (r = 0.46, p < 0.001) and negatively with PTH (p < 0.05), while inflammatory biomarkers or the severity scores exhibited no correlation with 25(OH)D. Patients with septic shock and nonsurvivors had lower PTH than patients with sepsis and survivors respectively (42.2 ± 42.9 vs 73.4 ± 61.9 pg/mL, p = 0.04, and 18.3 ± 10.7 vs 69.9 ± 58.8 pg/mL, p = 0.001, respectively). C-reactive protein was negatively associated with PTH (r = -0.44, p = 0.001). In conclusion, vitamin D deficiency was present in 80 % of critically ill patients at sepsis onset, while nonsurvivors exhibited lower PTH than survivors. Additional, larger and multicenter studies are warranted to elucidate the contribution of vitamin D and PTH to the pathogenesis of sepsis and its outcomes.

Comparison of serum thrombospondin-1 and thrombospondin-2 levels among children with autism spectrum disorder and healthy controls.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, the etiology of which has not been clearly determined yet. There is increasing evidence that synaptic and dendritic changes are involved in the etiology of ASD. The aim of this study is to determine whether serum Thrombospondin-1 and Thrombospondin-2 differ between ASD patients and healthy controls. This study also investigates possible correlations between clinical symptomatology of ASD and serum Thrombospondin-1 and Thrombospondin-2 levels. Method: A total of 44 children with ASD and 21 healthy controls under 6 years of age were included in the study. Symptom severity and behavioral problems among children with ASD were evaluated by using Childhood Autism Rating Scale and Abnormal Behavior Checklist. Serum levels of Thrombospondin-1 and Thrombospondin-2 were measured by using commercial enzyme-linked immunosorbent assay kits. Result: No statistically significant differences were found between the two groups in terms of serum Thrombospondin-1 and Thrombospondin-2 levels. In addition, no correlation was determined between Thrombospondin-2 levels and clinical symptomatology and severity of ASD. However, the Thrombospondin-1 level was found to negatively correlated with the total score of Childhood Autism Rating Scale, inappropriate speech and stereotype subscale scores of Aberrant Behavior Checklist scale. Conclusion: Thrombospondin-1 might have a potential role in the etiopathogenesis of ASD. Further studies are required to clearly elucidate the association between Trombospondin-1 and ASD.

Differential impact of genetic deletion of TIGIT or PD-1 on melanoma-specific T-lymphocytes.

Immune checkpoint (IC) blockade and adoptive transfer of tumor-specific T-cells (ACT) are two major strategies to treat metastatic melanoma. Their combination can potentiate T-cell activation in the suppressive tumor microenvironment, but the autoimmune adverse effects associated with systemic injection of IC blockers persist with this strategy. ACT of tumor-reactive T-cells defective for IC expression would overcome this issue. For this purpose, PD-1 and TIGIT appear to be relevant candidates, because their co-expression on highly tumor-reactive lymphocytes limits their therapeutic efficacy within the tumor microenvironme,nt. Our study compares the consequences of PDCD1 or TIGIT genetic deletion on anti-tumor properties and T-cell fitness of melanoma-specific T lymphocytes. Transcriptomic analyses revealed down-regulation of cell cycle-related genes in PD-1KO T-cells, consistent with biological observations, whereas proliferative pathways were preserved in TIGITKO T-cells. Functional analyses showed that PD-1KO and TIGITKO T-cells displayed superior antitumor reactivity than their wild-type counterpart in vitro and in a preclinical melanoma model using immunodeficient mice. Interestingly, it appears that TIGITKO T-cells were more effective at inhibiting tumor cell proliferation in vivo, and persist longer within tumors than PD-1KO T-cells, consistent with the absence of impact of TIGIT deletion on T-cell fitness. Taken together, these results suggest that TIGIT deletion, over PD-1 deletion, in melanoma-specific T-cells is a compelling option for future immunotherapeutic strategies.

A hypoxia-derived gene signature to suggest cisplatin-based therapeutic responses in patients with cervical cancer.

Cervical cancer remains a significant global public health concern, often exhibits cisplatin resistance in clinical settings. Hypoxia, a characteristic of cervical cancer, substantially contributes to cisplatin resistance. To evaluate the therapeutic efficacy of cisplatin in patients with cervical cancer and to identify potential effective drugs against cisplatin resistance, we established a hypoxia-inducible factor-1 (HIF-1)-related risk score (HRRS) model using clinical data from patients treated with cisplatin. Cox and LASSO regression analyses were used to stratify patient risks and prognosis. Through qRT-PCR, we validated nine potential prognostic HIF-1 genes that successfully predict cisplatin responsiveness in patients and cell lines. Subsequently, we identified fostamatinib, an FDA-approved spleen tyrosine kinase inhibitor, as a promising drug for targeting the HRRS-high group. We observed a positive correlation between the IC50 values of fostamatinib and HRRS in cervical cancer cell lines. Moreover, fostamatinib exhibited potent anticancer effects on high HRRS groups in vitro and in vivo. In summary, we developed a hypoxia-related gene signature that suggests cisplatin response prediction in cervical cancer and identified fostamatinib as a potential novel treatment approach for resistant cases.

Long-acting HIV Treatments: Study Design, Logistics, and Access.

New long-acting HIV treatment products have the potential to change the HIV epidemic in the United States and globally. Phase 3 clinical trials of HIV treatments tend to underrepresent populations bearing a disproportionate burden of the HIV epidemic-including women, racial minorities, trans and gender-diverse people, older adults, the unhoused, people who inject drugs, those in rural areas, individuals with mental illness, and other marginalized groups. These populations commonly face significant challenges in adhering to daily HIV treatment regimens. Conducting clinical trials of long-acting treatment targeting specific unmet medical needs of these populations can improve understanding of optimal care approaches, broaden the indication for use of long-acting products, and inform treatment guidelines, all of which can influence reimbursement and access policies. Innovative trial designs and programmatic implementation can improve inclusivity for long-acting therapy. This article summarizes discussions of a multistakeholder workshop on study designs for long-acting HIV treatments.

Roles of cerebrospinal fluid-contacting neurons as potential neural stem cells in the repair and regeneration of spinal cord injuries.

Cerebrospinal fluid-contacting neurons (CSF-cNs) represent a distinct group of interneurons characterized by their prominent apical globular protrusions penetrating the spinal cord's central canal and their basal axons extending towards adjacent cells. Identified nearly a century back, the specific roles and attributes of CSF-cNs have just started to emerge due to the historical lack of definitive markers. Recent findings have confirmed that CSF-cNs expressing PKD2L1 possess attributes of neural stem cells, suggesting a critical function in the regeneration processes following spinal cord injuries. This review aims to elucidate the molecular markers of CSF-cNs as potential neural stem cells during spinal cord development and assess their roles post-spinal cord injury, with an emphasis on their potential therapeutic implications for spinal cord repair.

Heyingwuzi formulation alleviates diabetic retinopathy by promoting mitophagy via the HIF-1α/BNIP3/NIX axis.

BACKGROUND: Diabetic retinopathy (DR) is the primary cause of visual problems in patients with diabetes. The Heyingwuzi formulation (HYWZF) is effective against DR. AIM: To determine the HYWZF prevention mechanisms, especially those underlying mitophagy. METHODS: Human retinal capillary endothelial cells (HRCECs) were treated with high glucose (hg), HYWZF serum, PX-478, or Mdivi-1 in vitro. Then, cell counting kit-8, transwell, and tube formation assays were used to evaluate HRCEC proliferation, invasion, and tube formation, respectively. Transmission electron microscopy was used to assess mitochondrial morphology, and Western blotting was used to determine the protein levels. Flow cytometry was used to assess cell apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential. Moreover, C57BL/6 mice were established in vivo using streptozotocin and treated with HYWZF for four weeks. Blood glucose levels and body weight were monitored continuously. Changes in retinal characteristics were evaluated using hematoxylin and eosin, tar violet, and periodic acid-Schiff staining. Protein levels in retinal tissues were determined via Western blotting, immunohistochemistry, and immunostaining. RESULTS: HYWZF inhibited excessive ROS production, apoptosis, tube formation, and invasion in hg-induced HRCECs via mitochondrial autophagy in vitro. It increased the mRNA expression levels of BCL2-interacting protein 3 (BNIP3), FUN14 domain-containing 1, BNIP3-like (BNIP3L, also known as NIX), PARKIN, PTEN-induced kinase 1, and hypoxia-inducible factor (HIF)-1α. Moreover, it downregulated the protein levels of vascular endothelial cell growth factor and increased the light chain 3-II/I ratio. However, PX-478 and Mdivi-1 reversed these effects. Additionally, PX-478 and Mdivi-1 rescued the effects of HYWZF by decreasing oxidative stress and apoptosis and increasing mitophagy. HYWZF intervention improved the symptoms of diabetes, tissue damage, number of acellular capillaries, and oxidative stress in vivo. Furthermore, in vivo experiments confirmed the results of in vitro experiments. CONCLUSION: HYWZF alleviated DR and associated damage by promoting mitophagy via the HIF-1α/BNIP3/NIX axis.

X-Paste improves wound healing in diabetes via NF-E2-related factor/HO-1 signaling pathway.

BACKGROUND: Diabetic foot ulcers (DFU), as severe complications of diabetes mellitus (DM), significantly compromise patient health and carry risks of amputation and mortality. AIM: To offer new insights into the occurrence and development of DFU, focusing on the therapeutic mechanisms of X-Paste (XP) of wound healing in diabetic mice. METHODS: Employing traditional Chinese medicine ointment preparation methods, XP combines various medicinal ingredients. High-performance liquid chromatography (HPLC) identified XP's main components. Using streptozotocin (STZ)-induced diabetic, we aimed to investigate whether XP participated in the process of diabetic wound healing. RNA-sequencing analyzed gene expression differences between XP-treated and control groups. Molecular docking clarified XP's treatment mechanisms for diabetic wound healing. Human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of Andrographolide (Andro) on cell viability, reactive oxygen species generation, apoptosis, proliferation, and metastasis in vitro following exposure to high glucose (HG), while NF-E2-related factor-2 (Nrf2) knockdown elucidated Andro's molecular mechanisms. RESULTS: XP notably enhanced wound healing in mice, expediting the healing process. RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment. HPLC identified 21 primary XP components, with Andro exhibiting strong Nrf2 binding. Andro mitigated HG-induced HUVECs proliferation, metastasis, angiogenic injury, and inflammation inhibition. Andro alleviates HG-induced HUVECs damage through Nrf2/HO-1 pathway activation, with Nrf2 knockdown reducing Andro's proliferative and endothelial protective effects. CONCLUSION: XP significantly promotes wound healing in STZ-induced diabetic models. As XP's key component, Andro activates the Nrf2/HO-1 signaling pathway, enhancing cell proliferation, tubule formation, and inflammation reduction.

Therapeutic effects of Lingguizhugan decoction in a rat model of high-fat diet-induced insulin resistance.

BACKGROUND: Lingguizhugan (LGZG) decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet (HFD)-induced insulin resistance (IR) in animal studies. AIM: To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism. METHODS: To establish an IR rat model, a 12-wk HFD was administered, followed by a 4-wk treatment with LGZG. The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests. Using a targeted meta-bolomics platform to analyze changes in serum metabolites, quantitative real-time PCR (qRT-PCR) was used to assess the gene expression of the ribosomal protein S6 kinase beta 1 (S6K1). RESULTS: In IR rats, LGZG decreased body weight and indices of hepatic steatosis. It effectively controlled blood glucose and food intake while protecting islet cells. Metabolite analysis revealed significant differences between the HFD and HFD-LGZG groups. LGZG intervention reduced branched-chain amino acid levels. Levels of IR-related metabolites such as tryptophan, alanine, taurine, and asparagine decreased significantly. IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression, as shown by qRT-PCR. CONCLUSIONS: Our study strongly suggests that LGZG decoction reduces HFD-induced IR. LGZG may activate S6K1 via metabolic pathways. These findings lay the groundwork for the potential of LGZG as an IR treatment.

New perspectives in the management of diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and is also associated with increased risk for cardiovascular events. Until recently, strict glycemic control and blockade of the renin-angiotensin system (RAS) constituted the mainstay of treatment of DN. However, randomized controlled trials showed that sodium-glucose cotransporter 2 inhibitors further reduce the progression of DN. Therefore, these agents are recommended in all patients with DN regardless of DN stage and HbA1c levels. Moreover, additional blockade of the RAS with finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, was also shown to prevent both the decline of renal function and cardiovascular events in this population. Finally, promising preliminary findings suggest that glucagon-like peptide 1 receptor agonists might also exert reno- and cardioprotective effects in patients with DN. Hopefully, this knowledge will improve the outcomes of this high-risk group of patients.