Slipped capital femoral epiphysis in an adolescent with congenital adrenal hyperplasia: A case report.

In previous reports, hypothyroidism, hypopituitrism, and hypogonadism were common endocrine causes of SCFE, but this is the first time that congenital adrenal hyperplasia has been observed. As such, patients who have undergone long-term endocrine treatment for congenital adrenal hyperplasia could potentially be subjected to a higher risk for SCFE.

Global burden and cross-country inequalities in stroke and subtypes attributable to diet from 1990 to 2019.

DATA SOURCES: The Global Burden of Diseases, Injuries, and Risk Factors study (GBD) 2019. BACKGROUND: To describe burden, and to explore cross-country inequalities according to socio-demographic index (SDI) for stroke and subtypes attributable to diet. METHODS: Death and years lived with disability (YLDs) data and corresponding estimated annual percentage changes (EAPCs) were estimated by year, age, gender, location and SDI. Pearson correlation analysis was performed to evaluate the connections between age-standardized rates (ASRs) of death, YLDs, their EAPCs and SDI. We used ARIMA model to predict the trend. Slope index of inequality (SII) and relative concentration index (RCI) were utilized to quantify the distributive inequalities in the burden of stroke. RESULTS: A total of 1.74 million deaths (56.17% male) and 5.52 million YLDs (55.27% female) attributable to diet were included in the analysis in 2019.Between 1990 and 2019, the number of global stroke deaths and YLDs related to poor diet increased by 25.96% and 74.76% while ASRs for death and YLDs decreased by 42.29% and 11.34% respectively. The disease burden generally increased with age. The trends varied among stroke subtypes, with ischemic stroke (IS) being the primary cause of YLDs and intracerebral hemorrhage (ICH) being the leading cause of death. Mortality is inversely proportional to SDI (R = -0.45, p < 0.001). In terms of YLDs, countries with different SDIs exhibited no significant difference (p = 0.15), but the SII changed from 38.35 in 1990 to 45.18 in 2019 and the RCI showed 18.27 in 1990 and 24.98 in 2019 for stroke. The highest ASRs for death and YLDs appeared in Mongolia and Vanuatu while the lowest of them appeared in Israel and Belize, respectively. High sodium diets, high red meat consumption, and low fruit diets were the top three contributors to stroke YLDs in 2019. DISCUSSION: The burden of diet-related stroke and subtypes varied significantly concerning year, age, gender, location and SDI. Countries with higher SDIs exhibited a disproportionately greater burden of stroke and its subtypes in terms of YLDs, and these disparities were found to intensify over time. To reduce disease burden, it is critical to enforce improved dietary practices, with a special emphasis on mortality drop in lower SDI countries and incidence decline in higher SDI countries.

Metformin improves cognitive dysfunction through SIRT1/NLRP3 pathway-mediated neuroinflammation in db/db mice.

Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1ß, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.

Effects of acupuncture on hypothalamic-pituitary-adrenal axis: Current status and future perspectives.

The hypothalamic-pituitary-adrenal (HPA) axis is a critical component of the neuroendocrine system, playing a central role in regulating the body's stress response and modulating various physiological processes. Dysregulation of HPA axis function disrupts the neuroendocrine equilibrium, resulting in impaired physiological functions. Acupuncture is recognized as a non-pharmacological type of therapy which has been confirmed to play an important role in modulating the HPA axis and thus favorably targets diseases with abnormal activation of the HPA axis. With numerous studies reporting the promising efficacy of acupuncture for neuroendocrine disorders, a comprehensive review in terms of the underlying molecular mechanism for acupuncture, especially in regulating the HPA axis, is currently in need. This review fills the need and summarizes recent breakthroughs, from the basic principles and the pathological changes of HPA axis dysfunction, to the molecular mechanisms by which acupuncture regulates the HPA axis. These mechanisms include the modulation of multiple neurotransmitters and their receptors, neuropeptides and their receptors, and microRNAs in the paraventricular nucleus, hippocampus, amygdala and pituitary gland, which alleviate the hyperfunctioning of the HPA axis. This review comprehensively summarizes the mechanism of acupuncture in regulating HPA axis dysfunction for the first time, providing new targets and prospects for further exploration of acupuncture. Please cite this article as: Zheng JY, Zhu J, Wang Y, Tian ZZ. Effects of acupuncture on hypothalamic-pituitary-adrenal axis: Current status and future perspectives. J Integr Med. 2024; Epub ahead of print.

The Potential Significance of the EMILIN3 Gene in Augmenting the Aggressiveness of Low-Grade Gliomas is Noteworthy.

Purpose: Low-grade gliomas (LGG) are common brain tumors with high mortality rates. Cancer cell invasion is a significant factor in tumor metastasis. Novel biomarkers are urgently needed to predict LGG prognosis effectively. Methods: The data for LGG were obtained from the Bioinformatics database. A consensus clustering analysis was performed to identify molecular subtypes linked with invasion in LGG. Differential expression analysis was performed to identify differentially expressed genes (DEGs) between the identified clusters. Enrichment analyses were then conducted to explore the function for DEGs. Prognostic signatures were placed, and their predictive power was assessed. Furthermore, the invasion-related prognostic signature was validated using the CGGA dataset. Subsequently, clinical specimens were procured in order to validate the expression levels of the distinct genes examined in this research, and to further explore the impact of these genes on the glioma cell line LN229 and HS-683. Results: Two invasion-related molecular subtypes of LGG were identified, and we sifted 163 DEGs between them. The enrichment analyses indicated that DEGs are mainly related to pattern specification process. Subsequently, 10 signature genes (IGF2BP2, SRY, CHI3L1, IGF2BP3, MEOX2, ABCC3, HOXC4, OTP, METTL7B, and EMILIN3) were sifted out to construct a risk model. Besides, the survival (OS) in the high-risk group was lower. The performance of the risk model was verified. Furthermore, a highly reliable nomogram was generated. Cellular experiments revealed the ability to promote cell viability, value-addedness, migratory ability, invasive ability, and colony-forming ability of the glioma cell line LN229 and HS-683. The qRT-PCR analysis of clinical glioma samples showed that these 10 genes were expressed at higher levels in high-grade gliomas than in low-grade gliomas, suggesting that these genes are associated with poor prognosis of gliomas. Conclusion: Our study sifted out ten invasion-related biomarkers of LGG, providing a reference for treatments and prognostic prediction in LGG.

DMAP-promoted oxidative functionalization of α-amino ketones via oxygen delivery from water/alcohols.

This paper shows a novel oxidative functionalization of α-amino ketones to yield the corresponding α-ketoamides and α-acylimidates. The reaction proceeds via oxygen delivery from water/alcohols in conjunction with an electron acceptor and 4-dimethylaminopyridine (DMAP). Mechanistic study indicates that DMAP exhibits a dual function of nucleophilic catalysis and proton abstraction.

Rhodiolin inhibits the PI3K/AKT/mTOR signaling pathway via the glycolytic enzyme GPI in human papillary thyroid cancer.

BACKGROUND: Papillary thyroid carcinoma (PTC) is an endocrine malignant tumor of the head and neck. Surgery and chemotherapy are PTC treatments, but have adverse effects. Exploration of new non-toxic anti-PTC drugs for PTC treatment is an unmet need. METHODS: We aimed to identify anti-PTC drugs that could inhibit PTC-cell proliferation through high-throughput screening of a library of well-characterized naturally occurring small-molecule compounds. Then, the anti-PTC function of rhodiolin was validated by in vitro cell models and xenograft tumor models RESULTS: We initially demonstrated that rhodiolin inhibited the growth and induced the apoptosis of PTC cells significantly in vitro and in vivo. At the metabolic level, rhodiolin blocked glycolysis through glucose 6-phosphate isomerase (GPI), which suggested that glycolytic inhibition may be involved in mediating the anti-PTC function of rhodiolin. Transcriptomics analysis combined with bioinformatics analysis identified rhodiolin treatment to inhibit phosphorylation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Collectively, our findings demonstrated that rhodiolin inhibited the proliferation and induced the apoptosis of PTC cells by blocking glycolysis through the glycolytic enzyme GPI, thereby inhibiting phosphorylation of the PI3K/Akt/mTOR signaling pathway. CONCLUSION: Our study demonstrates the potential use of rhodiolin in inhibiting the proliferation and inducing the apoptosis of PTC cells. Inhibition of phosphorylation of the PI3K/Akt/mTOR signaling pathway mediated by GPI plays an extremely important part in the ant-PTC function of rhodiolin. These results suggest that rhodiolin is a promising drug in the treatment of PTC progression. Our results provide a novel target and cell signaling pathway for PTC therapy from the perspective of energy metabolism, which could provide new perspectives and new drug choices for PTC therapy. In addition to that, our study will help to make up for the lack of drug research for PTC.

OCIAD2 promotes pancreatic cancer progression through the AKT signaling pathway.

BACKGROUND: OCIAD2（Ovarian carcinoma immunoreactive antigen-like protein 2） is a protein reported in various cancers. However, the role of OCIAD2 has not been explored in pan-cancer datasets. The purpose of this research lies in analyzing the expression level and prognostic-related value of OCIAD2 in different human cancers, as well as revealing the underlying mechanism in specific cancer type (pancreatic adenocarcinoma, PAAD). METHODS: The correlation between OCIAD2 expression level and clinical relevance in different human cancers was investigated from bioinformatical perspective (GTEx and TCGA). The OCIAD2 expression level and clinical significance in PAAD were explored in GEO datasets and tissue microarray. Functional experiments were used to determine the OCIAD2 cell functions in vitro and in vivo. GSEA, western blot and immunohistochemistry were used to uncover the potential mechanism. RESULTS: OCIAD2 expression level was closely correlated with clinical relevance in many cancer types through pan-cancer analysis, and we found OCIAD2 was highly expressed in PAAD and associated with poorer prognosis. OCIAD2 acted as the promotor of Warburg effect and influenced PAAD cells proliferation, migration and apoptosis. Mechanistically, OCIAD2 upregulation may boost glycolysis in PAAD via activating the AKT signaling pathway in PAAD. CONCLUSIONS: In PAAD, OCIAD2 promotes Warburg effect via AKT signaling pathway and targeting cancer cells metabolic reprogramming could be a potential treatment.

Targeted Quantification of Glutathione/Arginine Redox Metabolism Based on a Novel Paired Mass Spectrometry Probe Approach for the Functional Assessment of Redox Status.

Glutathione (GSH) redox control and arginine metabolism are critical in regulating the physiological response to injury and oxidative stress. Quantification assessment of the GSH/arginine redox metabolism supports monitoring metabolic pathway shifts during pathological processes and their linkages to redox regulation. However, assessing the redox status of organisms with complex matrices is challenging, and single redox molecule analysis may not be accurate for interrogating the redox status in cells and in vivo. Herein, guided by a paired derivatization strategy, we present a new ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based approach for the functional assessment of biological redox status. Two structurally analogous probes, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) and newly synthesized 2-methyl-6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (MeAQC), were set for paired derivatization. The developed approach was successfully applied to LPS-stimulated RAW 264.7 cells and HDM-induced asthma mice to obtain quantitative information on GSH/arginine redox metabolism. The results suggest that the redox status was remarkably altered upon LPS and HDM stimulation. We expect that this approach will be of good use in a clinical biomarker assay and potential drug screening associated with redox metabolism, oxidative damage, and redox signaling.

A case of surgically treated non-metastatic SMARCA4-deficient undifferentiated thoracic tumor: a case report and literature review.

SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-UT) is a rare malignant tumor characterized by inactivation of the SMARCA4 gene and the presence of undifferentiated or rhabdoid morphology in the tissue. This tumor is highly invasive, typically diagnosed at advanced stages III or IV, and commonly involves thoracic structures, such as the mediastinum and chest wall. Reported cases are limited and treatment guidelines have not yet been established. Here, we present a rare case of surgically treated non-metastatic SMARCA4-UT. The patient presented with blood-tinged sputum, dyspnea, and a history of heavy smoking, and underwent surgery after preoperative evaluation ruled out contraindications. The tumor was successfully removed along with the relevant lymph nodes; analysis determined it to be stage IIB T3N0M0. No recurrence was detected at two months post-surgery. However, four months after surgery, the tumor recurred and invaded the adjacent ribs. The diagnosis, differential diagnosis, and treatment of SMARCA4-deficient undifferentiated lung tumors is considered. The combination of chemotherapy and immunotherapy has shown efficacy, and other treatments such as anti-angiogenic drugs, histone deacetylase inhibitors (HDACi), enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors, and oxidative phosphorylation (OXPHOS) inhibitors may also be beneficial in treating SMARCA4-UT.

Taohong Siwu decoction alleviates cognitive impairment by suppressing endoplasmic reticulum stress and apoptosis signaling pathway in vascular dementia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear. AIM OF STUDY: This study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway. MATERIALS AND METHODS: A total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression. RESULTS: In the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins. CONCLUSION: In this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway.

Endometrial microbial dysbiosis and metabolic alteration promote the development of endometrial cancer.

OBJECTIVE: Emerging evidence suggests that the endometrial microbiome plays important roles in the development of endometrial cancer (EC). Here, we evaluate stage-specific roles of microbial dysbiosis and metabolic disorders in patients with EC, patients with endometrial hyperplasia (EH), and patients afflicted with benign uterine conditions (CK). METHODS: This prospective cohort study included 33 women with EC, 15 women with endometrial EH, and 15 women with benign uterine conditions (CK) from November 2022 to September 2023. Different typical endometrial samples were imaged with a scanning electron microscope and a transmission electron microscope. The endometrial microbiome was assessed by sequencing the V3-V4 region of the 16S rRNA gene and the ITS1 to fill the gap in relation to the study of the uterine fungal microbiome. Moreover, liquid chromatography-mass spectrometry-based metabolomics was used to identify and quantify metabolic changes among these groups. RESULTS: The endometrial microbiome revealed that there is a structural microbiome shift and an increase in the α-diversity in the EC and EH cases, distinguishable from the benign cases, especially the fungal community structure. The fungal microbiome from patients with EC and EH was altered relative to controls and dominated by Penicillium sp. By contrast, Sarocladium was more abundant in controls. Significant differences were observed in the composition and content of compounds between benign cases and EC, especially estradiol-like metabolism-related substances. Altered microbiota was correlated with the concentrations of interleukin-6 (IL-6), IL-11, transforming growth factor-beta, and ß-glucuronidase activity especially the relative abundance increase of Penicillium sp. CONCLUSIONS: This study suggested that the endometrial microbiome is complicit in modulating the development of EC such as estrogen activity and a pro-inflammatory response. Our work provides a new insight into the endometrial microbiome from a perspective of stages, which opens up new avenues for EC prognosis and therapy.

Elevated neutrophil extracellular trap levels in periodontitis: Implications for keratinization and barrier function in gingival epithelium.

AIM: To explore the levels of neutrophil extracellular traps (NETs) in patients with periodontitis and examine their effects on keratinization, barrier function of human gingival keratinocytes (HGKs) and the associated mechanisms. MATERIALS AND METHODS: Saliva, gingival crevicular fluid (GCF), clinical periodontal parameters and gingival specimens were collected from 10 healthy control subjects and 10 patients with stage II-IV periodontitis to measure the NET levels. Subsequently, mRNA and protein levels of keratinization and barrier indicators, as well as intracellular calcium and epithelial barrier permeability, were analysed in HGKs after NET stimulation. RESULTS: The study showed that NET levels significantly elevated in patients with periodontitis, across multiple specimens including saliva, GCF and gingival tissues. Stimulation of HGKs with NETs resulted in a decrease in the expressions of involucrin, cytokeratin 10, zonula occludens 1 and E-cadherin, along with decreased intracellular calcium levels and increased epithelial barrier permeability. Furthermore, the inhibition of keratinization by NETs is ERK-KLF4-dependent. CONCLUSIONS: This study indicates that NETs impair the barrier function of HGKs and suppress keratinization through ERK/KLF4 axis. These findings provide potential targets for therapeutic approaches in periodontitis to address impaired gingival keratinization.

A mild deprotection of isopropylidene ketals from 2-deoxyglycosides using AcOH/H2O/DME: An efficient regioselective deprotection of terminal isopropylidene ketals.

This paper describes a mild and efficient catalytic deprotection method for isopropylidene ketals and benzylidene acetals using AcOH/H2O/DME(1,2-Dimethoxyethane). The method effectively removes ketal and acetal protecting groups from 2-deoxyglycosides which are prone to hydrolysis under acidic conditions. Moreover, it enables the selective removal of the terminal ketal over an internal one.

Osthole accelerates osteoporotic fracture healing by inducing the osteogenesis-angiogenesis coupling of BMSCs via the Wnt/ß-catenin pathway.

Osthole, a natural coumarin derivative, has been shown to have multiple pharmacological activities. However, its effect on osteoporotic fracture has not yet been examined. This research was designed to explore the unknown role and potential mechanism of osthole on osteoporotic fracture healing. We first evaluated the osteogenic and angiogenic abilities of osthole. Then angiogenesis-related assays were conducted to investigate the relationship between osteogenesis and angiogenesis, and further explore its molecular mechanism. After that, we established osteoporotic fracture model in ovariectomy-induced osteoporosis rats and treated the rats with osthole or placebo. Radiography, histomorphometry, histology, and sequential fluorescent labeling were used to evaluate the effect of osthole on osteoporotic fracture healing. In vitro research revealed that osthole promoted osteogenesis and up-regulated the expression of angiogenic-related markers. Further research found that osthole couldn't facilitate the angiogenesis of human umbilical vein endothelial cells in a direct manner, but it possessed the ability to induce the osteogenesis-angiogenesis coupling of bone marrow mesenchymal stem cells (BMSCs). Mechanistically, this was conducted through activating the Wnt/ß-catenin pathway. Subsequently, using ovariectomy-induced osteoporosis tibia fracture rat model, we observed that osthole facilitated bone formation and CD31hiEMCNhi type H-positive capillary formation. Sequential fluorescent labeling confirmed that osthole could effectively accelerate bone formation in the fractured region. The data above indicated that osthole could accelerate osteoporotic fracture healing by inducing the osteogenesis-angiogenesis coupling of BMSCs via the Wnt/ß-catenin pathway, which implied that osthole may be a potential drug for treating osteoporosis fracture.

Chloride salt enhances plant resistance to biotic stresses.

Biotic stresses caused by bacterial and fungal pathogens damage crops; identifying treatments that enhance disease resistance provides important information for understanding plant defenses and sustainable agriculture. Salt stress affects crop yields worldwide; however, studies have focused on the toxic sodium ion, leaving the effects of the chloride ion unclear. In this study, we found that irrigation with a combination of chloride salts (MgCl2, CaCl2, and KCl) suppressed the cell death phenotype of the ceramide kinase mutant acd5. Chloride salt pre-irrigation also significantly limited the cell death caused by Pseudomonas syringae pv maculicola infection and inhibited the multiplication of this bacterial pathogen in a mechanism partially dependent on the salicylic acid pathway. Moreover, chloride salt pre-irrigation improved plant defenses against the fungal pathogen challenge, confining the lesion area caused by Botrytis cinerea infection. Furthermore, the growth of herbivorous larvae of Spodoptera exigua was retarded by feeding on chloride salt irrigated plants. Thus, our data suggest that treatment with Cl- increases broad spectrum resistance to biotic challenges.

Platinum single atom on CsPbBr3 nanocrystals as electrocatalyst boosts electrochemical sensing of ascorbic acid.

Monitoring ascorbic acid (AA) levels in human body can provide valuable clues for disease diagnosis. Anchoring noble metal single atoms on perovskite substrate is a promising strategy to design electrocatalysts with outstanding electrocatalytic performance. Herein, we design an electrochemical method for detecting AA by utilizing Pt single atoms-doped CsPbBr3 nanocrystals (Pt SA/CsPbBr3 NCs) fixed on a glassy carbon electrode as an electrochemical catalyst. The uncharged 3,5,3',5'-tetramethylbenzidine (TMB) undergoes oxidation to form the positively charged oxidized TMB (oxTMB) owing to the exceptional electrochemical catalytic performance of Pt SA/CsPbBr3 NCs. Subsequently, the target AA reduces oxTMB to TMB, which is then electrocatalytically oxidized to oxTMB, producing significant oxidation current. In this way, such characteristic provides a sensitive electrochemical strategy for AA detection, achieving a concentration range of 50-fold with the detection limit of 0.0369 µM. The developed electrochemical method also successfully generates accurate detection response of AA in complex sample media (urine). Overall, this approach is expected to offer a novel way for early disease diagnosis.

[4 + 2] Cyclization or Lossen Rearrangement: Rhodium-Catalyzed Divergent Synthesis of Carboline Derivatives with Anticancer Activity.

An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and ß-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.

MathEagle: Accurate prediction of drug-drug interaction events via multi-head attention and heterogeneous attribute graph learning.

BACKGROUND: Drug-drug interaction events influence the effectiveness of drug combinations and can lead to unexpected side effects or exacerbate underlying diseases, jeopardizing patient prognosis. Most existing methods are restricted to predicting whether two drugs interact or the type of drug-drug interactions, while very few studies endeavor to predict the specific risk levels of side effects of drug combinations. METHODS: In this study, we propose MathEagle, a novel approach to predict accurate risk levels of drug combinations based on multi-head attention and heterogeneous attribute graph learning. Initially, we model drugs and three distinct risk levels between drugs as a heterogeneous information graph. Subsequently, behavioral and chemical structure features of drugs are utilized by message passing neural networks and graph embedding algorithms, respectively. Ultimately, MathEagle employs heterogeneous graph convolution and multi-head attention mechanisms to learn efficient latent representations of drug nodes and estimates the risk levels of pairwise drugs in an end-to-end manner. RESULTS: To assess the effectiveness and robustness of the model, five-fold cross-validation, ablation experiments, and case studies were conducted. MathEagle achieved an accuracy of 85.85 % and an AUC of 0.9701 on the drug risk level prediction task and is superior to all comparative models. The MathEagle predictor is freely accessible at http://120.77.11.78/MathEagle/. CONCLUSIONS: The experimental results indicate that MathEagle can function as an effective tool for predicting accurate risk of drug combinations, aiding in guiding clinical medication, and enhancing patient outcomes.

TRPV3 facilitates lipolysis and attenuates diet-induced obesity via activation of the NRF2/FSP1 signaling axis.

Transient receptor potential vanilloid (TRPV) ion channels play a crucial role in various cellular functions by regulating intracellular Ca2+ levels and have been extensively studied in the context of several metabolic diseases. However, the regulatory effects of TRPV3 in obesity and lipolysis are not well understood. In this study, utilizing a TRPV3 gain-of-function mouse model (TRPV3G568V/G568V), we assessed the metabolic phenotype of both TRPV3G568V/G568V mice and their control littermates, which were randomly assigned to either a 12-week high-fat diet or a control diet. We investigated the potential mechanisms underlying the role of TRPV3 in restraining obesity and promoting lipolysis both in vivo and in vitro. Our findings indicate that a high-fat diet led to significant obesity, characterized by increased epididymal and inguinal white adipose tissue weight and higher fat mass. However, the gain-of-function mutation in TRPV3 appeared to counteract these adverse effects by enhancing lipolysis in visceral fat through the upregulation of the major lipolytic enzyme, adipocyte triglyceride lipase (ATGL). In vitro experiments using carvacrol, a TRPV3 agonist, demonstrated the promotion of lipolysis and antioxidation in 3T3-L1 adipocytes after TRPV3 activation. Notably, carvacrol failed to stimulate Ca2+ influx, lipolysis, and antioxidation in 3T3-L1 adipocytes treated with BAPTA-AM, a cell-permeable calcium chelator. Our results revealed that TRPV3 activation induced the action of transcriptional factor nuclear factor erythroid 2-related factor 2 (NRF2), resulting in increased expression of ferroptosis suppressor protein 1 (FSP1) and superoxide dismutase2 (SOD2). Moreover, the inhibition of NRF2 impeded carvacrol-induced lipolysis and antioxidation in 3T3-L1 adipocytes, with downregulation of ATGL, FSP1, and SOD2. In summary, our study suggests that TRPV3 promotes visceral fat lipolysis and inhibits diet-induced obesity through the activation of the NRF2/FSP1 signaling axis. We propose that TRPV3 may be a potential therapeutic target in the treatment of obesity.