Overview of a novel osmotin abolishes abnormal metabolic-associated adiponectin mechanism in Alzheimer's disease: Peripheral and CNS insights.

Alzheimer's disease (AD) is a degenerative brain disease that affects millions of people worldwide. It is caused by abnormalities in cholinergic neurons, oxidative stress, and inflammatory cascades. The illness is accompanied by personality changes, memory issues, and dementia. Metabolic signaling pathways help with fundamental processes like DNA replication and RNA transcription. Being adaptable is essential for both surviving and treating illness. The body's metabolic signaling depends on adipokines, including adiponectin (APN) and other adipokines secreted by adipose tissues. Energy homeostasis is balanced by adipokines, and nutrients. Overconsumption of nutrients messes with irregular signaling of adipokines, such as APN in both peripheral and brain which leads to neurodegeneration, such as AD. Despite the failure of traditional treatments like memantine and cholinesterase inhibitors, natural plant bioactive substances like Osmotin (OSM) have been given a focus as potential therapeutics due to their antioxidant properties, better blood brain barrier (BBB) permeability, excellent cell viability, and especially nanoparticle approaches. The review highlights the published preclinical literature regarding the role of OSM in AD pathology while there is a need for more research to investigate the hidden therapeutic potential of OSM which may open a new gateway and further strengthen its healing role in the pathogenesis of neurodegeneration, especially AD.

Analysis of metabolic syndrome in bilateral upper urinary tract stones: A retrospective study of 3905 cases.

Bilateral upper urinary tract stones are significantly related to renal function damage. However, few studies characterized the risk factors of bilateral upper urinary tract stones. We retrospectively enrolled 3905 patients with urinary tract stones from March 2019 to March 2022 at the Second Hospital of Tianjin Medical University. Patients were divided into two groups according to the location of the stones, and the related data were evaluated. In this study, 2485 unilateral and 1420 bilateral stone patients were included. Multivariate logistic regression analysis showed that BMI, gout, hyperparathyroidism, uric acid stone, urine PH, 24-h urinary calcium, blood uric acid, and metabolic syndrome (Mets) were independent risk factors for bilateral stone formation(P < 0.05). Based on these results, we construct a discrimination model. This model revealed good discrimination with an area under the receiver operating characteristic curves of 0.617, and the sensitivity and specificity were 0.592 and 0.586, respectively. Furthermore, the number of Mets components increased the risk of bilateral upper urinary tract stones. Hypertension, hyperglycemia, and low HDL level were strongly associated with bilateral upper urinary tract stones (P < 0.05). Patients with 5 components Mets had 1.89-fold higher risk of bilateral upper urinary tract stones than those with 1 component Mets (OR 3.381; 95 % CI 1.221-9.360; P = 0.013). Additionally, male patients with Mets had higher risk of bilateral upper urinary tract stones than female patients. Our analysis revealed that eight clinical factors were associated with the formation of bilateral upper urinary tract stones, namely BMI, gout, hyperparathyroidism, uric acid stone, urine PH, 24-h urinary calcium, blood uric acid, and Mets. This study could help clinicians adjust treatment strategies for high-risk patients with bilateral upper urinary tract stones.

WRN loss accelerates abnormal adipocyte metabolism in Werner syndrome.

BACKGROUND: Metabolic dysfunction is one of the main symptoms of Werner syndrome (WS); however, the underlying mechanisms remain unclear. Here, we report that loss of WRN accelerates adipogenesis at an early stage both in vitro (stem cells) and in vivo (zebrafish). Moreover, WRN depletion causes a transient upregulation of late-stage of adipocyte-specific genes at an early stage. METHODS: In an in vivo study, we generated wrn-/- mutant zebrafish and performed histological stain and Oil Red O staining to assess the fat metabolism. In an in vitro study, we used RNA-seq and ATAC-seq to profile the transcriptional features and chromatin accessibility in WRN depleted adipocytes. Moreover, we performed ChIP-seq to further study the regulatory mechanisms of metabolic dysfunction in WS. RESULTS: Our findings show that mechanistically WRN deficiency causes SMARCA5 upregulation. SMARCA5 is crucial in chromatin remodeling and gene regulation. Additionally, rescuing WRN could normalize SMARCA5 expression and adipocyte differentiation. Moreover, we find that nicotinamide riboside (NR) supplementation restores adipocyte metabolism in both stem cells and zebrafish models. CONCLUSIONS: Our findings unravel a new mechanism for the influence of WRN in the early stage of adipogenesis and provide a possible treatment for metabolic dysfunction in WS. These data provide promising insights into potential therapeutics for ageing and ageing-related diseases.

Emerging nanomaterials targeting macrophage adapted to abnormal metabolism in cancer and atherosclerosis therapy (Review).

Macrophages, as highly heterogeneous and plastic immune cells, occupy a pivotal role in both pro­inflammatory (M1) and anti­inflammatory (M2) responses. While M1­type macrophages secrete pro­inflammatory factors to initiate and sustain inflammation, M2­type macrophages promote inflammation regression and uphold tissue homeostasis. These distinct phenotypic transitions in macrophages are closely linked to significant alterations in cellular metabolism, encompassing key response pathways such as glycolysis, pentose phosphate pathway, oxidative phosphorylation, lipid metabolism, amino acid metabolism, the tricarboxylic acid cycle and iron metabolism. These metabolic adaptations enable macrophages to adapt their activities in response to varying disease microenvironments. Therefore, the present review focused primarily on elucidating the intricate metabolic pathways that underlie macrophage functionality. Subsequently, it offers a comprehensive overview of the current state­of­the­art nanomaterials, highlighting their promising potential in modulating macrophage metabolism to effectively hinder disease progression in both cancer and atherosclerosis.

Abnormal Iron and Lipid Metabolism Mediated Ferroptosis in Kidney Diseases and Its Therapeutic Potential.

Ferroptosis is a newly identified form of regulated cell death driven by iron-dependent phospholipid peroxidation and oxidative stress. Ferroptosis has distinct biological and morphology characteristics, such as shrunken mitochondria when compared to other known regulated cell deaths. The regulation of ferroptosis includes different molecular mechanisms and multiple cellular metabolic pathways, including glutathione/glutathione peroxidase 4(GPX4) signaling pathways, which are involved in the amino acid metabolism and the activation of GPX4; iron metabolic signaling pathways, which are involved in the regulation of iron import/export and the storage/release of intracellular iron through iron-regulatory proteins (IRPs), and lipid metabolic signaling pathways, which are involved in the metabolism of unsaturated fatty acids in cell membranes. Ferroptosis plays an essential role in the pathology of various kidneys diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), autosomal dominant polycystic kidney disease (ADPKD), and renal cell carcinoma (RCC). Targeting ferroptosis with its inducers/initiators and inhibitors can modulate the progression of kidney diseases in animal models. In this review, we discuss the characteristics of ferroptosis and the ferroptosis-based mechanisms, highlighting the potential role of the main ferroptosis-associated metabolic pathways in the treatment and prevention of various kidney diseases.

Glomerular Hyperfiltration Interacts With Abnormal Metabolism to Enhance Arterial Stiffness in Middle-Aged and Elderly People.

Introduction: Glomerular hyperfiltration (GHF) is an early kidney injury. We investigated whether GHF is associated with arterial stiffness expressed by increase of brachial-ankle pulse wave velocity (baPWV) and pulse pressure (PP), and whether the coexistence of GHF and abnormal metabolism increases the risk of arterial stiffness. Methods: In this prospective cohort study, 2,133 non-chronic kidney disease (CKD) participants aged ≥40 years were followed for a mean period of 3.3 years. The extent of arterial stiffness was expressed by measures of baPWV and PP. GHF was defined as eGFR exceeding the age- and sex-specific 90th percentile. Multivariate logistic regression models were used to assess the association between GHF/abnormal metabolism and increased baPWV/PP. The interaction indexes of GHF and abnormal metabolism on arterial stiffness were calculated based on the OR in a multivariate logistic regression model. Results: GHF alone was not associated with increased baPWV or PP in all participants in this study. However, when GHF coexisted with abnormal metabolism, the risk of increased PP increased 3.23-fold [OR = 3.23(1.47-7.13)] compared with participants with normal filtration and normal metabolism, in which the interaction accounted for 55.1% of the total effect and 79.8% of the effect from GHF and abnormal metabolism. After subtracting the independent effects of GHF and abnormal metabolism, their combined effect still resulted in a 1.78-fold increase in PP. Conclusion: GHF could interact with abnormal metabolism to significantly enhance arterial stiffness. Since abnormal metabolism commonly exists in the general population, even slight changes in renal function should be distinguished to prevent arterial stiffness risk.

Abnormal amyloid beta metabolism in systemic abnormalities and Alzheimer's pathology: Insights and therapeutic approaches from periphery.

Alzheimer's disease (AD) is an age-associated, multifactorial neurodegenerative disorder that is incurable. Despite recent success in treatments that partially improve symptomatic relief, they have failed in most clinical trials. Re-holding AD for accurate diagnosis and treatment is widely known as a challenging task. Lack of knowledge of basic molecular pathogenesis might be a possible reason for ineffective AD treatment. Historically, a majority of therapy-based studies have investigated the role of amyloid-ß (Aß peptide) in the central nervous system (CNS), whereas less is known about Aß peptide in the periphery in AD. In this review, we provide a comprehensive summary of the current understanding of Aß peptide metabolism (anabolism and catabolism) in the brain and periphery. We show that the abnormal metabolism of Aß peptide is significantly linked with central-brain and peripheral abnormalities; the interaction between peripheral Aß peptide metabolism and peripheral abnormalities affects central-brain Aß peptide metabolism, suggesting the existence of significant communication between these two pathways of Aß peptide metabolism. This close interaction between the central brain and periphery in abnormal Aß peptide metabolism plays a key role in the development and progression of AD. In conclusion, we need to obtain a full understanding of the dynamic roles of Aß peptide at the molecular level in both the brain and periphery in relation to the pathology of AD. This will not only provide new information regarding the complex disease pathology, but also offer potential new clues to improve therapeutic strategies and diagnostic biomarkers for the successful treatment of AD.

Bacteroides Fragilis Polysaccharide A Ameliorates Abnormal Voriconazole Metabolism Accompanied With the Inhibition of TLR4/NF-κB Pathway.

The antifungal agent voriconazole (VRC) exhibits extreme inter-individual and intra-individual variation in terms of its clinical efficacy and toxicity. Inflammation, as reflected by C-reactive protein (CRP) concentrations, significantly affects the metabolic ratio and trough concentrations of voriconazole. Bacteroides fragilis (B. fragilis) is an important component of the human intestinal microbiota. Clinical data have shown that B. fragilis abundance is comparatively higher in patients not presenting with adverse drug reactions, and inflammatory cytokine (IL-1ß) levels are negatively correlated with B. fragilis abundance. B. fragilis natural product capsular polysaccharide A (PSA) prevents various inflammatory disorders. We tested the hypothesis that PSA ameliorates abnormal voriconazole metabolism by inhibiting inflammation. Germ-free animals were administered PSA intragastrically for 5 days after lipopolysaccharide (LPS) stimulation. Their blood and liver tissues were collected to measure VRC concentrations. PSA administration dramatically improved the resolution phase of LPS-induced hepatic VRC metabolism and inflammatory factor secretion. It reversed inflammatory lesions and alleviated hepatic pro-inflammatory factor secretion. Both in vitro and in vivo data demonstrate that PSA reversed LPS-induced IL-1ß secretion, downregulated the TLR4/NF-κB signaling pathway and upregulated CYP2C19 and P-gp. To the best of our knowledge, this study is the first to show that PSA from the probiotic B. fragilis ameliorates abnormal voriconazole metabolism by inhibiting TLR4-mediated NF-κB transcription and regulating drug metabolizing enzyme and transporter expression. Thus, PSA could serve as a clinical adjunct therapy.

Mechanisms Underlying Hepatocellular Carcinoma Progression in Patients with Type 2 Diabetes.

Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths from solid tumors worldwide. The incidence of type 2 diabetes mellitus (T2DM) has increased worldwide in conjunction with the expansion of the Western lifestyle. Furthermore, patients with T2DM have been documented to have an increased risk of HCC, as well as bile tract cancer. Growing evidence shows that T2DM is a strong additive metabolic risk factor for HCC, but how diabetes affects the incidence of HCC requires additional investigation. In this review, we discuss the underlying mechanisms of HCC in patients with T2DM. Topics covered include abnormal glucose and lipid metabolism, hyperinsulinemia, and insulin resistance; the effect of activated platelets; hub gene expression associated with HCC; inflammation and signaling pathways; miRNAs; altered gut microbiota and immunomodulation. The evidence suggests that reducing obesity, diabetes, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis through efficient measures of prevention may lead to decreased rates of T2DM-related HCC.

Possible Metabolic Alterations among Autistic Male Children: Clinical and Biochemical Approaches.

The present cross-sectional, hospital-based study was carried out on 146 Egyptian male children, 73 males with autism who were comparable with another 73 healthy age- and sex-matched children, recruited from the outpatients' psychiatric clinics of the Neuropsychiatric and Pediatric Departments of South Valley and Assiut University Hospitals, Egypt. Neuropsychological assessments of autistic males were done using CARS, short sensory profile and intelligent quotients. Serum markers of mitochondrial dysfunction (lactate, pyruvate, and lactate to pyruvate ratio, creatine kinase (CK), L-carnitine, ammonia, lactate dehydrogenase, pyruvate kinase, alanine transaminase and aspartate transaminase), oxidative stress and blood levels of heavy metals (mercury, lead and aluminium) were measured. Serum cholesterol, cortisol, free testosterone, estradiol, dehydroepiandrostenedione, adenosine deaminase and Helicobacter pylori antigen in stool were also performed. There was evidence of mitochondrial dysfunction among autistic children. Additionally, there were significantly lower serum total cholesterol, cortisol and estradiol as well as significantly higher dehydroepiandrostenedione (DHEA) and free testosterone (p < 0.05 for all markers). Twenty-eight (38%) cases were positive for H. pylori antigen in their stool with significant higher serum ammonia and lower adenosine deaminase than in H. pylori-negative autistic children. Mitochondrial dysfunction, H. pylori infection and low cholesterol were prevalent among autistic male children, which should be targeted during autism management.

A newly discovered ubiquitin-conjugating enzyme E2 correlated with the cryogenic autolysis of Volvariella volvacea.

In Volvariella volvacea, a species of edible mushroom, cryogenic autolysis is a typical part of abnormal metabolism. Previous functional annotation cluster analyses of cold-induced gene expression profiles have shown that the ubiquitin-conjugating enzyme E2 (UBE2), rather than the cyclin-like F-box domain alone, forms the functional cluster. In this study, analysis of gene expression profiling showed that only one type of UBE2 in V. volvacea (UBEV2) was significantly up-regulated. Further quantitative real-time PCR analysis confirmed that the expression of UBEV2 was significantly up-regulated (P<0.05) after cold-treatment lasting 4, 6, and 8h. This provided evidence that UBEV2 was closely correlated with cryogenic autolysis. The specific distribution of UBEV2 in recently diverged herb decay fungi indicated that UBEV2 was not evolutionarily correlated with early diverging fungi. Phylogenetic analysis indicated that UBEV2 was generated by horizontal gene transfer (HGT) from the ancestry of Selaginella moellendorffii UBE2. Further relative time estimation and detection of natural selection showed that there has been recent positive selection after HGT in UBEV2. Molecular modeling and logo analysis showed that the cysteine-cysteine motif is the characteristic of the UBEV2 family. These observations indicate that UBEV2 is a new type of UBE2 correlated with the cryogenic autolysis of V. volvacea.

A specific type of cyclin-like F-box domain gene is involved in the cryogenic autolysis of Volvariella volvacea.

Cryogenic autolysis is a typical phenomenon of abnormal metabolism in Volvariella volvacea. Recent studies have identified 20 significantly up-regulated genes via high-throughput sequencing of the mRNAs expressed in the mycelia of V. volvacea after cold exposure. Among these significantly up-regulated genes, 15 annotated genes were used for functional annotation cluster analysis. Our results showed that the cyclin-like F-box domain (FBDC) formed the functional cluster with the lowest P-value. We also observed a significant expansion of FBDC families in V. volvacea. Among these, the FBDC3 family displayed the maximal gene expansion in V. volvacea. Gene expression profiling analysis revealed only one FBDC gene in V. volvacea (FBDV1) that was significantly up-regulated, which is located in the FBDC3 family. Comparative genomics analysis revealed the homologous sequences of FBDV1 with high similarity were clustered on the same scaffold. However, FBDV1 was located far from these clusters, indicating the divergence of duplicated genes. Relative time estimation and rate test provided evidence for the divergence of FBDV1 after recent duplications. Real-time RT-PCR analysis confirmed that the expression of the FBDV1 was significantly up-regulated (P < 0.001) after cold-treatment of V. volvacea for 4 h. These observations suggest that the FBDV1 is involved in the cryogenic autolysis of V. volvacea.