Search Results (31)

Tibia morphology is a significant factor in poultry germplasm and market traits. Copy number variation (CNV) has been identified as a structural source of genetic variation for complex traits. We profiled genome-wide CNVs in Dong Tao chickens and nine other local breeds and performed a breed-based case–control CNV-GWAS (Dong Tao vs. reference breeds). We sequenced 152 chickens, including 46 Dong Tao, and annotated genes and pathways. A total of 22,972 CNVs were detected, of which 2193 were retained after filtration across 33 chromosomes, with sizes ranging from 2 kilobases to 12.8 megabases. Principal component analysis indicated an overall weakness in the breed structure and a sex-related trend within Dong Tao. A deletion on chromosome 3 at 36,529,501 to 36,539,000 was observed in Dong Tao. The exploratory screen identified 44 CNV regions at nominal significance (p < 0.05), distinguishing Dong Tao from other breeds. Thirty-seven regions contained 99 genes, including CHRM3 within the chromosome 3 deletion and CRADD overlapping two CNVs. Enrichment analysis indicated thiamine metabolism and growth hormone receptor signalling as the primary pathways of interest, with TPK1, SOCS2, and FHIT identified as potential candidates. These results provide a CNV landscape for Dong Tao and prioritize variant regions and pathways potentially relevant to its robust tibia morphology; however, no direct CNV–tibia phenotype regression was performed. Full article

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Since numerous studies highlight the significance of cholinergic system components in tumor development, acetylcholine (ACh) and the differential activation of its receptors could play a crucial role in GBM progression. The aim of this study was to test this hypothesis by assessing the relevance of the cholinergic system in GBM cells and their microenvironment. We analyzed bulk RNA-seq expression data using the TIMER2.0 web server, focusing on the impact of patient survival in relation to muscarinic receptors (CHRM) and neutrophil infiltration in low-grade glioma (LGG) and GBM. Our analysis revealed a marked decrease in survival associated with all CHRMs, particularly in LGG. Moreover, GBM showed higher neutrophil infiltration and reduced survival, especially in relation to CHRM3. These findings were validated in the U251 cell line and in human GBM tumor biopsies (GBM-b), which also displayed CHRM3 expression. Additionally, we show that GBM cells exposed to cholinergic stimulation exhibited increased vascular endothelial growth factor (VEGF), IL-8 production, and PD-L1 expression, while the VEGF increase was blocked by tiotropium (Tio), a CHRM3 antagonist. Similarly, polymorphonuclear cells from GBM patients (PMN-p) displayed increased PD-L1 expression and IL-8 production upon cholinergic stimulation. Finally, as we previously reported on the relevance of thymic stromal lymphopoietin (TSLP) in GBM pathophysiology, here, we found that TSLP upregulated CHRM3 expression. Our findings highlight the importance of the cholinergic system in the tumor microenvironment, where it may act directly on tumor cells or influence neutrophil physiology, thereby modulating tumor progression. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, oxidative/nitrosative stress, and neuroinflammation. Marine green algae Caulerpa racemosa are rich in neuroactive lipids and fatty acid derivatives with reported antioxidant and anti-inflammatory properties. However, their integrated mechanistic potential against AD remains largely underexplored. This study aimed to elucidate the neuroprotective mechanisms of C. racemosa metabolites against AD using integrative metabolomics, network pharmacology, molecular docking, and in vitro validation assays. Untargeted LC–HRMS profiling was performed to identify major metabolites in the ethanolic extract of C. racemosa. Neuroprotective targets were predicted via TargetNet, STRING, and Cytoscape (MCODE, CytoNCA). Functional enrichment was conducted using KEGG, GO (BP, MF, CC), and ClueGO. Molecular docking (CB-Dock2) validated compound–target interactions with ACHE, CHRM1, NOS1, and NOS2. Antioxidant (DPPH) and cholinesterase (AChE/BChE) inhibitory activities were evaluated in vitro. Metabolomic profiling identified lipid-dominant metabolites—oleamide, hexadecanamide, palmitoyl ethanolamide, α-linolenic acid, α-eleostearic acid, and 9-oxo-octadecadienoic acid. Network analysis revealed key AD-related hubs (ACHE, CHRM1, NOS1, NOS2) enriched in cholinergic regulation, arachidonic-acid metabolism, oxidative stress response, and nitric oxide signaling. Docking showed moderate multi-target affinities (−6.0 to −8.4 kcal/mol), with α-linolenic acid, α-eleostearic acid, and oxidized C18 lipids exhibiting the strongest interactions—particularly with ACHE and NOS isoforms. In vitro assays showed moderate antioxidant activity (IC₅₀ = 120.97 ± 10.93 µg/mL) and cholinesterase inhibition (AChE IC₅₀ = 136.48 ± 1.70 µg/mL; BChE IC₅₀ = 145.98 ± 3.28 µg/mL), aligning with predicted multi-target interactions. C. racemosa extract exhibits neuroprotective potential through a synergistic combination of cholinergic modulation, antioxidant activity, NOS-mediated nitrosative stress reduction, and suppression of arachidonic-acid inflammatory pathways. These findings support C. racemosa as a promising marine-derived multi-target candidate for AD intervention, warranting further mechanistic and in vivo evaluation. Full article

Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent urological malignancy, accounting for approximately 1.6% of all cancer-related deaths in 2022. While endocrine-disrupting chemicals (EDCs) have been implicated as risk factors for ccRCC, the toxicological profiles and immune mechanisms underlying Bisphenol A (BPA) exposure in ccRCC progression remain inadequately understood. Materials and Methods: Protein–protein interaction (PPI) analysis and visualization were performed on overlapping genes between ccRCC and BPA exposure. This was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to elucidate potential underlying mechanisms. Subsequently, 108 distinct machine learning algorithm combinations were evaluated to identify the optimal predictive model. An integrated CoxBoost and Ridge regression model was constructed to develop a prognostic signature, the performance of which was rigorously validated across two independent external datasets. Finally, molecular docking analyses were employed to investigate interactions between key genes and BPA. Results: A total of 114 overlapping targets associated with both ccRCC and BPA were identified. GO and KEGG analyses revealed enrichment in cancer-related pathways, including pathways in cancer, endocrine resistance, PD-L1 expression and PD-1 checkpoint signaling, T-cell receptor signaling, endocrine function, and immune responses. Machine learning algorithm selection identified the combined CoxBoost-Ridge approach as the optimal predictive model (achieving a training set concordance index (C-index) of 0.77). This model identified eight key genes (CHRM3, GABBR1, CCR4, KCNN4, PRKCE, CYP2C9, HPGD, FASN), which were the top-ranked by coefficient magnitude in the prognostic model. The prognostic signature demonstrated robust predictive performance in two independent external validation cohorts (C-index = 0.74 in cBioPortal; C-index = 0.81 in E-MTAB-1980). Furthermore, molecular docking analyses predicted strong binding affinities between BPA and these key targets (Vina scores all <−6.5 kcal/mol), suggesting a potential mechanism through which BPA may modulate their activity to promote renal carcinogenesis. Collectively, These findings suggested potential molecular mechanisms that may underpin BPA-induced ccRCC progression, generating hypotheses for future experimental validation. Conclusions: These findings enhance our understanding of the molecular mechanisms by which BPA induces ccRCC and highlight potential targets for therapeutic intervention, particularly in endocrine and immune-related pathways. This underscores the need for collaborative efforts to mitigate the impact of environmental toxins like BPA on public health. Full article

Background/Objectives: Type 2 diabetes (T2D) is a clinically and genetically heterogeneous disease. In this study, we aimed to stratify patients with T2D from the Volga-Ural region of Eurasia into distinct subgroups based on clinical characteristics and to investigate the genetic underpinnings of these clusters. Methods: A total of 254 Tatar individuals with T2D and 361 ethnically matched controls were recruited. Clinical clustering was performed using k-means and hierarchical algorithms on five variables: age at diagnosis, body mass index (BMI), glycated hemoglobin (HbA1c), insulin resistance (HOMA-IR), and β-cell function (HOMA-B). Genetic association analysis was conducted using logistic regression under an additive model, adjusted for age and sex, and corrected for multiple comparisons using the Benjamini–Hochberg method. Results: Four distinct T2D subtypes were identified—mild age-related diabetes (MARD, n = 25), mild obesity-related diabetes (MOD, n = 72), severe insulin-resistant diabetes (SIRD, n = 66), and severe insulin-deficient diabetes (SIDD, n = 52)—each with unique clinical and comorbidity profiles. SIDD patients exhibited the highest burden of microvascular complications and lowest estimated glomerular filtration rate. Nine genetic variants showed significant associations with T2D and/or specific subtypes, including loci in genes related to neurotransmission (e.g., HTR1B, CHRM5), appetite regulation (NPY2R), insulin signaling (TCF7L2, PTEN), and other metabolic pathways. Some variants demonstrated subtype-specific associations, underscoring the genetic heterogeneity of T2D. Conclusions: Our findings support the utility of clinical clustering in uncovering biologically and clinically meaningful T2D subtypes and reveal genetic variants that may contribute to this heterogeneity. These insights may inform future precision medicine approaches for T2D diagnosis and management. Full article

Background/Objectives: BuZhong Yiqi Formula (BZYQF) has significant ameliorative effects on type 2 diabetes mellitus (T2DM). However, its efficacy in alleviating the hyposalivation caused by T2DM needs to be confirmed, and its mechanism is unclear. Methods: Network pharmacology and molecular docking were combined to analyze the molecular mechanism by which BZYQF alleviates T2DM-caused hyposalivation. A T2DM rat model was induced to evaluate the efficacy of BZYQF. The total saliva before and after acid stimulation was collected to determine the salivary flow rate and salivary alpha-amylase (sAA) activity. The parotid (PG) and submandibular glands (SMG) of experimental rats were removed to perform histopathology observation, biochemical indicator determination, and expression detection of signaling molecules in the salivary secretion pathway. Results: The present study screened out 1014 potential targets of BZYQF regarding the treatment of T2DM. These targets were mainly involved in the formation of the receptor complex, exercising the neurotransmitter receptor activity and regulating secretion. They were significantly enriched in the salivary secretion pathway of β1-AR/PKA/AMY1 and CHRM3/IP3R/AQP5. Furthermore, in BZYQF, nine validated compounds were able to dock into the active site of β1-AR, and three validated compounds were able to dock into the active site of CHRM3. Animal experiments confirmed that BZYQF significantly reduces fasting blood glucose, total cholesterol and triglyceride levels; enhances insulin level and HOMA-IS (p < 0.05); and increases salivary flow rate (Basal: increase from 21.04 ± 14.31 to 42.65 ± 8.84 μL/min, effect size of Cohen’s d = 6.80, p = 0.0078; Stimulated: increase from 36.88 ± 17.48 to 72.63 ± 17.67 μL/min, effect size of Cohen’s d = 7.61, p = 0.0025) and sAA activity (Basal: increase from 0.68 ± 0.32 to 2.17 ± 0.77 U/mL, effect size of Cohen’s d = 9.49, p = 0.0027; Stimulated: increase from 1.15 ± 0.77 to 4.80 ± 1.26 U/mL, effect size of Cohen’s d = 13.10, p = 0.0001) in basal and stimulated saliva in T2DM rats. Further mechanistic studies revealed that BZYQF reduces glucose and lipid accumulation, enhances acetylcholine content, improves pathological lesions and inflammation, and significantly increases the expression of salivary secretion pathway signaling molecules, including PKA, IP3R, β1-AR, AQP5, CHRM3, and AMY1 in the PG and SMG of T2DM rats (p < 0.05). Conclusions: The present study demonstrated that BZYQF is able to alleviate T2DM-caused hyposalivation by improving glucose metabolism and activating the salivary secretion pathway in the PG and SMG of T2DM rats. This study might provide a novel rationale and treatment strategy for BZYQF in diabetes-induced hyposalivation in a clinical setting. Full article

Knowledge of how novel antigens or dietary stimuli affect stomach development and function in pigs remains limited. This study aimed to investigate stomach characteristics, parietal cell numbers, and the expression of genes essential to the functioning of the fundic and pyloric gland regions at weaning compared to seven days post-weaning and to examine whether maternal probiotic supplementation or piglet dietary tryptophan (Trp) levels influence these stomach parameters. This study has a 2 × 3 factorial design, with 48 sows assigned to one of two diets: basal or basal supplemented with Bacillus subtilis and Bacillus amyloliquefaciens. Their litters received creep diets containing 0.22, 0.27, or 0.33% standardized ileal digestible (SID) Trp. In total, 96 pigs were sacrificed for gastric sampling, 48 on the day of weaning and 48 on day 7 post-weaning. At 7 days post-weaning, pigs had an increased number of parietal cells and expression of parietal cell activity and digestive enzyme (PGA5 and CHIA) genes in the fundic gland region (p < 0.05), although the expression of signaling molecules involved in the regulation of acid secretion was unchanged in the fundic gland region (p > 0.05) and reduced in the pyloric gland region (p < 0.05), compared to the day of weaning. Overall, maternal probiotic supplementation had a significant impact on gene expression in the fundic gland region of the offspring, elevating several genes related to parietal cell activity (CLIC6, HRH2, KCNE1, KCNQ1, CHRM3, CCKBR, and SSTR2) (p < 0.05). Additionally, there were time × maternal interactions, where certain acid secretion pathway (ATP4A and HDC), chitinase enzyme (CHIA), and ghrelin (GHRL) genes were increased in offspring from probiotic sows compared to control sows at weaning (p < 0.05), but not at 7 days post-weaning (p > 0.05). Maternal probiotic supplementation did not influence growth performance pre-weaning or during the 7-day post-weaning period. There was a limited effect of creep Trp level or maternal × creep interactions on performance, gene expression, or parietal cell counts. Low pre-weaning creep intake may have confounded this analysis. In conclusion, maternal probiotic supplementation accelerated the maturation of the offspring’s stomach, particularly in terms of the expression of genes linked to acid secretion from parietal cells. Full article

Background: The study presents a detailed examination and follow-up of a Slovenian patient with an Leber Hereditary Optic Neuropathy (LHON)-like phenotype and bilateral optic neuropathy in whom genetic analysis identified a novel variant MT-CYB:m.15309T>C (Ile188Thr). Methods: We provide detailed analysis of the clinical examinations of a male patient with bilateral optic neuropathy from the acute stage to 8 years of follow-up. Complete ophthalmological exam, electrophysiology and optical coherence tomography (OCT) segmentation were performed. The genotype analysis was performed with a complete screening of the mitochondrial genome. Furthermore, proteomic analysis of the protein structure and function was performed to assess the pathogenicity of a novel variant of unknown significance. Mitochondrial function analysis of the patient’s peripheral blood mononuclear cells (PBMCs) was performed with the objective of evaluating the mutation effect on mitochondrial function using flow cytometry and high-resolution respirometry. Results: The patient had a profound consecutive bilateral visual loss at 19 years of age due to optic neuropathy with characteristics of LHON; however, unlike patients with typical LHON, the patient experienced a fluctuation in visual function and significant late recovery. He had a total of three visual acuity deteriorations and improvements in the left eye, with concomitant visual loss in the right eye and a final visual acuity drop reaching nadir 9 months after onset. The visual loss was characterized by centrocecal scotoma, abnormal color vision and abnormal VEP, while deterioration of PERG N95 followed with a lag of several months. The OCT examination showed retinal nerve fiber layer thinning matching disease progression. Following a two-year period of legal blindness, the patient’s visual function started to improve, and over the course of 5 years, it reached 0.5 and 0.7 Snellen (0.3 and 0.15 LogMAR) visual acuity (VA). Mitochondrial sequencing identified a presumably pathogenic variant m.15309T>C in the MT-CYB gene at 65% heteroplasmy, belonging to haplogroup K. Mitochondrial function assessment of the patient’s PBMCs showed a lower respiration rate, an increase in reactive oxygen species production and the presence of mitochondrial depolarization, compared to an age- and sex-matched healthy control’s PBMCs. Conclusions: A novel variant in the MT-CYB:m.15309T>C (Ile188Thr) gene was identified in a patient with optic nerve damage and the LHON phenotype without any additional systemic features and atypical presentation of the disease with late onset of visual function recovery. The pathogenicity of the variant is supported by proteomic analysis and the mitochondrial dysfunction observed in the patient’s PBMCs. Full article

Sleep bruxism (SB) involves involuntary jaw movements during sleep and is potentially caused by motor neuronal hyperexcitability and GABAergic system dysfunction. However, the molecular basis remains unclear. In this study, we aimed to investigate changes in the expression of several genes associated with the pathophysiology of SB. Bulk RNA sequencing (bulk RNA-seq) and single-nucleus RNA sequencing (snRNA-seq) of neurons derived from patient and control human induced pluripotent stem cells (hiPSCs) were performed to comprehensively assess gene expression and cell type-specific alterations, respectively. Bulk RNA-seq revealed significant upregulation of calcium signaling-related genes in SB neurons, including those encoding G protein-coupled receptors and receptor-operated calcium channels. snRNA-seq confirmed the increased expression of GRIN2B (an N-methyl-D-aspartate receptor subunit) and CHRM3 (an M3 muscarinic acetylcholine receptor), particularly in glutamatergic and GABAergic neurons. These alterations were linked to hyperexcitability, with GRIN2B contributing to glutamatergic signaling and CHRM3 contributing to cholinergic signaling. These findings suggest that disrupted calcium signaling and overexpression of GRIN2B and CHRM3 drive neuronal hyperexcitability, providing insight into the pathophysiology of SB. Targeting these pathways may inform therapeutic strategies for SB treatment. Full article

Parkinson’s disease (PD) is characterized by a long prodromal period, during which patients often have sleep disturbances. The histaminergic system and circadian rhythms play an important role in the regulation of the sleep–wake cycle. Changes in the functioning of these systems may be involved in the pathogenesis of early stages of PD and may be age-dependent. Here, we have analyzed changes in the expression of genes associated with the regulation of the sleep–wake cycle (Hnmt, Hrh1, Hrh3, Per1, Per2, and Chrm3) in the substantia nigra (SN) and striatum of normal male mice of different ages, as well as in young and adult male mice with an MPTP-induced model of the early symptomatic stage (ESS) of PD. Age-dependent expression analysis in normal mouse brain tissue revealed changes in Hrh3, Per1, Per2, and Chrm3 genes in adult mice relative to young mice. When gene expression was examined in mice with the MPTP-induced model of the ESS of PD, changes in the expression of all studied genes were found only in the SN of adult mice with the ESS model of PD. These data suggest that age is a significant factor influencing changes in the expression of genes associated with sleep–wake cycle regulation in the development of PD. Full article

Olanzapine is an atypical antipsychotic drug and a potent muscarinic M3 receptor (M3R) antagonist. Olanzapine has been reported to cause metabolic disorders, including dyslipidemia. Anaplastic lymphoma kinase (Alk), a tyrosine kinase receptor well known in the pathogenesis of cancer, has been recently identified as a key gene in the regulation of thinness via the regulation of adipose tissue lipolysis. This project aimed to investigate whether Olanzapine could modulate the hepatic Alk pathway and lipid metabolism via M3R. Female rats were treated with Olanzapine and/or Cevimeline (an M3R agonist) for 9 weeks. Lipid metabolism and hepatic Alk signaling were analyzed. Nine weeks’ treatment of Olanzapine caused metabolic disturbance including increased body mass index (BMI), fat mass accumulation, and abnormal lipid metabolism. Olanzapine treatment also led to an upregulation of Chrm3, Alk, and its regulator Ptprz1, and a downregulation of Lmo4, a transcriptional repressor of Alk in the liver. Moreover, there were positive correlations between Alk and Chrm3, Alk and Ptprz1, and a negative correlation between Alk and Lmo4. However, cotreatment with Cevimeline significantly reversed the lipid metabolic disturbance and adipose tissue accumulation, as well as the upregulation of the hepatic Alk signaling caused by Olanzapine. This study demonstrates evidence that Olanzapine may cause metabolic disturbance by modulating hepatic Alk signaling via M3R, which provides novel insight for modulating the hepatic Alk signaling and potential interventions for targeting metabolic disorders. Full article

Disordered eating contributes to weight gain, obesity, and type 2 diabetes (T2D), but the precise mechanisms underlying the development of different eating patterns and connecting them to specific metabolic phenotypes remain unclear. We aimed to identify genetic variants linked to eating behaviour and investigate its causal relationships with metabolic traits using Mendelian randomization (MR). We tested associations between 30 genetic variants and eating patterns in individuals with T2D from the Volga-Ural region and investigated causal relationships between variants associated with eating patterns and various metabolic and anthropometric traits using data from the Volga-Ural population and large international consortia. We detected associations between HTR1D and CDKAL1 and external eating; between HTR2A and emotional eating; between HTR2A, NPY2R, HTR1F, HTR3A, HTR2C, CXCR2, and T2D. Further analyses in a separate group revealed significant associations between metabolic syndrome (MetS) and the loci in CRP, ADCY3, GHRL, CDKAL1, BDNF, CHRM4, CHRM1, HTR3A, and AKT1 genes. MR results demonstrated an inverse causal relationship between external eating and glycated haemoglobin levels in the Volga-Ural sample. External eating influenced anthropometric traits such as body mass index, height, hip circumference, waist circumference, and weight in GWAS cohorts. Our findings suggest that eating patterns impact both anthropometric and metabolic traits. Full article

NMR and MS/MS-based metabolomics of a cyanobacterial extract from Piti Bomb Holes, Guam, indicated the presence of unique enyne-containing halogenated fatty acid amides. We isolated three new compounds of this class, taveuniamides L-N (1–3), along with the previously reported taveuniamide F (4), which was the most abundant analog. The planar structures of the new compounds were established using 1D and 2D NMR as well as mass spectrometry. We established the configuration of this chemical class to be R at C-8 via Mosher’s analysis of 4 after reduction of the carboxamide group. Our biological investigations with 4 revealed that the compound binds to the cannabinoid receptor CNR1, acting as an antagonist/inverse agonist in the canonical G-protein signaling pathways. In selectivity profiling against 168 GPCR targets using the β-arrestin functional assay, we found that 4 antagonizes GPR119, NPSR1b, CCR9, CHRM4, GPR120, HTR2A, and GPR103, in addition to CNR1. Interestingly, 4 showed a 6.8-fold selectivity for CNR1 over CNR2. The binding mode of 4 to CNR1 was investigated using docking and molecular dynamics simulations with both natural and unnatural stereoisomers, revealing important CNR1 residues for the interaction and also providing a possible reasoning for the observed CNR1/CNR2 selectivity. Full article

The farnesoid-X receptor (FXR), a member of the nuclear hormone receptor superfamily, can be activated by bile acids (BAs). BAs binding to FXR activates BA signaling which is important for maintaining BA homeostasis. FXR is differentially expressed in human organs and exists in immune cells. The dysregulation of FXR is associated with a wide range of diseases including metabolic disorders, inflammatory diseases, immune disorders, and malignant neoplasm. Recent studies have demonstrated that FXR influences tumor cell progression and development through regulating oncogenic and tumor-suppressive pathways, and, moreover, it affects the tumor microenvironment (TME) by modulating TME components. These characteristics provide a new perspective on the FXR-targeted therapeutic strategy in cancer. In this review, we have summarized the recent research data on the functions of FXR in solid tumors and its influence on the TME, and discussed the mechanisms underlying the distinct function of FXR in various types of tumors. Additionally, the impacts on the TME by other BA receptors such as takeda G protein-coupled receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic receptors (CHRM2 and CHRM3), have been depicted. Finally, the effects of FXR agonists/antagonists in a combination therapy with PD1/PD-L1 immune checkpoint inhibitors and other anti-cancer drugs have been addressed. Full article

(1) Introduction: Symptom spectrum can be of great diversity and heterogeneity in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) patients in clinical practice. Here, we report a case of MELAS presenting asymptomatic refractory hypotension with m.3243 A>G mutation. (2) Case representation: A 51-year-old male patient presented with a headache, vertigo, and difficulty in expression and understanding. The magnetic resonance imaging of the brain revealed an acute stroke-like lesion involving the left temporoparietal lobe. A definitive diagnosis of MELAS was given after the genetic test identified the chrM-3243 A>G mutation. The patient suffered recurrent stroke-like episodes in the 1-year follow-up. Notably, refractory hypotension was observed during hospitalizations, and no significant improvement in blood pressure was found after continuous use of vasopressor drugs and fluid infusion therapy. (3) Conclusions: We report a case of refractory hypotension which was unresponsive to fluid infusion therapy found in a patient with MELAS. Our case suggests that comprehensive management should be paid attention to during treatment. A further study on the pathological mechanism of the multisystem symptoms in MELAS would be beneficial to the treatment of patients. Full article