Journal of Biomedical Research最新文献

Cholestatic liver disease, caused by the accumulation of hazardous bile acids in the liver, may result in cirrhosis, fibrosis, or liver failure. Activation of sirtuin 6 (SIRT6) prevents cholestasis-associated pathological events, such as oxidative stress and mitochondrial biogenesis dysfunction, and inhibits bile acid synthesis to alleviate cholestatic liver injury. However, it remains uncertain which pathway mediates the therapeutic effect of SIRT6 in reducing cholestasis. Therefore, we treated liver-specific Sirt6 knockout mice with N-acetylcysteine, KEAP1-NRF2-IN-1, or acadesine to alleviate oxidative stress and/or promote mitochondrial biogenesis after modeling cholestatic liver disease, but these measures did not significantly improve cholestatic symptoms. However, MDL801, a SIRT6 agonist that downregulates cholesterol 7α-hydroxylase (CYP7A1, the key enzyme in bile acid synthesis) levels, exhibited favorable therapeutic effects. Additionally, the hepatic knockdown of Cyp7a1 further demonstrated that inhibiting hepatic bile acid synthesis might be the main pathway through which SIRT6 alleviates cholestatic liver disease. These findings provide a solid basis for the potential application of SIRT6 agonists in treating cholestatic liver disease.

The current study aims to identify potential metabolic biomarkers that predict the progression to prediabetes in women with a history of gestational diabetes mellitus (GDM). We constructed a prediabetes group ( n = 42) and a control group ( n = 40) based on a 2-h 75 g oral glucose tolerance test for women with a history of GDM from six weeks to six months postpartum, and collected their clinical data and biochemical test results. We performed the plasma metabolomics analysis of the subjects at the fasting and 2-h post-load time points using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). We found that the prediabetes group was older and had higher 2-h post-load glucose levels during pregnancy than the control group. The metabolomic analysis identified 164 differential metabolites between the groups. Compared with the control group, 15 metabolites in the prediabetes group exhibited consistent change trends at both time points, including three increased and 12 decreased metabolites. By building a prediction model of the progression from GDM to prediabetes, we found that a combination of three clinical markers yielded an area under the curve (AUC) of 0.71 (95% confidence interval [CI], 0.60-0.82). We also assessed the discriminative power of the panel of 15 metabolites for distinguishing between postpartum prediabetes and normal glucose tolerance of the subjects at the fasting (AUC, 0.98; 95% CI, 0.94-1.00) and 2-h post-load (AUC, 0.99; 95% CI, 0.97-1.00) time points. The metabolic pathway analysis indicated that energy metabolism and branched-chain amino acids played a role in prediabetes development in women with a history of GDM during the early postpartum period. In conclusion, this study identified potential metabolic biomarkers and pathways associated with the progression from GDM to prediabetes in the early postpartum period. A panel of 15 metabolites showed promising discriminative power for distinguishing between postpartum prediabetes and normal glucose tolerance. These findings provide insights into the underlying pathophysiology of this transition and suggest the feasibility of developing a metabolic profiling test for the early identification of women at high risk of prediabetes following GDM.

Adiponectin receptor 1 ( Adipor1) deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice. Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic (pTh17) and non-pathogenic (npTh17) cells, with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions. In the current study, we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and induced mitochondrial dysfunction in pTh17 cells. RNA sequencing demonstrated a significant increase in the expression levels of Fundc1, a gene related to mitochondrial function, in Adipor1-deficient CD4 ⁺ T cells. Fundc1 knockdown in Adipor1-deficient CD4 ⁺ T cells partially reversed the effects of Adipor1 deficiency on mitochondrial function and pTh17 differentiation. In conclusion, the current study demonstrated a novel role of Adipor1 in regulating mitochondrial function via Fundc1 to promote pTh17 cell differentiation, providing some insight into potential therapeutic targets for autoimmune and inflammatory diseases.

The skeletal muscle is the largest organ present in the body and is responsible for mechanical activities like maintaining posture, movement, respiratory function, and support for the health and functioning of other systems of the body. Skeletal muscle atrophy is a condition characterized by a reduction in muscle size, strength, and activity, which leads to an increased dependency on others for movement, an increased risk of falls, and a reduced quality of life. Various conditions like osteoarthritis, osteoporosis, and fractures are directly associated with increased muscle atrophy. Additionally, numerous risk factors, like aging, malnutrition, physical inactivity, and certain disease conditions, through distinct pathways, negatively affect skeletal muscle health and lead to muscle atrophy. Among various determinants of overall muscle health, the rate of muscle protein synthesis and degradation is an important parameter that eventually alters the fate of overall muscle health. In conditions of excessive skeletal muscle atrophy, including sarcopenia, the rate of muscle protein degradation usually exceeds the rate of protein synthesis. The availability of amino acids in the systemic circulation is a crucial step in muscle protein synthesis. The current review aims to consolidate the existing evidence on amino acids, highlight their mechanisms of action, and assess their roles and effectiveness in enhancing skeletal muscle health.

The global nutritional transition has led to the increased frequency and severity of chronic degenerative diseases worldwide, primarily driven by chronic inflammatory stress. At mealtimes, various pharmaceutical products aim to prevent such inflammatory stress, but they usually cause various systemic side effects. Therefore, the supplementation of natural and safe ingredients is a promising strategy to reduce the risk and severity of inflammatory stress-related diseases. Palmitoylethanolamide (PEA), an endocannabinoid-like mediator, has been extensively studied for its diverse actions, including anti-inflammatory, antimicrobial, immunostimulatory, neuroprotective, and pain-reducing effects, with high tolerability and safety in both animals and humans. Because of its multiple molecular targets and mechanisms of action, PEA has demonstrated therapeutic benefits in various diseases, including neurological, psychiatric, ophthalmic, metabolic, oncological, renal, hepatic, immunological, rheumatological, and gastrointestinal conditions. The current review highlights the roles and functions of PEA in various physiological and pathological conditions, further supporting its use as an important dietary agent.

IBI351, a synthetic compound, exerts its anti-tumor effects by specifically, covalently, and irreversibly modifying the 12th cysteine residue of KRAS G12C. However, the pharmacokinetic profile of IBI351 in humans has not yet been reported. The current study aimed to investigate the pharmacokinetics and safety of IBI351 in healthy Chinese male subjects. A single oral dose of 600 mg combined with 150 μCi [ ¹⁴C]IBI351 was administered to six healthy male volunteers. Blood, urine, and fecal samples were collected at multiple time points to quantify the parent drug and its metabolites. IBI351 showed favorable pharmacokinetic characteristics and was well tolerated by all participants. Seventeen major metabolites were identified in plasma, urine, and feces. The main metabolic pathways included oxidation, hydrogenation, sulfonate conjugation, glucuronide conjugation, and cysteine conjugation. Excretion of IBI351 and its metabolites occurred mainly through feces. Collectively, this first-in-human study provides essential data on the metabolism and safety of IBI351 in Chinese subjects and lays the foundation for its further clinical development as a novel anti-tumor drug.

Colorectal cancer (CRC) ranks among the top five most common malignant tumors worldwide and has a high mortality rate. Angiogenesis plays an important role in CRC progression; however, anti-angiogenesis therapy still has many limitations. Long non-coding RNAs (lncRNAs) participate in tumor progression by regulating the expression of vascular endothelial growth factor in metastatic CRC. Thus, targeting specific lncRNAs may provide some new hope for anti-angiogenic strategies. Through analyzing data from both clinical samples and The Cancer Genome Atlas database, we found that the lncRNA LINC01503 was specifically upregulated in CRC tissues and was associated with tumor progression and poor overall survival. We also demonstrated that LINC01503 enhanced the capacity for tube formation and migration of vascular endothelial cells, thus promoting CRC tumorigenesis by upregulating vascular endothelial growth factor A (VEGFA) expression in CRC cells. Mechanistically, LINC01503 promoted the expression of VEGFA by simultaneously regulating both mRNA and protein stability of VEGFA by binding to miR-342-3p and the chaperone HSP60, respectively. The upregulation of LINC01503 in CRC cells was attributed to the CREB-binding protein CBP/p300-mediated H3K27 acetylation of the LINC01503 promoter region. Taken together, our findings clarify the mechanism by which LINC01503 may promote CRC angiogenesis, implying that LINC01503 may serve as a potential prognostic biomarker and therapeutic target for CRC.

Rod-shaped gold nanomaterials, known as gold nanorods (GNRs), may undergo specific surface modification, because of their straightforward surface chemistry. This feature makes them appropriate for use as functional and biocompatible nano-formulations. By optimizing the absorption of longitudinally localized surface plasmon resonance in the near-infrared region, which corresponds to the near-infrared bio-tissue window, GNRs with appropriate modifications may improve the results of photothermal treatment (PTT). In dermatology, potential noninvasive uses of GNRs to enhance wound healing, manage infections, combat cutaneous malignancies, and remodel skin tissues via PTT have attracted research attention in recent years. The review discussed the basic properties of GNRs, such as their shape, size, optical performance, photothermal efficiency, and metabolism. Then, the disadvantages of using these particles in photodynamic therapy are highlighted. Next, biological applications of GNRs-based PTT are explored in detail. Finally, the limitations and future perspectives of this research are addressed, providing a comprehensive perspective on the potential GNRs with PTT.

In the present study, we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition (EMT) and angiogenesis. In a clinical case, anlotinib reversed osimertinib resistance in non-small cell lung cancer (NSCLC). Therefore, we performed immunohistochemical analyses on tumor tissues from three NSCLC patients with osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A (VEGFA) before and after the development of osimertinib resistance. The results revealed the downregulation of E-cadherin, coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance, compared with those in tissues from patients before receiving osimertinib. Subsequently, we established osimertinib-resistant (Osi-R) cell lines and found that the Osi-R cells acquired EMT features. Next, we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT. The expression levels of VEGFA and tube formation were analyzed in the combination group in vitro. Finally, we determined the reversal of osimertinib resistance by the combination of osimertinib and anlotinib in vivo using 20 nude mice. The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of Osi-R cells, inhibited tumor growth, exerted antitumor activity, and ultimately reversed osimertinib resistance in mice. The co-administration of osimertinib and anlotinib demonstrated synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients, ultimately reversing osimertinib resistance.

Parasitic helminths, taxonomically comprising trematodes, cestodes, and nematodes, are multicellular invertebrates widely disseminated in nature and have afflicted humans continuously for a long time. Helminths play potent roles in the host by generating a variety of novel molecules, including some excretory/secretory products and others that are involved in intracellular material exchange and information transfer as well as the initiation or stimulation of immune and metabolic activation. The helminth-derived molecules have developed powerful and diverse immunosuppressive effects to achieve immune evasion for parasite survival and establish chronic infections. However, they also improve autoimmune and allergic inflammatory responses and promote metabolic homeostasis by promoting metabolic reprogramming of various immune functions, and then inducing alternatively activated macrophages, T helper 2 cells, and regulatory T cell-mediated immune responses. Therefore, a deeper exploration of the immunopathogenic mechanism and immune regulatory mechanisms of helminth-derived molecules exerted in the host is crucial for understanding host-helminth interactions, as well as the development of therapeutic drugs for infectious or non-infectious diseases. In this review, we focus on the properties of helminth-derived molecules to give an overview of the most recent scientific knowledge about their pathogenic and pharmacopeial roles in immune-metabolic homeostasis.