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Protists are polyphyletic single-celled eukaryotes that underpin global ecosystem functioning, particularly in the oceans. Most remain uncultured, limiting the investigation of their physiology and cell biology. MArine STramenopiles (MASTs) are heterotrophic protists that, although related to well-characterized photosynthetic diatoms and parasitic oomycetes, are poorly studied. The Nanomonadea (MAST-3) species Show less

Microtubule associated series/threonine kinase-3 (MAST3) is a member of microtubule associated serine/threonine kinase family (MAST1-4, MAST-like), and the expression and underlying molecular mechanism of MAST3 in human tumors, including breast cancer, is not yet elucidated. We employed immunohistochemistry to assess the significant expression of MAST3 in breast cancer tissue samples. Additionally, we utilized an overexpression vector and shRNA to bi-directionally regulate MAST3 expression, aiming to observe the impact of MAST3 on the proliferation, migration, and invasion capabilities of breast cancer cells. Furthermore, we employed immunoprecipitation, immunoblotting, luciferase reporter genes and real-time quantitative PCR to investigate the interaction between MAST3 and YAP, as well as the regulatory effects on the expression of Hippo pathway-related target genes. Low MAST3 expression was observed both in breast cancer cells and tissues, which was significantly associated with advanced tumor T stage, lymph node metastasis, and poor patient prognosis. Functional experiments found that overexpression of MAST3 can gradually inhibit the proliferation and invasion of breast cancer cells, knocking-out MAST3 showed the opposite functional effect. Immunoprecipitation showed that MAST3 interacts with the key effector factor, yes-associated protein (YAP), in the Hippo pathway. The combination of MAST3-YAP promoted the phosphorylation of YAP, which led to its degradation through the ubiquitin-proteasome pathway and reduced nuclear translocation. MAST3 was identified as a novel tumor suppressor protein in breast cancer, which directly regulates the expression of YAP through the non-dependent mammalian sterile-20-like (MST)-large tumor suppressor (LATS) classical signaling pathway, providing a theoretical and experimental basis for the development of small-molecule tumor inhibitors in breast cancer. Show less

Head and neck squamous cell carcinoma (HNSCC) poses a global health challenge. The management of HNSCC is complicated by the difficulty in detecting occult lymph node metastases, leading to dilemmas in elective neck dissection decisions, which will impair patients' quality of life without improving survival for nodal negative patients. We conducted a comparative analysis of the clinical features, genomic alterations, gene expression and methylation, tumor microenvironment and cellular states between the clinically N0 and pathologically N0 (cN0-pN0) patients and occult lymph node metastatic patients. Patients with occult lymph node metastases typically present with more poorly differentiated primary tumors and higher rates of angiolymphatic and perineural invasion. We identified a distinctive genomic mutation spectrum in the primary tumors of patients with occult metastases, notably in genes such as NSD1, ARHGAP15 and SMARCA4. A whole-genome DNA hypomethylation and altered gene expression profiles are identified in occult lymph node metastatic patients. Analysis of the tumor microenvironment revealed an enrichment of CARNS1 + NK cells and CBX1 + tumor cells in occult metastatic patients. In conclusion, patients with occult lymph node metastases exhibit distinct molecular and clinical features compared with cN0-pN0 patients. Show less

Hypothalamic obesity (HO) is a disabling disease caused by central nervous system (CNS) damage due to neurosurgery, trauma, or tumors, especially in hypothalamus. The pathological mechanism of its neural circuits is still unclear, and there is currently no corresponding drug due to the complex etiology. G protein-coupled receptors (GPCRs) regulate neural function in many CNS diseases. Among them, melanocortin 4 receptor (MC4R) regulate metabolism and appetite in the hypothalamus. Setmelanotide, an MC4R agonist, has demonstrated anti-obesity effects in genetic forms of obesity; however, its efficacy and mechanisms in HO remain unexplored. This study explored the potential of treating HO by setmelanotide-targeted activation of MC4R in the paraventricular nucleus (PVN). We established a rat hypothalamic injury model to replicate human HO symptoms, such as hyperphagia (50% increase in food intake), elevated Lee index, and more than 25% weight gain. Immunofluorescence and immunoblot analysis showed that HO disrupted the PVN neuropeptides, leading to the inhibition of MC4R via calmodulin-dependent protein kinase kinase 2 (CaMKK2) and AMP-activated protein kinase (AMPK) signaling. Crucially, administration of setmelanotide restored CaMKK2/AMPK activity, reactivated MC4R neurons, and normalized appetite and feeding behavior during fasting-refeeding and the long-term treatment of obese rats (60% reduction in food intake), ultimately reversing obesity (23% weight loss). These findings underscore the critical role of MC4R dysfunction in hypothalamic injury and highlight the strategies to pharmacologically activate MC4R via CaMKK2/AMPK signaling to restore metabolic homeostasis, proposing a translatable therapeutic agent to manage obesity caused by CNS injury. Show less

Atherosclerosis is often associated with inflammation and non-alcoholic liver disease due to high-cholesterol diet and the side effects of conventional treatment. This study aimed to determine the efficacy of Hypercholesterolemia induction was achieved by oral administration of feed with lard for 21 days in male Wistar rats. Next, the animals were treated with 4 mg/kg BW of BBLE (single dose) and 4 mg/kg BW of BBLE+SAE (combined dose) for 3 months, and continued to be given a high cholesterol diet. The negative control was a high cholesterol diet, and the positive control was simvastatin. Blood samples were taken to determine total cholesterol, apolipoprotein-E (Apo-E), interleukin-6, tumor necrosis factor-α, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. Meanwhile, the weight of the liver and histopathology preparations were weighed. Giving BBLE+SAE was able to reduce body weight, liver weight, and cholesterol levels significantly compared to negative controls ( Administration of BBLE+SAE acts as an anti-atherosclerotic and hepatoprotective agent for the liver through reducing pro-inflammatory cytokines, and its use was promising for clinical studies. Show less

A large fraction of the genome interacts with the nuclear periphery through lamina-associated domains (LADs), repressive regions which play an important role in genome organization and gene regulation across development. Despite much work, LAD structure and regulation are not fully understood, and a mounting number of studies have identified numerous genetic and epigenetic differences within LADs, demonstrating they are not a uniform group. Here, we profile lamin B1, CBX1 (also known as HP1B), H3K9me3, H3K9me2, H3K27me3, H3K14ac, H3K27ac, and H3K9ac in MEF cell lines derived from the same mouse colony, and cluster LADs based on the abundance and distribution of these features across LADs. We find that LADs fall into three groups, each enriched in a unique set of histone modifications and genomic features. Each group is defined by a different heterochromatin modification (H3K9me3, H3K9me2, or H3K27me3), suggesting that all three of these marks play important roles in regulation of LAD chromatin and potentially of lamina association. We also discover unique features of LAD borders, including a LAD border-specific enrichment of H3K14ac. These results reveal important distinctions between LADs and highlight the rich diversity and complexity in LAD structure and regulatory mechanisms. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder driven by dysregulated lipid metabolism and remains a leading cause of cardiovascular morbidity. The Shen-Hong-Tong-Luo (SHTL) preparation has demonstrated clinical benefit in stabilizing atherosclerotic plaques, yet its molecular mechanisms are not fully defined. This research sought to elucidate the protective effects exerted by SHTL on AS progression. To investigate the impact of SHTL on macrophage function and plaque stability, we utilized ApoE SHTL markedly attenuated the progression of AS, demonstrated by reduced plaque formation within both the aortic root and aorta, diminished plasma lipid concentrations, and suppressed inflammatory responses. SHTL demonstrates significant anti-inflammatory and lipid-regulatory effects, attenuating AS progression through the PPARγ/Mfge8 pathway, thereby enhancing macrophage efferocytosis. These findings highlight a novel mechanism by which SHTL may contribute to preventing and treating atherosclerotic diseases. Show less

Statins can effectively reduce low-density lipoprotein cholesterol (LDL-C), but additional options are needed for inadequate responses to statins or statin intolerance. Bempedoic acid is a small-molecule oral LDL-C-lowering drug that inhibits ATP citrate lyase, an enzyme 2 steps upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the metabolic pathway for cholesterol synthesis. The CLEAR-J trial evaluated bempedoic acid 180 mg/day for 12 weeks in Japanese patients with inadequately controlled LDL-C. Percentage changes in LDL-C between baseline and Week 12 (primary endpoint) were -25.25% and -3.46% in the bempedoic acid and placebo groups, respectively, with a significant between-group difference (-21.78%; 95% confidence interval [CI] -26.71%, -16.85%; P<0.001). Changes in secondary endpoints in the bempedoic acid and placebo groups were as follows: non-high-density lipoprotein cholesterol, -20.33% and -2.76%, respectively (between-group difference -17.57%; 95% CI -22.03%, -13.12%); total cholesterol -16.36% and -2.23%, respectively (between-group difference -14.13%; 95% CI -17.79%, -10.47%); and apolipoprotein B -18.10% and -0.67%, respectively (between-group difference -17.43%; 95% CI -21.97%, -12.89%). At 12 weeks, 62.5% of the bempedoic acid group had achieved target LDL-C values. Treatment-emergent adverse events appeared in 3 patients taking bempedoic acid and 2 patients taking placebo. This study confirmed the safety and efficacy of bempedoic acid after 12 weeks treatment in Japanese patients with high LDL-C who had inadequate response to statins or statin intolerance. Show less

Alzheimer's disease (AD) is a common neurodegenerative condition involving a complex blend of disturbances in synaptic development and maintenance, neurovascular cross-talk, ionic and nutrient transport, and mitochondrial metabolism. The precise molecular profile of AD onset with insight for major pathological contributors remains unclear with corresponding impedances in therapeutic development. The current study sought two objectives, as (i) to resolve the molecular pathogenesis from cognitive impairment to the onset of AD-like neuropathology and (ii) whether the novel agent cannabidiol (CBD), noted for its neuroprotective effects, influences the molecular transition associated with AD onset. Dietary CBD was administered daily (80-100 mg/kg/day) in male There were >1,000 differentially expressed markers of AD onset, whereby >75% were either eliminated or reversed in the direction of expression in response to CBD. Signaling pathways encompassed synaptic development and plasticity (e.g., Foxp2), neurovascular interactions (Smad9, Angptl6), receptors and ion channels (Gria4, Chrna2, Rgs7/Rgs7bp), mitochondrial genes (Ndufa7, Cox7a2), immunity (Ncr1), oxidation-reduction (Esr1), lipid synthesis (Fasn, ApoE), and carbohydrate metabolism (Mafa, Mlxipl). As potentially addressable with CBD treatment, AD onset represents molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and aberrations in developmental genes with involvement of major pathological contributors such as inflammation, oxidative signaling, dyslipidemia, and insulin resistance. Show less

Brown adipose tissue (BAT) comprises a heterogeneous population of adipocytes and non-adipocyte cell types. To characterize these cellular subpopulations and their adaptation to cold, we performed single-nucleus mRNA-sequencing (snRNA-seq) on interscapular BAT from mice maintained at room temperature or exposed to acute (24h) or chronic (10 days) cold (6 °C). To investigate the role of the de novo lipogenesis (DNL)-regulating transcription factor carbohydrate response element-binding protein (ChREBP), we analyzed control and brown adipocyte-specific ChREBP knockout mice. We identified different cell populations, including seven brown adipocyte subtypes with distinct metabolic profiles. One of them highly expressed ChREBP and DNL enzymes. Notably, these lipogenic adipocytes were highly sensitive to acute cold exposure, showing a marked depletion in BAT of control mice that was compensated by other brown adipocyte subtypes maintaining DNL. Chronic cold exposure resulted in an expansion of basal brown adipocytes and adipocytes putatively derived from stromal and endothelial precursors. In ChREBP-deficient mice, lipogenic adipocytes were almost absent under all conditions, identifying the transcription factor as a key determinant of this adipocyte subtype. Detailed expression analyses revealed Ttc25 as a specific marker of lipogenic brown adipocytes and as a downstream target of ChREBP. Furthermore, pathway and cell-cell interaction analyses implicated a Wnt-ChREBP axis in the maintenance of lipogenic adipocytes, with Wnt ligands from stromal and muscle cells providing instructive cues. Our findings provide a comprehensive atlas of BAT cellular heterogeneity and reveal a critical role for ChREBP in lipogenic adipocyte identity, with implications for BAT plasticity and metabolic function. Show less

Recent advancements in transcriptomic analysis, combined with single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, have deepened our understanding of the tumor microenvironment and cellular heterogeneity, laying the groundwork for personalized therapies. The aim of this research is to explore the heterogeneity of tumor cells in colorectal cancer (CRC) and evaluate their prognostic value in different therapeutic contexts, emphasizing the impact of tumor cell heterogeneity on disease progression. scRNA-seq alongside spatial transcriptomics was employed to analyze the heterogeneity of tumor cells in CRC, the spatial distribution of tumor cells, and their interactions with the microenvironment. We identified nine distinct tumor cell subtypes, with MLXIPL + neoplasm prevalent in advanced CRC, while ADH1C + and MUC2 + neoplasms were more common in early-stage CRC. MLXIPL + neoplasm was significantly associated with chemotherapy and targeted therapy efficacy. Analysis of spatial transcriptomics indicated that MLXIPL + neoplasm is located in the core area of the tumor cells. We developed a 13-gene prognostic signature (PS) using machine learning algorithm (StepCox backward), which predicts the prognosis of CRC patients. Furthermore, the patients with low PS score demonstrated higher immune cell infiltration and immune regulatory factors, suggesting enhanced immune surveillance and treatment response. The findings highlight the critical role of tumor cell heterogeneity in CRC progression and treatment response, suggesting the need for personalized therapeutic strategies targeting different subpopulations. The constructed PS demonstrates significant clinical application value in predicting patient prognosis. Show less

The Carbohydrate-Responsive Element-Binding Protein (ChREBP) is a glucose-sensitive transcription factor that regulates the carbohydrate and lipid metabolism. We investigated its cell-type-specific role in hepatocarcinogenesis using a chemically induced mouse model. Additionally, we examined the functions of its isoforms, ChREBPα and ChREBPβ. After the diethylnitrosamine (DEN) administration, we analyzed hepatocellular adenomas and carcinomas in systemic ChREBP-knockout (KO), hepatocyte-specific ChREBP-KO (L-KO), and wildtype (WT) mice at 4, 12, and 36 weeks using histology, morphometry, proliferation measurements, immunohistochemistry, a Western blot, and a quantitative PCR. Tumors developed 36 weeks after the DEN administration in 27% of WT mice but less frequently in KO (18%) and L-KO (9%) mice. However, preneoplastic foci were less common in KO mice but not in L-KO mice (39% vs. 9%; Show less

Brown adipose tissue (BAT), a thermogenic tissue that plays an important role in systemic energy expenditure, has histological and functional sex differences. BAT thermogenic activity is higher in female mice than in male mice. However, the molecular mechanism underlying this functional sex difference has not been fully elucidated. Herein, we demonstrate the role and mechanism of PGC-1α in this sex difference. Inducible adipocyte-specific PGC-1α knockout (KO) mice display mitochondrial morphological defects and decreased BAT thermogenesis only in females. Expression of carbohydrate response-element binding protein beta (Chrebpβ) and its downstream de novo lipogenesis (DNL)-related genes are both reduced only in female KO mice. BAT-specific knockdown of ChREBPβ displays decreased DNL-related gene expression and mitochondrial morphological defects followed by reduced BAT thermogenesis in female wild-type mice. Lipidomics reveals that, PGC-1α increases ether-linked phosphatidylethanolamine (PE) and cardiolipin(18:2) Show less

Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, this induction of FGF21 occurs at the level of gene transcription and is regulated by two byproducts of ethanol metabolism, glycerol-3-phosphate (G3P) and acetyl-CoA. Using cell-based reporter and thermal shift binding assays, we show that G3P binds to a conserved domain and activates the transcription factor carbohydrate-responsive element-binding protein (ChREBP), which regulates the Show less

Diabetic kidney disease (DKD), characterized by mesangial fibrosis and renal dysfunction, is a major microvascular complication of diabetes. Studies have shown that miRNAs are closely related to the progression of DKD. Therefore, in this study, we aimed to explore whether miR-1225-3p can regulate Smad ubiquitin regulatory factor 2 (SMURF2)-mediated carbohydrate response element binding protein (ChREBP) ubiquitination through Rho GTPase-activating protein 5 (ARHGAP5) to affect fibrosis in DKD. DKD mice were established by intraperitoneally injecting streptozocin (STZ), and a DKD cell model was generated by culturing in media supplemented with 25 mmol/L glucose (high glucose, HG). StarBase was used to predict the target binding sites between miR-1225-3p and ARHGAP5, and a dual-luciferase reporter gene assay was used to verify this relationship. Western blotting, RT-qPCR, flow cytometry, immunoprecipitation, ELISAs, HE staining, and Masson staining were used to detect relevant indicators. ARHGAP5 and SMURF2 expression was decreased, but ChREBP was highly expressed in the renal tissue of DKD mice and HG-induced mouse mesangial cells (MMCs). miR-1225-3p could target and regulate the transcription of ARHGAP5, and an association between ARHGAP5 and SMURF2 was revealed. miR-1225-3p facilitated fibrosis and oxidative stress in MCCs by inhibiting ARHGAP5. In addition, SMURF2 promoted the ubiquitination of HA-ChREBP, and miR-1225-3p facilitated fibrosis and oxidative stress by mediating the ARHGAP5/SMURF2-mediated ubiquitination of ChREBP in MCCs. Furthermore, the miR-1225-3p inhibitor inhibited fibrosis and inflammation in the renal tissues of DKD mice. miR-1225-3p facilitates fibrosis and oxidative stress by mediating ARHGAP5/SMURF2-mediated ubiquitination of ChREBP. Show less

The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomic and metabolomic analyses in rats with GalNac-siRNA-mediated suppression of ChREBP expression in liver reveal other ChREBP functions. GalNac-siChREBP treatment reduces expression of genes involved in coenzyme A (CoA) biosynthesis, with lowering of CoA and short-chain acyl-CoA levels. Despite suppression of pyruvate kinase, pyruvate levels are maintained, possibly via increased expression of pyruvate and amino acid transporters. In addition, expression of multiple anaplerotic enzymes is decreased by GalNac-siChREBP treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP treatment suppresses late steps in purine and NAD synthesis, with increases in precursors and lowering of end products in both pathways. In sum, our study reveals functions of ChREBP beyond its canonical roles in carbohydrate and lipid metabolism to include regulation of substrate transport, mitochondrial function, and energy balance. Show less

Here, we identified a type of hypothetical T7SS effector in This alternative strategy facilitates effectors' delivery, even for fragmented substrates, highlighting its importance in ensuring the functionality of T7SS. Show less

Overweight and obesity are widespread in Mexico, often linked to dyslipidemia and higher cardiovascular risk. The search for safe and effective treatments has promoted interest in natural supplements such as Ashwagandha (Withania somnifera), recognized for its adaptogenic and potential lipid-lowering properties. To assess the impact of Ashwagandha supplementation on serum lipid profiles and anthropometric parameters in Mexican adults with overweight and obesity. A double-blind, randomized, placebo-controlled pilot clinical trial was carried out with 43 adults (n = 17 in the control group and n = 21 in the intervention group) over 40 days. Participants followed a monitored diet and received one daily capsule containing 500 mg of Ashwagandha or a placebo, in addition to a guided unrestricted dietary plan. Anthropometric and biochemical measurements were taken at baseline and after the intervention. In silico analysis was also performed to examine the binding affinity of Ashwagandha bioactive compounds to key proteins involved in lipid metabolism. Ashwagandha supplementation did not produce statistically significant changes in body weight, body mass index (BMI), or waist circumference (WC). However, significant reductions were observed in triglyceride and VLDL-c levels (p = 0.0082 and p = 0.0321, respectively). In silico results supported these findings, showing favorable interactions between compounds such as withanolide A and lipid metabolism targets, including AMPK, CETP, and LPL. Ashwagandha supplementation improved serum lipid profiles in adults with overweight and obesity, suggesting potential lipid-lowering effects when combined with a prescribed dietary plan. Also, it was possible to elucidate some metabolic pathways in which Ashwagandha composition has an influence on producing the reported effects. Further long-term studies with controlled dietary intake are needed to confirm these findings and clarify the underlying molecular mechanisms. Show less

Related studies have shown that propionate metabolism-related genes (PMRGs) were associated with the progress of cancers. However, the roles of PMRGs in ovarian cancer (OC) were unclear. In this study, OC-related transcriptome data and clinical information were extracted from The Cancer Genome Atlas (TCGA),Genotype-Tissue Expression (GTEx) and Gene Expression Omnibus (GEO) databases. Firstly, the differentially expressed genes (DEGs) between OC and healthy control (HC) samples were screened by differential expression analysis. Then, the differentially expressed PMRGs (DE-PMRGs) were obtained by intersecting the DEGs with PMRGs. Next, the enrichment analyses of DEGs and DE-PMRGs were conducted to investigate the functions. Moreover, the biomarkers of OC were screened and the risk score was calculated. Then, the nomogram predicting the survival of OC was constructed. Furthermore, the tumor microenvironment analyses and drug sensitivity analysis were proceeded. In addition, the transcription factor (TF)-mRNA regulatory network was constructed to reveal the potential molecular-level regulation of biomarkers. Additionally, the expression levels of biomarkers in IOSE-80, OVCA429, hey and OVCAR-8 were detected through the Quantitative Real-time Polymerase Chain Reaction (qRT-PCR). Immunohistochemistry (IHC) was performed to validate the protein expression of key biomarkers (CETP, ALDH5A1, and PTH) in ovarian cancer tissue microarrays. Totals of 280 DE-PMRGs were obtained by intersecting the 9,466 DEGs and 531 PMRGs, and these genes were associated with steroid and fatty acid metabolic process. Five biomarkers (ALDH5A1, CETP, GRIA1, PTH, and TPMT) were identified, and the nomogram was constructed with risk score, age and TMB. Among them, GRIA1 was a negative factor, while age and risk score were negatively associated with patients' survival. Noticeable, the tumor purity was low and the level of immune escape was high in OC groups. Besides, AKT.inhibitor.VIII,A.443654,LFM.A13,BMS.509744 and BMS.536924 were positively associated with the risk score. Furthermore, the TF-mRNA regulatory network of OC was constructed, among them, EGR1 was the key TF which could regulate ALDH5A1 and TPMT simultaneously. The qRT-PCR proved the up-regulated expression levels of ALDH5A1, CETP, PTH and TPMT in OVCA429, hey and OVCAR-8. IHC results confirmed significantly higher protein expression of CETP, ALDH5A1, and PTH in ovarian cancer tissues compared to normal controls (p < 0.05), further validating their roles as potential prognostic biomarkers. This study identified 5 biomarkers associated with the prognosis of OC, which might be helpful in understanding the roles of PMRGs in the development of OC in depth. The IHC validation provided additional evidence at the protein level, reinforcing the clinical relevance of these findings. Show less

Xylaria nigripes, is a rare medicinal fungus known as Wulingshen in China. It has a neutral and sweet nature and belongs to the heart and kidney meridians. Rich in a variety of bioactive ingredients, it serves as a nutrient-dense food and a therapeutic agent for disease prevention. Wuling powder, a fermented form of X. nigripes, leverages biotechnology to harness the fungus's health benefits, showing significant therapeutic efficacy clinically, offering patients a safer and more effective treatment option. This article reviews the recent progress in the biological characteristics, chemical constituents, and pharmacological effects of X. nigripes. Additionally, it evaluates the modern clinical applications of Wuling powder and the current state of product development, aiming to provide insights for its further development and utilization. Research materials were collected from databases including SciFinder, PubMed, and Web of Science, encompassing over 20 years of academic literature, including books, doctoral dissertations, and master's theses from 2004 to October 2024. The literature search integrated keywords related to "X. nigripes", "Wulingshen", "Leizhenzi", "Wuling powder", "biological characteristics", "pharmacological profile", "chemical constituents", and "clinical applications", used in both English and Chinese. This review highlights the chemical diversity and bioactivities of 82 compounds identified from X. nigripes between 2004 and October 2024. Among these, 26 compounds exhibit diverse pharmacological properties, including antioxidant, anti-inflammatory, neuroprotective, anti-tumor, and cholesteryl ester transfer protein (CETP) inhibitory activities. Both aqueous and ethanol extracts of X. nigripes demonstrate comparable bioactivities. Clinical studies have further validated the efficacy of Wuling powder (dried mycelium product of X. nigripes) in regulating mental health, alleviating insomnia, and treating related disorders. The review also explores the product development status and potential of X. nigripes, analyzing its market prospects. Furthermore, it addresses advancements in artificial cultivation and industrial production, emphasizing the importance of sustainable supply chains for ongoing research and commercial applications. X. nigripes, with its elusive specific ingredients, is recognized for its potential health benefits and has been extensively researched. Due to its notable bioactive effects on human health, X. nigripes and its application, Wuling powder, have garnered considerable attention and have undergone extensive research. Recent multidimensional and interdisciplinary research approaches have achieved a deeper understanding of the biochemical nature and pharmacological effects of X. nigripes. This has led to the accumulation of substantial practical experience in the clinical application of Wuling powder-based medicines. Concurrently, the development of health products, deep fermentation technology, artificial cultivation and deep fermentation technology of X. nigripes have been successfully achieved. It is anticipated that X. nigripes holds the potential to emerge as a pivotal resource for the development of novel pharmaceuticals and therapeutic strategies targeting various human ailments. Show less

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as Show less

This study examines pediatric cardiomyopathies by analyzing genetic and clinical data from 55 patients (2021-2024) at Beijing Anzhen Hospital. Four subtypes were studied: dilated (DCM, 24), hypertrophic (HCM, 22), arrhythmogenic right ventricular (ARVC, 7), and restrictive (RCM, 2). Clinical data, imaging, labs, and family histories were collected, with whole-exome sequencing (WES) identifying disease-causing variants classified via ACMG guidelines. Statistical analysis revealed a median age of 11 years, a proportion of 58% male participants, and ethnic diversity (21 northern Han, 29 southern Han, 5 minorities). In the cohort, 13 cases had an LVEF below 35%. Pathogenic/likely pathogenic (P/LP) variants were found in 21.8% of the patients, and variants of uncertain significance (VUS) were present in 38.2%, with Show less

Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensively studied. This study aimed to explore clinical characteristics and the usage of electrolytes and AAs in children with PCMs. Children diagnosed with PCMs who had genetic test reports were included. Relevant information was collected and processed, and clinical characteristics and mutated genes were clarified. Gene databases were searched to explore related electrolytes and AAs in the treatment of PCMs. The effect of calcium was explored in children with DCM. Paired samples T tests and nonparametric Wilcoxon signed-rank tests were performed for comparison between before and after using calcium. In this study, 27 children with gene test results were enrolled to perform gene-related analysis. The median age was 2.5 years old. Mutated genes were collected, including pathogenic, likely pathogenic, uncertain significance, and other mutations. The most frequently mutated genes related to dilated cardiomyopathy (DCM) were For children with DCM, calcium supplements may be beneficial. AAs, including serine, cysteine, and arginine, could be used for supplementary treatment in children with DCM and HCM. Show less

Multiplexed assays of variant effect (MAVEs) systematically measure variant function but have been limited to cancer cell lines rather than disease-relevant cell types. We developed saturation genome editing in human iPSCs (iPSC-SGE) to introduce variant libraries into a single allele of a target gene while programming the genetic background of the second allele, enabling variant assessment across differentiated cell types and genetic contexts at scale. We edited 1,137 variants into Show less

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, is characterized by phenotypic and genetic heterogeneity. The present study describes the genotype data of a Swedish cohort of patients with HCM, the largest genetics study on Swedish HCM patients to date. The primary aims of this study were to unravel the main genetic findings and explore genotype-phenotype associations in this HCM cohort. Longitudinal data on 225 unrelated HCM index patients from the Southeast health care region in Sweden from 2010 until 2021 were assessed retrospectively. Patients were 46 ± 15.5 years-old, 67.6% males. In the cohort, 172/225 (76.4%) had genetic testing, of whom, 65/172 (38%) were considered genotype positive (G +) for a pathogenic/ likely pathogenic variant, mainly in the two most common sarcomeric genes: MYBPC3 (57%) and MYH7 (34%). In 43% (74/172) of patients, no reportable variants were detected, classified as genotype negative (G-). In the remaining 33 patients (19%), variants of uncertain significance (VUS) were identified; this group was not included in the comparative analyses. Genotype positive patients (G +) were characterized by younger age (p = 0.010), higher prevalence of family history of HCM (p < 0.001), greater maximum left ventricle wall thickness (p = 0.03) and an increased incidence of sudden cardiac death (SCD) (p = 0.045). At first clinical screening, HCM was diagnosed in 28/65(43%) in the G + families and in 2/74 (2.7%) G-families (p < 0.001). Genotype-positive HCM patients differ with respect to age at presentation, family history of the disease, morphology, incidence of SCD and presence of HCM in their family members at first clinical assessment from genotype-negative patients. Genotype negative status in this HCM cohort, though, did not confer immunity from adverse complications. Show less

Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N cases ~ 13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Show less

Primary hypertrophic cardiomyopathy (HCM) is predominantly a genetic disease causing left ventricular hypertrophy in the absence of other cardiac and systemic metabolic diseases. Currently, limited data exist on the prevalence of clinically actionable gene variants for primary HCM in South Asian Indian (SAI) patients, which are necessary for minimizing disparities in interpreting ancestry-specific variants. The ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel categorized HCM-causing genes into 5 categories according to their clinical relevance: definitive, strong, moderate, limited, and disputed. However, comprehensive studies examining this classification in SAI patients are lacking. Whole-exome sequencing was performed for 335 primary SAI patients with HCM, including all known cardiovascular genes and clinically actionable gene categories to determine their allele frequencies. SAI HCM exomes revealed a total of 193 pathogenic/likely pathogenic variants and variants of uncertain significance across 26 clinically actionable genes in 119 (35.52%) of 335 cases. The SAI HCM exhibited significantly fewer variants in the 12 definitive category genes compared with other global HCM cohorts (15.77% versus 43.23%; The clinically actionable gene variants in SAI HCM differed significantly from other global HCM cohorts, specifically Show less