Regulation Of Energy Metabolism Research Articles

Petiveria alliacea Reduces Tumor Burden and Metastasis and Regulates the Peripheral Immune Response in a Murine Myeloid Leukemia Model.

The poor response, adverse effects and drug resistance to treatment of acute myeloid leukemia (AML) have led to searching for safer and more effective therapeutic alternatives. We previously demonstrated that the alcoholic extract of Petiveria alliacea (Esperanza) has a significant in vitro antitumor effect on other tumor cells and also the ability to regulate energy metabolism. We evaluated the effect of the Esperanza extract in vitro and in vivo in a murine model of AML with DA-3/ER-GM cells. First, a chemical characterization of the extract was conducted through liquid and gas chromatography coupled with mass spectrometry. In vitro findings showed that the extract modulates tumor metabolism by decreasing glucose uptake and increasing reactive oxygen species, which leads to a reduction in cell proliferation. Then, to evaluate the effect of the extract in vivo, we standardized the mouse model by injecting DA-3/ER-GM cells intravenously. The animals treated with the extract showed a lower percentage of circulating blasts, higher values of hemoglobin, hematocrit, and platelets, less infiltration of blasts in the spleen, and greater production of cytokines compared to the control group. These results suggest that the antitumor activity of this extract on DA-3/ER-GM cells can be attributed to the decrease in glycolytic metabolism, its activity as a mitocan, and the possible immunomodulatory effect by reducing tumor proliferation and metastasis.

A Newly Synbiotic Combination Alleviates Obesity by Modulating the Gut Microbiota-Fat Axis and Inhibiting the Hepatic TLR4/NF-κB Signaling Pathway.

Obesity has been recognized as a worldwide public health crisis, this is accompanied by dysregulation of the intestinal microbiota and upregulation of liver steatosis and adipose inflammation. Synbiotic as a novel alternative therapy for obesity have recently gained much attention. This study innovatively research the anti-obesity properties of a newly synbiotic composed of Lactobacillus acidophilus, Bifidobacterium infantis and konjac glucomannan oligosaccharides. The synbiotic treatment can reduce body weight, fat mass, blood sugar, liver steatosis and adipose inflammation in obesity mice fed by high-fat diet (HFD). Meanwhile, synbiotic treatment activated brown adipose tissue and improve energy, glucose and lipid metabolism. In addition, synbiotic treatment not solely enhanced the protection of intestinal barrier, but also ameliorated gut microbiota dysbiosis directly by enhancing beneficial microbes and reducing potentially harmful bacteria. Furthermore, the microbiome phenotype and functional prediction showed that synbiotic treatment can improve the gut microbiota functions involving inflammatory state, immune response, metabolism and pathopoiesia. The synbiotic may be an effective candidate treatment strategy for the clinical prevention and treatment of obesity and other associated metabolic diseases such as hyperlipidemia, nonalcoholic fatty liver diseases by alleviating inflammatory response, regulating energy metabolism and maintaining the balance of intestinal microecology.

Yin/Yang associated differential responses to Psoralea corylifolia Linn. In rat models: an integrated metabolomics and transcriptomics study

Ethnopharmacological relevancePsoralea corylifolia Linn. (BGZ) is a commonly used traditional Chinese medicine (TCM) for the treatment of kidney-yang deficiency syndrome (Yangsyn) with good curative effect and security. However, BGZ was also reported to induce liver injury in recent years. According to TCM theory, taking BGZ may induce a series of adverse reactions in patients with kidney-yin deficiency syndrome (Yinsyn), which suggests that BGZ-induced liver damage may be related to its unreasonable clinical use.Aim of the studyLiver injury caused by TCM is a rare but potentially serious adverse drug reaction, and the identification of predisposed individuals for drug-induced liver injury (DILI) remains challenging. The study aimed to investigate the differential responses to BGZ in Yangsyn and Yinsyn rat models and identify the corresponding characteristic biomarkers.Materials and methodsThe corresponding animal models of Yangsyn and Yinsyn were induced by hydrocortisone and thyroxine + reserpine respectively. Body weight, organ index, serum biochemistry, and Hematoxylin and Eosin (HE) staining were used to evaluate the liver toxicity effect of BGZ on rats with Yangsyn and Yinsyn. Transcriptomics and metabonomics were used to screen the representative biomarkers (including metabolites and differentially expressed genes (DEGs)) changed by BGZ in Yangsyn and Yinsyn rats, respectively.ResultsThe level changes of liver organ index, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), suggested that BGZ has liver-protective and liver-damaging effects on Yangsyn and Yinsyn rats, respectively, and the results also were confirmed by the pathological changes of liver tissue. The results showed that 102 DEGs and 27 metabolites were significantly regulated related to BGZ’s protective effect on Yangsyn, which is mainly associated with the glycerophospholipid metabolism, arachidonic acid metabolism, pantothenate, and coenzyme A (CoA) biosynthesis pathways. While 28 DEGs and 31 metabolites, related to the pathway of pantothenate and CoA biosynthesis, were significantly regulated for the BGZ-induced liver injury in Yinsyn. Furthermore, 4 DEGs (aldehyde dehydrogenase 1 family member B1 (Aldh1b1), solute carrier family 25 member 25 (Slc25a25), Pim-3 proto-oncogene, serine/threonine kinase (Pim3), out at first homolog (Oaf)) and 4 metabolites (phosphatidate, phosphatidylcholine, N-Acetylleucine, biliverdin) in the Yangsyn group and 1 DEG [galectin 5 (Lgals5)] and 1 metabolite (5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate) in Yinsyn group were significantly correlated to the ALT and AST levels of BGZ treated and untreated groups (receiver operating characteristic (ROC) ≥ 0.9).ConclusionsYinsyn and Yangsyn are the predisposed syndromes for BGZ to exert liver damage and liver protection respectively, which are mainly related to the regulation of amino acid metabolism, lipid metabolism, energy metabolism, and metabolism of cofactors and vitamins. The results further suggest that attention should be paid to the selection of predisposed populations when using drugs related to the regulation of energy metabolism, and the Yinsyn/Yangsyn animal models based on the theory of TCM syndromes may be a feasible method for identifying the susceptible population to receive TCM.

REPTOR and CREBRF encode key regulators of muscle energy metabolism

Metabolic flexibility of muscle tissue describes the adaptive capacity to use different energy substrates according to their availability. The disruption of this ability associates with metabolic disease. Here, using a Drosophila model of systemic metabolic dysfunction triggered by yorkie-induced gut tumors, we show that the transcription factor REPTOR is an important regulator of energy metabolism in muscles. We present evidence that REPTOR is activated in muscles of adult flies with gut yorkie-tumors, where it modulates glucose metabolism. Further, in vivo studies indicate that sustained activity of REPTOR is sufficient in wildtype muscles to repress glycolysis and increase tricarboxylic acid (TCA) cycle metabolites. Consistent with the fly studies, higher levels of CREBRF, the mammalian ortholog of REPTOR, reduce glycolysis in mouse myotubes while promoting oxidative metabolism. Altogether, our results define a conserved function for REPTOR and CREBRF as key regulators of muscle energy metabolism.

The RNA-binding protein RBP42 regulates cellular energy metabolism in mammalian-infective Trypanosoma brucei.

RNA-binding proteins (RBPs) are key players in coordinated post-transcriptional regulation of functionally related genes, defined as RNA regulons. RNA regulons play particularly critical roles in parasitic trypanosomes, which exhibit unregulated co-transcription of long unrelated gene arrays. In this report, we present a systematic analysis of an essential RBP, RBP42, in the mammalian-infective bloodstream form of African trypanosome and show that RBP42 is a key regulator of parasite's central carbon and energy metabolism. Using individual-nucleotide resolution UV cross-linking and immunoprecipitation to identify genome-wide RBP42-RNA interactions, we show that RBP42 preferentially binds within the coding region of mRNAs encoding core metabolic enzymes. Global quantitative transcriptomic and proteomic analyses reveal that loss of RBP42 reduces the abundance of target mRNA-encoded proteins, but not target mRNA, suggesting a positive translational regulatory role of RBP42. Significant changes in central carbon metabolic intermediates, following loss of RBP42, further support its critical role in cellular energy metabolism. Trypanosoma brucei infection, transmitted through the bite of blood-feeding tsetse flies, causes deadly diseases in humans and livestock. This disease, if left untreated, is almost always fatal. Existing therapies are toxic and difficult to administer. During T. brucei's lifecycle in two different host environments, the parasite progresses through distinctive life stages with major morphological and metabolic changes, requiring precise alteration of parasite gene expression program. In the absence of regulated transcription, post-transcriptional processes mediated by RNA-binding proteins play critical roles in T. brucei gene regulation. In this study, we show that the RNA-binding protein RBP42 plays crucial roles in cellular energy metabolic regulation of this important human pathogen. Metabolic dysregulation observed in RBP42 knockdown cells offers a breadth of potential interest to researchers studying parasite biology and can also impact research in general eukaryotic biology.

Microglia Sirt6 modulates the transcriptional activity of NRF2 to ameliorate high-fat diet-induced obesity.

Microglia play a pivotal role in neuroinflammation, while obesity triggers hypothalamic microglia activation and inflammation. Sirt6 is an important regulator of energy metabolism in many peripheral tissues and hypothalamic anorexic neurons. However, the exact mechanism for microglia Sirt6 in controlling high-fat diet-induced obesity remain unknown. Microglia Sirt6 expression levels under various nutritional conditions were measured in the hypothalamus of mice. Also, microglia Sirt6-deficient mice were provided various diets to monitor metabolic changes and hypothalamic inflammatory response. Besides, RNA-seq and Co-IP of microglia with Sirt6 alterations were conducted to further investigate the detailed mechanism by which Sirt6 modulated microglia activity. We found that Sirt6 was downregulated in hypothalamic microglia in mice given a high-fat diet (HFD). Additionally, knockout of microglia Sirt6 exacerbated high-fat diet-induced hypothalamic microglial activation and inflammation. As a result, mice were more prone to obesity, exhibiting a decrease in energy expenditure, impaired glucose tolerance, insulin and leptin resistance, and increased food intake. In vitro, Sirt6 overexpression in BV2 cells displayed protective effects against oleic acid and palmitic acid treatment-derived inflammatory response. Mechanically, Sirt6 deacetylated and stabilised NRF2 to increase the expression of anti-oxidative genes and defend against reactive oxygen species overload. Pharmacological inhibition of NRF2 eliminated the beneficial modulating effects of Sirt6 on microglial activity. Collectively, our results revealed that microglial Sirt6 was a primary contributor of microglial activation in the central regulation of obesity. Thus, microglial Sirt6 may be an important therapeutic target for obesity.

Identification of a novel PAK1/HDAC6 dual inhibitor ZMF-23 that triggers tubulin-stathmin regulated cell death in triple negative breast cancer

Triple-negative breast cancer (TNBC) is the most poorly treated subtype of breast cancer, and targeting the heterogeneity of TNBC has emerged as a fascinating therapeutic strategy. In this study, we propose for the first time that dual-targeting PAK1 and HDAC6 is a promising novel strategy for TNBC treatment due to their essential roles in the regulation of energy metabolism and epigenetic modification. We discovered a novel dual-targeting PAK1/HDAC6 inhibitor, 6 - (2-(cyclopropylamino) - 6 - (2,4-dichlorophenyl) - 7 - oxopyrido [2,3-d] pyrimidin - 8 (7H) -yl) - N-hydroxyhexanamide (ZMF-23), which presented profound inhibitory activity against PAK1 and HDAC6 and robust antiproliferative potency in MDA-MB-231 cells. In addition, SPR and CETSA assay demonstrated the targeted binding of ZMF-23 with PAK1/HDAC6. Mechanically, ZMF-23 strongly inhibited the cellular PAK1 and HDAC6 activity, impeded PAK1 and HDAC6 regulated aerobic glycolysis and migration. By RNA-seq analysis, ZMF-23 was found to induce TNF-α-regulated necroptosis, which further enhanced apoptosis. Additionally, ZMF-23 triggered PAK1-tubulin/HDAC6-Stathmin regulated microtubule structure changes, which further induced the G2/M cycle arrest. Moreover, prominent anti-proliferative effect of ZMF-23 was confirmed in the TNBC xenograft zebrafish and mouse model via PAK1 and HDAC6 inhibition. Collectively, ZMF-23 is a novel dual PAK1/HDAC6 inhibitor with TNBC treatment potential.

Postmortem Metabolism and Pork Quality Development Are Affected by Electrical Stimulation across Three Genetic Lines.

Variations in postmortem metabolism in muscle impact pork quality development. Curiously, some genetic lines are more refractile to adverse pork quality development than others and may regulate energy metabolism differently. The aim of this study was to challenge pork carcasses from different genetic populations with electrical stimulation (ES) to determine how postmortem metabolism varies with genetic line and explore control points that reside in glycolysis in dying muscle. Three genetic populations (GP) were subjected to ES (100 V or 200 V, 13 pulses, 2 s on/2 s off) at 15- or 25-min post-exsanguination, or no stimulation (NS). Genetic population affected relative muscle relative abundance of different myosin heavy chains, glycogen, G6P, and lactate concentrations. Genetic lines responded similarly to ES, but a comparison of ES treatment groups revealed a trend for an interaction between voltage, time of ES, and time postmortem. Higher voltage accelerated pH decline at 20 min up to 60 min postmortem. Trends in color and firmness scores and L* values were consistent with pH and metabolite data. These data show that genetic populations respond differently to postmortem perturbation by altering glycolytic flux and suggest differences in postmortem glycolysis may be partially responsible for differences in meat quality between genetic populations, though not entirely.

Effects of Metformin on Ischemia/Reperfusion Injury: New Evidence and Mechanisms.

The search for new drugs with the potential to ensure therapeutic success in the treatment of cardiovascular diseases has become an essential pathway to follow for health organizations and committees around the world. In June 2021, the World Health Organization listed cardiovascular diseases as one of the main causes of death worldwide, representing 32% of them. The most common is coronary artery disease, which causes the death of cardiomyocytes, the cells responsible for cardiac contractility, through ischemia and subsequent reperfusion, which leads to heart failure in the medium and short term. Metformin is one of the most-used drugs for the control of diabetes, which has shown effects beyond the control of hyperglycemia. Some of these effects are mediated by the regulation of cellular energy metabolism, inhibiting apoptosis, reduction of cell death through regulation of autophagy and reduction of mitochondrial dysfunction with further reduction of oxidative stress. This suggests that metformin may attenuate left ventricular dysfunction induced by myocardial ischemia; preclinical and clinical trials have shown promising results, particularly in the setting of acute myocardial infarction. This is a review of the molecular and pharmacological mechanisms of the cardioprotective effects of metformin during myocardial ischemia-reperfusion injury.

Time-restricted eating for chronodisruption-related chronic diseases.

The circadian timing system enables organisms to adapt their physiology and behavior to the cyclic environmental changes including light-dark cycle or food availability. Misalignment between the endogenous circadian rhythms and external cues is known as chronodisruption and is closely associated with the development of metabolic and gastrointestinal disorders, cardiovascular diseases, and cancer. Time-restricted eating (TRE, in human) is an emerging dietary approach for weight management. Recent studies have shown that TRE or time-restricted feeding (TRF, when referring to animals) has several beneficial health effects, which, however, are not limited to weight management. This review summarizes the effects of TRE/TRF on regulating energy metabolism, gut microbiota and homeostasis, development of cardiovascular diseases and cancer. Furthermore, we will address the role of circadian clocks in TRE/TRF and propose ways to optimize TRE as a dietary strategy to obtain maximal health benefits.

Clock genes regulate skeletal muscle energy metabolism through NAMPT/NAD+/SIRT1 following heavy-load exercise.

The biological clock is an invisible "clock" in the organism, which can regulate behavior, physiology, and biochemical reactions. However, the relationship between clock genes and energy metabolism in postexercise skeletal muscle is not well known. The purpose of this study was to determine the mechanisms through which peripheral clock genes regulate energy metabolism in skeletal muscle. We analyzed the rhythm of mRNA expression of the clock genes Bmal1 and Clock in skeletal muscle following heavy-load exercise and measured related indicators of mitochondrial structure and function. We obtained the following experimental results. First, heavy-load exercise induced loss of circadian rhythm of Bmal1 between ZT0 and ZT24, and the circadian rhythm of Clock was not restored between ZT0 and ZT72. Second, analysis of mitochondrial morphology in group E showed abnormal swelling and ridge structure damage at ZT0, which recovered somewhat at ZT24 and ZT48, and the damage had essentially disappeared by ZT72. Third, the expression of NAMPT/NAD+/SIRT1 signaling axis proteins in group E was abnormal at ZT0, the content of NAMPT and the activity of SIRT1 significantly increased, and the content of NAD+ significantly decreased. Fourth, the expression of BMAL1 and PGC-1α in group E significantly increased, whereas the ATP and ADP content, as well as the activities of COXII and COXIV, were significantly changed. Finally, the colocalization of BMAL1 and SIRT1 in group E was significantly upregulated at ZT0. These results suggest that the skeletal muscle clock gene Bmal1 may regulate the energy metabolism level of skeletal muscle after exercise through the NAMPT/NAD+/SIRT1 signaling pathway.

Milk Yields and Milk Fat Composition Promoted by Pantothenate and Thiamine via Stimulating Nutrient Digestion and Fatty Acid Synthesis in Dairy Cows.

Considering the synergistic effect of pantothenate and thiamine on the regulation of energy metabolism, this study investigated the influences of coated calcium pantothenate (CCP) and coated thiamine (CT) on milk production and composition, nutrients digestion, and expressions of genes involved in fatty acids synthesis in mammary glands. Forty-four multiparous Chinese Holstein cows (2.8 ± 0.19 of parity, 772 ± 12.3 kg of body weight [BW], 65.8 ± 8.6 days in milk [DIM] and 35.3 ± 1.9 kg/d of milk production, mean ± SD) were blocked by parity, BW, DIM, and milk production, and they were allocated into one of four treatments in a 2 × 2 factorial block design. Additional CCP (0 mg/kg [CCP-] or 55 mg/kg dry matter [DM] of calcium pantothenate from CCP [CCP+]) and CT (0 g/kg [CT-] or 5.3 mg/kg DM of thiamine from CT [CT+]) were hand-mixed into the top one-third of total mixed ration. Both CCP and CT additives increased milk production, fat content, true protein, and lactose by promoting nutrient digestibility. The CCP or/and CT supplementation induced the elevation of C11:0, C12:0, C13:0, C14:0, C14:1, C15:0, C15:1, C16:00, C16:1, C24:00, C24:1 fatty acids, saturated fatty acid, and C4-16 fatty acid contents in milk fat; but it decreased C17-22 fatty acid content. Ruminal total VFA content was increased, but pH was decreased by both additives. The ruminal fermentation pattern was altered, and a tendency of acetate formation was implied by the increased acetate-to-propionate ratio after both additives' supplementation. The expressions of PPARγ, SREBPF1, ACACA, FASN, SCD, and FABP3 mRNAs were enhanced by CCP or CT addition, but the relative expression of LPL mRNA was upregulated by CT addition only. Additionally, blood glucose, triglyceride, insulin-like growth factor-1, and total antioxidant capacity were promoted by both additives. The combination of CCP and CT more effectively increased the ruminal total VFA concentration, the acetate to propionate ratio, and blood glucose level, and decreased ammoniacal nitrogen concentration than that achieved by CCP or CT alone. The results suggested that CCP and CT supplementation stimulated lactation performance by promoting nutrient digestion and fatty acid synthesis in the mammary glands.

UCP1 alleviates renal interstitial fibrosis progression through oxidative stress pathway mediated by SIRT3 protein stability

BackgroundRenal interstitial fibrosis is a common pathway for the progressive development of chronic renal diseases (CKD) with different etiology, and is the main pathological basis leading to end-stage renal disease. Although the current research on renal interstitial fibrosis is gradually deepening, the diagnosis and treatment methods are still very lacking. Uncoupling protein 1 (UCP1) is a nuclear encoded protein in mitochondria inner membrane and plays an important role in regulating energy metabolism and mitochondrial homeostasis. However, the biological significance of UCP1 and potential regulatory mechanisms in the development of CKD remain unclear.MethodsUnilateral ureteral obstruction (UUO) model was used to construct the animal model of renal fibrosis, and TGF-β1 stimulation of HK2 cells was used to construct the vitro model of renal fibrosis. UCP1 expression was detected by Western blot, immunoblot analysis and immunohistochemistry. UCP1 was upregulated by UCP1 overexpressing lentivirus and UCP1 agonist CL316243. Western blot and immunofluorescence were used to detect epithelial mesenchymal transition (EMT)-related markers, such as collagen I, fibronectin, antioxidant enzyme SOD2 and CAT. Reactive oxygen species (ROS) production was detected by ROS detection kit. SIRT3 knockdown was performed by siRNA.ResultsThis study presents that UCP1 is significantly downregulated in patients with renal fibrosis and UUO model. Further studies discover that UCP1 overexpression and CL316243 treatments (UCP1 agonists) reversed EMT and extracellular matrix (ECM) accumulation in renal fibrosis models in vivo and in vitro. Simultaneously, UCP1 reduced the ROS production by increasing the stability of SIRT3. When SIRT3 was knocked down, the production of ROS decreased.ConclusionsElevating the expression of UCP1 can inhibit the occurrence of oxidative stress by stabilizing SIRT3, thereby reducing EMT and ECM accumulation, and ultimately alleviating renal interstitial fibrosis. It will provide new instructions and targets for the treatment of CKD.

Triad3A-Mediated K48-Linked ubiquitination and degradation of TLR9 impairs mitochondrial bioenergetics and exacerbates diabetic cardiomyopathy

IntroductionTargeted protein degradation represents a promising therapeutic approach, while diabetic cardiomyopathy (DCM) arises as a consequence of aberrant insulin secretion and impaired glucose and lipid metabolism in the heart.. ObjectivesConsidering that the Toll-like receptor 9 (TLR9) signaling pathway plays a pivotal role in regulating energy metabolism, safeguarding cardiomyocytes, and influencing glucose uptake, the primary objective of this study was to investigate the impact of TLR9 on diabetic cardiomyopathy (DCM) and elucidate its underlying mechanism. MethodsMouse model of DCM was established using intraperitoneal injection of STZ, and mice were transfected with adeno-associated virus serotype 9-TLR9 (AAV9-TLR9) to assess the role of TLR9 in DCM. To explore the mechanism of TLR9 in regulating DCM disease progression, we conducted interactome analysis and employed multiple molecular approaches. ResultsOur study revealed a significant correlation between TLR9 expression and mouse DCM. TLR9 overexpression markedly mitigated cardiac dysfunction, myocardial fibrosis, oxidative stress, and apoptosis in DCM, while inflammation levels remained relatively unaffected. Mechanistically, TLR9 overexpression positively modulated mitochondrial bioenergetics and activated the AMPK-PGC1a signaling pathway. Furthermore, we identified Triad3A as an interacting protein that facilitated TLR9′s proteasomal degradation through K48-linked ubiquitination. Inhibiting Triad3A expression improved cardiac function and pathological changes in DCM by enhancing TLR9 activity. ConclusionsThe findings of this study highlight the critical role of TLR9 in maintaining cardiac function and mitigating pathological alterations in diabetic cardiomyopathy. Triad3A-mediated regulation of TLR9 expression and function has significant implications for understanding the pathogenesis of DCM. Targeting TLR9 and its interactions with Triad3A may hold promise for the development of novel therapeutic strategies for diabetic cardiomyopathy. Further research is warranted to fully explore the therapeutic potential of TLR9 modulation in the context of cardiovascular diseases.

Synthesis of 2′,4′,6′-trimethoxy-3′,5′-dimethylchalcone derivatives and their anti-diabetic and anti-atherosclerosis effects

AMP-activated protein kinase (AMPK) is an important regulator of energy metabolism and is considered a promising target for the treatment of metabolic diseases including diabetes. However, no AMPK agonist is used clinically at present. Here, we synthesized various derivatives of 2′,4′,6′-trimethoxy-3′,5′-dimethylchalcone and tested whether they activated AMPK and improved glucose tolerance in an obese mouse model. The derivatives activated AMPK at a much lower concentration than 5-aminoimidazole-4-carboxamide ribonucleotide, a well-known AMPK agonist, in C2C12 myotubes. Among them, compounds 2c and 2i showed predominant AMPK activation effects and increased the fatty acid oxidation (FAO) rate more than 2-fold in C2C12 myotubes. When compound 2i was administered to high fat diet-induced obese mice for two weeks, the glucose tolerance was improved and skeletal muscle FAO rate increased (1.6-fold). In addition, several derivatives, including compound 2i, suppressed the migration of vascular smooth muscle cells treated with platelet-derived growth factor, and inhibited tumor necrosis factor-α-induced adhesion between monocytes and endothelial cells. These results suggest these derivatives have anti-atherosclerosis effects. Taken together, the derivatives, especially compound 2i, might be therapeutic agents against diabetes and atherosclerosis.

A comparative metabolomics study between grain-sized moxibustion and suspended moxibustion on rats with gastric ulcers

Grain-sized moxibustion (GS-Moxi) and suspended moxibustion (S-Moxi) represent the two typical local heat therapies in Traditional Chinese Medicine (TCM) and have been extensively used in treating gastric ulcers (GU) in China. However, the difference in biological response between the two moxibustion therapies in treating GU remains unclear. Here we investigated the therapeutic effect and potential mechanistic difference underlying the two moxibustion methods. Ethanol-induced GU model was established and was treated with GS-Moxi or S-Moxi at ST36 and ST21 for 5 days separately. And then, gastric histopathological examination, immunohistochemical staining for repair factors (EGFR, VEGF, Ki67), and 1H NMR-based metabolomics analysis of plasma and stomach of rats were conducted. We found GS-Moxi and S-Moxi effectively alleviated gastric damage and significantly increased the expression of related repair factors. However, S-Moxi corrected aberrant energy metabolism and lipids metabolism in GU rats but had little effect on neurotransmitter-related metabolism, while GS-Moxi regulated energy metabolism and neurotransmitter-related metabolism in GU rats but had no effect on lipids metabolism. We further proposed that the main target of S-Moxi may be liver and vasculature, whereas GS-Moxi specially targeted the stomach via regulating nervous system. This study strongly verified the outstanding gastroprotective effects of moxibustion and enriched our understanding of the varied biological responses triggered by different moxibustion methods.

Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms

Rheumatoid arthritis (RA) is a common chronic inflammatory disorder that usually affects joints. It was found that roburic acid (RBA), an ingredient from anti-RA herb Gentiana macrophylla Pall., displayed strong anti-inflammatory activity. However, its medical application is limited by its hydrophobicity, lack of targeting capability and unclear functional mechanism. Here, we constructed a pH responsive dual-target drug delivery system hitchhiking RBA (RBA-NPs) that targeted both CD44 and folate receptors, and investigated its pharmacological mechanism. In rat RA model, the nanocarriers effectively delivered RBA to inflammatory sites and significantly enhanced the therapeutic outcomes compared with free RBA, as well as strongly reducing inflammatory cytokine levels and promoting tissue repair. Following analysis revealed that M1 macrophages in the joints were reprogrammed to M2 phenotype by RBA. Since the balance of pro- and anti-inflammatory macrophages play important roles in maintaining immune homeostasis and preventing excessive inflammation in RA, this reprogramming is likely responsible for the anti-RA effect. Furthermore, we revealed that RBA-NPs drove M1-to-M2 phenotypic switch by down-regulating the glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway. Thus, our work not only developed a targeting delivery system that remarkably improved the anti-RA efficiency of RBA, but also identified a potential molecular target to reversely reprogram macrophages though energy metabolism regulation.

Functional role of skeletal muscle-derived interleukin-6 and its effects on lipid metabolism.

The detrimental impact of obesity on human health is increasingly evident with the rise in obesity-related diseases. Skeletal muscle, the crucial organ responsible for energy balance metabolism, plays a significant role as a secretory organ by releasing various myokines. Among these myokines, interleukin 6 (IL-6) is closely associated with skeletal muscle contraction. IL-6 triggers the process of lipolysis by mobilizing energy-storing adipose tissue, thereby providing energy for physical exercise. This phenomenon also elucidates the health benefits of regular exercise. However, skeletal muscle and adipose tissue maintain a constant interaction, both directly and indirectly. Direct interaction occurs through the accumulation of excess fat within skeletal muscle, known as ectopic fat deposition. Indirect interaction takes place when adipose tissue is mobilized to supply the energy for skeletal muscle during exercise. Consequently, maintaining a functional balance between skeletal muscle and adipose tissue becomes paramount in regulating energy metabolism and promoting overall health. IL-6, as a representative cytokine, participates in various inflammatory responses, including non-classical inflammatory responses such as adipogenesis. Skeletal muscle influences adipogenesis through paracrine mechanisms, primarily by secreting IL-6. In this research paper, we aim to review the role of skeletal muscle-derived IL-6 in lipid metabolism and other physiological activities, such as insulin resistance and glucose tolerance. By doing so, we provide valuable insights into the regulatory function of skeletal muscle-derived myokines in lipid metabolism.

Effect of Red Visible Lighting on Postharvest Ripening of Bananas via the Regulation of Energy Metabolism

The mechanism by which LED red light irradiation regulates postharvest banana ripening was evaluated in this study by the continuous irradiation of banana fruits at the mature-green stage. In this study, a self-developed LED banana fresh-keeping container lid was used to continuously irradiate the immature banana fruit. The light wavelength was 655.0 ± 1.0 nm, the light intensity was 800.0 ± 10.0 LX, and the height between the LED lamp and the fruit was 15.0 ± 0.5 cm. Bananas stored under dark conditions were used as the negative control group, and bananas stored under dark conditions after spraying with 500.0 mg/L ethephon diluent were used as the positive control group. Changes in physiological parameters related to postharvest banana ripening, such as the respiration rate, ethylene release, texture, color, carotenoid content, chlorophyll content, adenosine triphosphate content, and energy metabolism-related enzyme activities, were measured during 8 days of storage at 20.0 ± 0.1 °C to analyze the key factors determining postharvest banana ripening in response to red light. The red light-irradiated bananas had higher total color differences and higher rates of chlorophyll degradation and carotenoid synthesis than those of the ethephon-treated group during the storage period. Red light irradiation promoted banana fruit ripening and senescence mainly by promoting carotenoid synthesis, capturing absorbed light energy, accelerating energy metabolism, effectively enhancing the activities of the respiratory and energy metabolism-related enzymes H+ adenosine triphosphatase, Ca2+ adenosine triphosphatase, succinate dehydrogenase, cytochrome C oxidase, and malic enzyme, and promoting organic acid degradation. In conclusion, LED red light can be used as a new physical ripening technology for bananas, with a similar effect to that of traditional ethephon treatment.

The Peptide Fractions of Cheddar Cheese Made with Lactobacillus helveticus 1.0612 Play Protective Effects in H2O2-Induced Oxidative-Damaged Caco-2 Cells Models.

In this study, water-soluble peptide (WSP) fractions of cheddar cheese made with Lactobacillus helveticus 1.0612 were purified into WSP-Ⅰ (<3 kDa), WSP-Ⅱ (3-10 kDa), and WSP-Ⅲ (>10 kDa). The protective effects of WSP, WSP-Ⅰ, WSP-Ⅱ, and WSP-Ⅲ fractions against oxidative stress in Caco-2 cells were assayed, and the cytoprotective mechanism of WSP-Ⅰ on cells oxidative damage was elucidated via metabolomics. The results showed that all four peptide fractions were able to attenuate the decrease in cell viability caused by oxidative stress and also could reduce the production of reactive oxygen species and malondialdehyde caused by oxidative stress, and increased cellular catalase and superoxide dismutase activities, thereby enhancing cellular antioxidant capacity. The WSP-Ⅰ fraction with the highest protective effect was used for metabolomics analysis, and 15 significantly different metabolites were screened. Functional pathway analysis revealed that the protective effect of the WSP-I fraction was related with nine metabolic pathways and weakened the metabolic disorders caused by H2O2 via regulating energy metabolism and amino acid metabolism. All in all, peptide fractions of cheddar cheese showed a cytoprotective effect through improved cellular metabolism.