Metabolic Properties Research Articles

Discovery of a Chiral 2,4-Substituted Pyrrolo[2,3-d]pyrimidine as a Potent, Selective, and Orally Bioavailable LRRK2 Inhibitor.

Inhibition of leucine-rich repeat kinase (LRRK2) activity with small molecules has emerged as a potential novel therapeutic target for Parkinson's disease (PD). We have previously reported the identification of SRI-29132 as a potent LRRK2 inhibitor, but the presence of a 6-thioether moiety, which is an oxidative liability, precludes its further development. Herein, we report another hit-to-lead optimization study that led to the discovery of the chiral 2,4-substituted pyrrolo[2,3-d]pyrimidine series as potent LRRK2 inhibitors. Our lead analog 6, derived from a high-throughput screening hit SRI-31255, exhibits excellent LRRK2 inhibition activity and, high selectivity across the kinome. Further, the molecule has acceptable absorption, distribution, metabolism, and excretion (ADME), and pharmacokinetic (PK) properties, as well as brain permeability and no off-target liabilities. This new class of compounds serves as a novel series for further study in the development of LRRK2 inhibitors for therapy.

Phytochemical and Biological Activity Evaluation of Globularia orientalis L

Abstract Globularia orientalis L., a member of the Oleaceae family, is well-adapted to warm climates and a medicinal and aromatic plant traditionally used in treatment methods. In this study, 80% ethanol extract of G. orientalis was obtained, and its enzyme inhibition activity, antioxidant, antimicrobial, and anticancer activities were investigated. Additionally, the metabolic properties of the plant were elucidated through in silico methods. The data revealed '2-Propenoic acid, tridecyl ester' as the major component of this plant. Furthermore, G. orientalis exhibited potent antioxidant activity, and its cytotoxic activity against breast cancer was found to be robust. G. orientalis' chemical constituents were shown to have different actions against breast cancer protein (PDB ID: 1A52 and 1JNX), anti-oxidant protein (PDB ID: 1HD2), AChE enzyme protein (PDB ID: 4M0E), BChE enzyme protein (PDB ID: 5NN0), and α-Gly protein (PDB ID: 1R47). High-activity compounds were subjected to ADME/T analysis. To investigate how compounds in the plant G. orientalis L. affect human metabolism, ADME/T calculations were performed. In conclusion, these findings suggest the need for continued research through activity-guided fractionation to identify the compounds responsible for these effects in future studies. Lastly, the binding free energy of the molecule with the best docking score is computed using MM/GBSA techniques.

Biothermodynamic Analysis of Caenorhabditis elegans: Model of Growth and Metabolism Based on Empirical Formulas, Metabolism Reactions, and Thermodynamic Properties of Living Matter and Metabolism

Caenorhabditis elegans is among the most important model organisms. It has been extensively studied from the perspective of life and biomedical sciences. However, no model of growth and metabolism of C. elegans is available in the literature that is based on biothermodynamics and bioenergetics. Such a model would provide insight into growth and metabolism of C. elegans from the perspective of the fundamental laws of nature. In this research, a chemical and thermodynamic characterization of C. elegans is performed, with the determination of empirical formulas, thermodynamic properties of living matter, reactions of biosynthesis, catabolism and metabolism, thermodynamic properties of biosynthesis, catabolism and metabolism, and phenomenological coefficients. Based on the determined properties, a model of the growth and metabolism of C. elegans is developed. The model is used to discuss the metabolism of C. elegans from the aspect of physical chemistry.

CEFIP-deficiency in mice enhances glucose tolerance despite compromised muscle function.

Mechanotransduction in skeletal muscles is crucial for promoting global physical performance by coordinating muscular strength and metabolic properties, yet the underlying mechanisms and key regulatory molecules remain poorly understood. We identified CEFIP, a Z-disc localized protein upregulated upon contractility acquisition, as a potential integrator maintaining the balance between muscular performance and glucose metabolism. CEFIP deficiency resulted in decreased physical fitness, including lower running capabilities and weaker grip strength, even with no apparent myofiber disorganization. At the molecular levels, CEFIP-deficient mice exhibited dampened expression of STARS, a key mechanosensitive factor, while FHL1 and FHL3 were upregulated, with FHL1 expression further increasing in response to exercise. Despite the overall compromised physical performance, CEFIP-deficient mice unexpectedly led to enhanced insulin responsiveness, and increased muscular AMPK phosphorylation. Moreover, CEFIP-deficient mice exhibited heightened susceptibility to an exercise load, as evidenced by PGC-1a upregulation and augmented GLUT4 regulation, and enhanced insulin sensitivity, as indicated by sarcolemmal GLUT4 translocation. Taken together, our findings suggest that CEFIP serves as a key regulatory link between exercise performance and metabolic properties, potentially through Z-disc-mediated mechanosensitive processes in exercising skeletal muscles.

Labdane Diterpenoids from Leonotis ocymifolia with Selective Cytotoxic Activity Against HCC70 Breast Cancer Cell Line

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Leonotis ocymifolia is a shrub widely used in traditional medicine to alleviate cancer-related symptoms. In a search to find safe and efficacious therapeutic agents from medicinal plants, Leonotis ocymifolia was studied to find compounds with anticancer activity against TNBC. Methods: Compounds from Leonotis ocymifolia were characterized using spectroscopic data such as IR, 1D and 2D NMR, and MS spectrometry and evaluated for cytotoxic activity against triple-negative breast cancer (HCC70), hormone receptor-positive breast cancer (MCF-7), and non-tumorigenic mammary epithelial cell lines (MCF-12A). Results: A previously unreported bis-spirolabdane, 13S-nepetaefolin (1), together with five known labdane diterpenoids, namely nepetaefolin (2), dubiin (3), nepetaefuran (4), leonotin (5), and leonotinin (6), from the genus Leonotis were isolated. Overall, the labdane diterpenoids showed selective activity toward triple-negative breast cancer cells (HCC70). Of the compounds extracted, 13S-nepetaefolin demonstrated the greatest cytotoxic activity with an IC50 of 24.65 µM (SI = 1.08) against HCC70 cells; however, it was equally cytotoxic to non-tumorigenic MCF-12A breast cells (IC50 of 26.55 µM), whereas its isomer (2) showed no activity. This suggests that stereochemistry might have an effect on the cytotoxic activity of the bis-spirolabdane diterpenoids. All the compounds (1–6) demonstrated adsorption, distribution, metabolism, and excretion properties (ADME), while leonotin (5) and leonotinin (6) exhibited lead-like properties and high synthetic accessibility scores. Conclusions: The findings from this study warrant further investigation of L. ocymifolia for potential triple-negative breast cancer (TNBC) therapeutic agents, including potential chemical derivatization of bis-spiro labdane diterpenoid (1) to improve selectivity to TNBC over non-cancer cells.

Assessing the impact of per- and polyfluoroalkyl substances on pregnancy loss: An environmental-wide association study in Northwest China.

Assessing the impact of per- and polyfluoroalkyl substances on pregnancy loss: An environmental-wide association study in Northwest China.

Disulfidoptosis: A New Key to Unlocking Cancer Treatment.

The metabolic properties of disulfidoptosis targeting cancer cells have become a new key to unlocking cancer treatment's lock. Conventional cancer therapies aim to kill tumor cells through apoptosis, but cell death is carried out by a network of cascading enzymes. Malignant cells can evade the death process by downregulating key enzymes or inhibiting death-inducing triggers, leading to cancer persistence and recurrence of cancer cells that are resistant to conventional therapies and immune escape, which has compelled researchers to explore new therapeutic avenues. Disulfidoptosis is triggered by the accumulation of excessive intracellular disulfides in cells with high expression of solute carrier family 7 member 11 (SLC7A11) under glucose starvation conditions, which simultaneously induces the breakage of intracellular disulfide bonds and leads to protein malfunction, thereby triggering cancer cell death. However, there is no comprehensive account of disulfidoptosis application in cancer therapy. This review comprehensively summarizes the mechanism of disulfidoptosis for cancer treatment, which provides new ideas for cancer treatment.

THE DIAGNOSTIC ROLE OF PET/CT IN PATIENTS WITH MALIGNANT PLEURAL EFFUSION

Abstract Background: Malignant pleural effusion is defined as the presence of malignant cells in pleural effusion (PE) or biopsy specimens and occurs in 15% of all cancer patients. The most common cause is lung cancer in men and breast cancer in women. The reason for hospital admission is usually shortness of breath. The main goal of treatment is to relieve symptoms and prevent recurrence. PET/CT is an imaging system that combines the metabolic properties of PET with the morphologic properties of computed tomography. The patient can be managed more rapidly if malignant effusion can be detected on PET/CT. In this study, we aimed to predict the diagnostic impact of metabolic uptake of fluid in patients with malignant pleural effusion. Methods: In our study, we aimed to find the contribution of PET/CT to the diagnosis of malignant pleural effusion by examining patients between 18 and 90 years of age who had malignancy as a result of pleural cytology and who underwent PET/CT with a primary diagnosis of malignancy. 26 patients were evaluated. The values analyzed were; the presence of PE FDG uptake, the presence of single or double uptake in PE, the presence of multiple pulmonary nodules, the presence of pleural thickness (PT) increase, PK diameter, the presence of FDG uptake in PK, primary pathology being lung or other organ, PE Standardized Uptake Value (SUV) max, PE SUVmax/ Med SUVmax, PE SUVmax/ Liver SUVmax, PE SUVmax/ primary tumor SUVmax, primary tumor SUV values. Results: 6 of 26 patients had bilateral effusions and 12 patients had FDG uptake. 5 patients had pleural thickening and 4 of them had pleural uptake. In the ROC analysis, PE SUVmax, PE SUV / Med SUV, PE SUV / Liver SUV, and PE SUV / Primary tm SUV values were found to be significant in terms of predicting PE FDG uptake, while PT diameter was not significant. Conclusions: Patients with malignant pleural effusion have a short life expectancy. Diagnosis and treatment management of patients should be performed effectively and rapidly. PET/CT can be used as a noninvasive diagnostic method for this purpose. Therefore, if further studies are performed, PET/CT in the diagnosis of MPE will contribute to patient management.

Integrated transcriptomics and metabolomics reveal the molecular characteristics and metabolic regulatory mechanisms among different muscles in Minxian black fur sheep

BackgroundMammalian skeletal muscle is comprised of heterogeneous fibers with various contractile and metabolic properties that affect muscle flavor. Thus, it is of great significance to identify and characterize the potential molecular characteristics and metabolic regulatory mechanisms associated with muscle fiber properties.ResultsIn this study, the muscle samples (Biceps femoris; longissimus dorsi; and infraspinatus) from Minxian black fur sheep were used to perform transcriptome and metabolome analyses. Then, the key genes regulating the metabolism of important flavor precursors (amino acids and lipids) were explored by integrating transcriptome and metabolome. Consequently, we identified 432 differentially expressed genes, which were mainly involved in muscle development and function maintenance (e.g., myofibril, myocyte differentiation, etc.), metabolism (e.g., fatty acid metabolism, arachidonic acid metabolism, PPAR signaling pathway, and PI3K-Akt signaling pathway, etc.), and homeostasis (e.g., regulation of actin cytoskeleton, ECM-receptor interaction, calcium signaling pathway, etc.). A total of 58 key genes affecting muscle fiber properties, including MYL2, HOXA/C/D, MYBPH8, MYH8, etc., were screened, which characterized the molecular differences in muscle fiber metabolic properties between oxidative and glycolytic muscle. Meanwhile, we identified 463 differentially accumulated metabolites. Except for glycerophospholipids, most flavor metabolites were higher in oxidative muscle. Subsequently, key genes highly related to flavor amino acids were identified by weighted gene co-expression network analysis, such as ALDH6A1, BCKDHB, SLC16A7, LDHB, etc. Based on KEGG enrichment analysis, a regulatory network with both lipid metabolism and its crosstalk with other metabolic pathways was constructed.ConclusionsIn conclusion, this study provides an in-depth understanding of the molecular mechanism of differences in muscle fiber properties among different muscles of Minxian black fur sheep, and also lays a foundation for further exploration of the regulatory mechanism of key genes on flavor metabolites.

Impact of CYP3A4 functional variability on ziprasidone metabolism

IntroductionZiprasidone is primarily metabolized by CYP3A4, an enzyme with genetic variability and susceptibility to inhibition or induction. This study explored the functional variability of CYP3A4 in ziprasidone metabolism, focusing on drug interactions and genetic polymorphisms.MethodsThe metabolic inhibition and kinetic properties of ziprasidone were evaluated through in vitro experiments utilizing rat liver microsomes (RLM), human liver microsomes (HLM), and CYP3A4 baculosomes. In vivo validation studies were conducted in Sprague-Dawley rats.ResultsQuercetin significantly inhibited ziprasidone metabolism in vitro, with in vivo coadministration led to marked increasing in ziprasidone’s AUC, CLz/F, and Cmax. Inhibition followed mixed mechanisms in RLM, HLM, and CYP3A4.1 systems. Analysis of CYP3A4 variants revealed distinct metabolic efficiencies: CYP3A4.3, 15, and 33 exhibited elevated clearance, while CYP3A4.24, 31, and 34 showed reduced activity. Quercetin’s inhibitory potency varied across alleles, with IC50 values of 17.59 ± 1.01 μM in CYP3A4.1 and 54.51 ± 1.35 μM in CYP3A4.33. Molecular docking identified ARG106, PHE108, PHE215, THR224, and GLU374 as key residues mediating inhibition.DiscussionThe findings of this study underscore the critical role of quercetin-mediated CYP3A4 inhibition and CYP3A4 genetic polymorphisms in modulating ziprasidone metabolism.

Network pharmacology, molecular docking, and molecular dynamics analyses to explore the molecular mechanism of paclitaxel in atherosclerosis therapy

Atherosclerosis is a chronic arterial disease and the leading cause of vascular death. Paclitaxel has long been recognized as an anticancer agent, but recent studies have shown that paclitaxel can also potentially reduce the progression of atherosclerosis. The aim of this study was to explore the molecular mechanism of paclitaxel as an atherosclerosis therapy using in silico study. Pharmacokinetic and pharmacodynamic analyses of paclitaxel were conducted using SwissADME, ProTox v3.0, and SCFbio websites. Cytoscape software was used to construct a network of protein-protein interactions, and the key proteins involved in paclitaxel-related atherosclerosis were identified, including AKT serine/threonine kinase 1 (AKT1), Jun N-terminal kinase (JNK), and Endothelin 1 (ET1). These key proteins were then subjected to molecular docking and molecular dynamic simulation using MOE and Yasara applications. Pharmacokinetic and pharmacodynamic analyses revealed that paclitaxel has good distribution, metabolism, and excretion properties. However, paclitaxel has shortcomings in absorption, toxicity, and water solubility. According to the results of molecular docking, paclitaxel showed consistent results as the most potential inhibitor of AKT1 (-9.59 kcal/mol), ET1 (-9.16 kcal/mol), JNK (-8.72 kcal/mol) when compared to the control ligands. Molecular dynamics simulations also confirmed the interaction stability between paclitaxel with AKT1, ET1, and JNK, with paclitaxel-AKT1 demonstrating the highest conformational stability (Carbon-α Root Mean Square Deviation <3.0 Å). Even though our in-silico results are promising, more experimental studies are required to confirm the efficacy of paclitaxel as an atherosclerosis therapy.

Abstract 4857: The role of tumor microenvironment lactic acid in the cancer cell resistance to anti-PD-L1 and anti-PD-1 blockade therapy

Abstract Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. However, despite its recent success, such impact has been shown to be limited to tumors encompassing specific tumor microenvironment characteristics. Furthermore, a significant proportion of initial responders eventually develop resistance. Combining PD-1/PD-L1 blockade with chemotherapy, radiotherapy, or targeted therapy have been suggested to overcome resistance, yet have been shown to be insufficient in fully accounting for resistance. Unlike normal, differentiated cells, most cancer cells produce large amounts of lactic acid. This metabolic property is often referred to as “aerobic glycolysis, ” a well-known metabolic reprogramming of cancer cells to sustain cell proliferation and a hallmark of cancer. Such property as well as others of the altered metabolism of cancer cells and its byproducts affect the anti-tumor immune response. Notably, glycolytic metabolites, such as lactate, regulate T cell proliferation and function. However, the mechanism behind how such metabolic alterations impact the cancer cells’ resistance to PD-1/PD-L1 blockade therapy remains unclear. Thus, we sought to decipher the role of tumor-cell derived lactic acid in PD-1/PD-L1 therapy resistance and propose new immunotherapeutic strategies to improve the efficacy of PD-1/PD-L1 blockade therapies. Here, we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. Altogether, the findings in this study uncover a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment strategy to overcome the tumor resistance to PD-1/PD-L1 blockade therapy and improve clinical outcomes. Citation Format: Alyssa Kim, Wonkyung Oh, Deepika Dhawan, Deborah W. Knapp, Seung-Oe Lim. The role of tumor microenvironment lactic acid in the cancer cell resistance to anti-PD-L1 and anti-PD-1 blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4857.

Biodiversity and Antimicrobial Potential of Acidophilic and Acidotolerant Actinomycetes

The spread of antibiotic resistance in pathogenic microorganisms is one of the main problems of modern medicine. Given the unique metabolic properties of extremophilic microorganisms, the search for producers of new antimicrobial compounds among extremophilic actinomycetes is reasonably justified. The review examines acidophilic and acidotolerant actinomycetes, which are an integral part of the microbiomes of acidic soils and, as studies show, have high antimicrobial potential.

XanthoMoClo─A Robust Modular Cloning Genetic Toolkit for the Genera Xanthobacter and Roseixanthobacter.

Interest in Xanthobacter species is increasing due to their unique metabolic capabilities. They can grow in both heterotrophic and fully autotrophic environments, including carbon dioxide, dinitrogen gas, and hydrogen as the sole carbon, nitrogen, and energy sources, respectively. Academic and industrial groups looking to leverage these metabolic properties are already using Xanthobacter strains for the sustainable production of food and commodities. However, only a handful of genetic parts and protocols exist in scattered genetic backgrounds, and there is an unmet need for reliable genetic engineering tools to manipulate Xanthobacter species. Here, we developed XanthoMoClo, a robust modular cloning genetic toolkit for Xanthobacter and Roseixanthobacter species and strains, providing extensive tools to transform them, manipulate their metabolism, and express genes of interest. The toolkit contains plasmid parts, such as replication origins, antibiotic selection markers, fluorescent proteins, constitutive and inducible promoters, a standardized framework to incorporate novel components into the toolkit, and a conjugation donor to transform Xanthobacter and Roseixanthobacter strains easily with no or minimal optimization. We validated these plasmid components in depth in three of the most commonly studied Xanthobacter strains: X. versatilis Py2, X. autotrophicus GZ29, and X. flavus GJ10, as well as in R. finlandensis VTT E-85241. Finally, we demonstrate robust toolkit functionality across 21 different species of Xanthobacter and Roseixanthobacter, comprising 23 strains in total. The XanthoMoClo genetic toolkit is available to the research community (through AddGene) and will help accelerate the genetic engineering of Xanthobacter to further their applications in sustainability and bioremediation efforts.

Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress

Huntington’s disease (HD) is a neurodegenerative disorder in which mutated fragments of the huntingtin protein (Htt) undergo misfolding and aggregation. Since aggregated proteins can cause cellular stress and cytotoxicity, there is an interest in the development of small molecule aggregation inhibitors as potential modulators of HD pathogenesis. Here, we study how a polyphenol modulates the aggregation mechanism of huntingtin exon 1 (HttEx1) even at sub-stoichiometric ratios. Sub-stoichiometric amounts of curcumin impacted the primary and/or secondary nucleation events, extending the pre-aggregation lag phase. Remarkably, the disrupted aggregation process changed both the aggregate structure and its cell metabolic properties. When administered to neuronal cells, the ‘break-through’ protein aggregates induced significantly reduced cellular stress compared to aggregates formed in absence of inhibitors. Structural analysis by electron microscopy, small angle X-ray scattering (SAXS), and solid-state NMR spectroscopy identified changes in the fibril structures, probing the flanking domains in the fuzzy coat and the fibril core. We propose that changes in the latter relate to the presence or absence of polyglutamine (polyQ) β-hairpin structures. Our findings highlight multifaceted consequences of small molecule inhibitors that modulate the protein misfolding landscape, with potential implications for treatment strategies in HD and other amyloid disorders.

Transplantation of Exercise-Enhanced Mesenchymal Stem Cells Improves Obesity and Glucose Tolerance via Immune Modulation in Adipose Tissue.

Exercise-conditioned mesenchymal stem cells (MSCs) may modulate immune responses and improve white adipose tissue (WAT) function. While MSCs are known to reduce inflammation, it remains unclear if exercise-stimulated MSCs can improve obesity-related dysfunctions. This study is the first to explore how exercise-conditioned MSCs may influence adipose tissue inflammation and remodeling in the context of obesity. MSCs were isolated from exercised- and sedentary donor mice, then cultured in vitro. After culture, MSCs were assessed for differentiation capacity and cytokine gene expression, including Il10, as indicators of immune modulation. Exercise-conditioned MSCs were then transplanted into obese recipient mice. Following transplantation, immune cell profiles, inflammatory markers, and adipocyte morphology in recipient WAT were analyzed. Flow cytometry was used to quantify macrophage subtypes (pro-inflammatory and anti-inflammatory), and histological analysis was performed to measure changes in adipocyte size. Exercise-activated MSCs showed a ± 35% increase in Il10 expression and a ± 20% enhancement in differentiation capacity compared to controls, indicating improved immunomodulatory potential. In recipient mice, transplantation led to a ± 25% reduction in pro-inflammatory macrophages (CD86+ CD206-) and a 15% decrease in adipocyte size within WAT. Additionally, WAT in treated mice showed balanced inflammatory profiles and reduced adipose hypertrophy, suggesting restored immune balance and metabolic health. These findings suggest that exercise-modified MSCs exhibit enhanced immunomodulatory and metabolic regulatory properties. This study provides evidence that exercise enhances MSC characteristics, potentially improving their capacity to modulate adipose tissue immune balance and metabolic function in obesity. Exercise-conditioned MSCs may serve as a foundation for future strategies that integrate exercise-induced stem cell modifications to modulate obesity-related metabolic dysfunction.

Discovery of Potent STING Inhibitors Bearing a Difluorobenzodioxol Structural Motif as Potent Anti-Inflammatory Agents.

Given the critical role of STING in autoimmune and inflammatory disorders, the development of targeted small-molecule inhibitors has been a promising strategy for the treatment of these diseases. Nevertheless, the currently reported STING inhibitors suffer from limited structural diversity, species sensitivity, and poor activity; therefore, none are suitable for clinical investigation. Herein, we performed a structural modification campaign on the tool compound 6 (H-151) based on its potential metabolic hotspots. Compound 66, bearing a difluorobenzodioxol moiety, was identified as one of the most potent STING inhibitors with IC50 values of 116 and 96.3 nM for h- and m-STING, respectively. This compound exhibited a notable enhancement in metabolic properties, especially in terms of metabolic stability. A mechanism study verified that 66 engaged with STING in a covalent manner akin to that of 6. In both the cisplatin-induced acute kidney injury and TREX1 D18N mouse models, 66 significantly alleviated tissue injury and inflammation.

Creation of knockin mice for the fluorescence protein based in vivo identification of skeletal myofiber types

Skeletal muscles of the mammalian trunk and limbs comprise myofibers that express four types of myosin heavy-chain (MyHC) isoforms, each with distinct contractile and metabolic properties. Despite histochemical and immunohistochemical staining to identify myofiber types, all myofiber types cannot be identified simultaneously in vivo. In this study, we generated a novel knock-in mouse model, termed “MusColor,” that enables the simultaneous identification of individual MyHC isoforms through the expression of four fluorescent proteins. The identification of fibre types by fluorescent expression in MusColor mice was consistent with that achieved by immunostaining and had higher sensitivity. By studying the aging-associated changes in myofiber types using the MusColor mice, we were able to identify changes in hybrid myofibers that simultaneously express multiple MyHCs. Furthermore, by culturing satellite cells isolated from MusColor mice and treatment of thyroid hormone or rapamycin, changes in myofiber type and metabolic function could be analysed in living cells. The MusColor mouse proved useful for elucidating the mechanisms of muscle fibre changes caused by diseases such as sarcopenia, neuromuscular and metabolic diseases, as well as by exercise and nutritional environments.

Bone in parathyroid diseases revisited: evidence from epidemiological, surgical and new drug outcomes.

Parathyroid hormone (PTH)-related disorders have a major impact on bone metabolism and skeletal properties, due to the pivotal role of PTH in calcium and phosphate homeostasis and bone remodeling.Hyperparathyroidism is characterized by continuous exposure to excessive endogenous PTH, causing increased bone turnover in favor of bone resorption. Depending on the background of PTH overproduction, hyperparathyroidism is divided into primary, secondary and tertiary hyperparathyroidism.The clinical presentation varies from deterioration of bone microarchitecture and decreased bone mineral density (BMD) to profound bone involvement, such as osteitis fibrosa cystica and fragility fractures. Although successful parathyroidectomy represents the definitive treatment and may promote regression of most of the skeletal defects, the medical approach of calcimimetics and antiresorptive agents is a promising alternative in cases where parathyroidectomy is not feasible or unsuccessful.Hypoparathyroidism is the pathophysiological counterpart of hyperparathyroidism and also leads to disorders of bone metabolism and structure. Chronic PTH deprivation is associated with low bone remodeling and increased BMD. The defective microarchitecture might affect bone strength and raise the risk for adverse skeletal events. Recombinant human PTH acts as a replacement therapy and is safe and efficient in restoring calcium/phosphate homeostasis and bone turnover. However, it is approved only for refractory cases, as conventional management with calcium and active vitamin D remains the first-line treatment. This article reviews the skeletal involvement in the most frequent parathyroid disorders, hyperparathyroidism and hypoparathyroidism, along with rare familial disorders of PTH metabolism, as assessed by clinical, laboratory and imaging parameters, and the effect of the available treatment strategies.

Targeting NLRP3 and AIM2 signaling pathways by Viscosol alleviates metabolic dysregulations induced inflammatory responses in diabetic neuro- and nephropathy: An in silico and in vivo study.

Type 2 Diabetes (T2D) is a chronic metabolic disorder, considered the fastest growing pandemic of the 21stcentury. Meta-inflammation is a pivotal characteristic of T2D. Hyperactivated PTP1B, NLRP3, and AIM2 inflammasomes are considered the major regulators of metabolic inflammation. The concept of diabetes as an inflammatory disease has changed the pathogenic vision of T2D and hence, the compounds that mitigateinflammation in the setting of T2D are under the limelight of research. Current study aimed to evaluatethe anti-inflammatory potency of Viscosol, a novel PTP1B inhibitor, isolated from Dodonaea viscosa, in the STZ-HFD-induced T2D mouse model. Herein, male mice(C57BL/6), were administrated with Streptozotocin (STZ) (40mg/kg) and Viscosol (33mg/kg), intraperitoneally. Computational profiling revealed good absorption, distribution, metabolism and excretion (ADME) properties, least toxicity, and high docking score of Viscosol with PTP1B(-6.4 kcal/mol), NLRP3(-7.2 kcal/mol), and AIM2(-7.4 kcal/mol). Viscosol treatment significantly restored normal body weight (p < 0.0001), decreased the blood glucose level (p < 0.001), serum ROS level(p < 0.05) and diminished the severity of histopathological lesions, inflammatory lobules and increased the cell count of both brain and kidney tissues. The RT-qPCR analysis showed that Viscosol significantly reduced the mRNA expression of PTP1B, NF-κB, NLRP3, and AIM2up to 2.7-folds, 2.6-folds, 5.7-folds and 14.2-folds in the kidney tissues and 1.6-folds, 1.2-folds, 10.2-folds and 1.5-folds in brain tissues. Conclusively, inhibition of PTP1B via Viscosol could attenuate meta-inflammation by suppressing the aberrant NLRP3 and AIM2 inflammasome signaling in diabetes-linked pathophysiology.