4'-O-methylbavachalcone alleviates ischemic stroke injury by inhibiting parthanatos and promoting SIRT3.

Cerebral ischemia-reperfusion injury (CIRI) can induce massive death of ischemic penumbra neurons via oxygen burst, exacerbating brain damage. Parthanatos is a form of caspase-independent cell death involving excessive activation of PARP-1, closely associated with intense oxidative stress following CIRI. 4'-O-methylbavachalcone (MeBavaC), an isoprenylated chalcone component in Fructus Psoraleae, has potential neuroprotective effects. This study primarily investigates whether MeBavaC can act on SIRT3 to alleviate parthanatos of ischemic penumbra neurons induced by CIRI. MeBavaC was oral gavaged to the middle cerebral artery occlusion-reperfusion (MCAO/R) rats after occlusion. The effects of MeBavaC on cerebral injury were detected by the neurological deficit score and cerebral infarct volume. In vitro, PC-12 cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R), and assessed cell viability and cell injury. Also, the levels of ROS, mitochondrial membrane potential (MMP), and intracellular Ca2+ levels were detected to reflect mitochondrial function. We conducted western blotting analyses of proteins involved in parthanatos and related signaling pathways. Finally, the exact mechanism between the neuroprotection of MeBavaC and parthanatos was explored. Our results indicate that MeBavaC reduces the cerebral infarct volume and neurological deficit scores in MCAO/R rats, and inhibits the decreased viability of PC-12 cells induced by OGD/R. MeBavaC also downregulates the expression of parthanatos-related death proteins PARP-1, PAR, and AIF. However, this inhibitory effect is weakened after the use of a SIRT3 inhibitor. In conclusion, the protective effect of MeBavaC against CIRI may be achieved by inhibiting parthanatos of ischemic penumbra neurons through the SIRT3-PARP-1 axis.

Inhibition of STAT3 alleviates LPS-induced apoptosis and inflammation in renal tubular epithelial cells by transcriptionally down-regulating TASL.

BACKGROUND: Systemic lupus erythematosus (SLE) is a common autoimmune disease that impacts various organs. Lupus nephritis (LN) significantly contributes to death in children with SLE. Toll-like receptor (TLR) adaptor interacting with SLC15A4 on the lysosome (TASL) acts as an innate immune adaptor for TLR and is implicated in the pathogenesis of SLE. A transcription factor known as signal transducer and activator of transcription 3 (STAT3), which is known to be linked to autoimmune diseases, is also involved in the development of SLE. METHODS: Bioinformatics and real-time quantitative PCR (qRT-PCR) was used to detect the expression of STAT3 and TASL in peripheral blood of SLE patients and their correlation. Bioinformatics analysis, qRT-PCR, luciferase assay and chromatin immunoprecipitation (ChIP) were used to verify the regulation of transcription factor STAT3 on TASL. The expression levels of STAT3, TASL and apoptosis-related genes in LPS-induced HK2 cells were detected by qRT-PCR and Western blot. TUNEL staining were used to detect the apoptosis of HK2 cells after LPS stimulation. ELISA and qRT-PCR were used to detect the levels of inflammatory cytokines in the cell culture supernatant. TASL knockdown in HK2 cells was used to detect the changes in apoptosis-related genes and inflammatory factors. The expression level of TASL in LPS-stimulated HK2 cells and its effect on cell apoptosis and inflammatory factors were observed by knocking down and overexpressing STAT3, respectively. It was also verified in a rescue experiment. RESULTS: The expressions of STAT3 and TASL were higher in SLE than in healthy children, and the expression of STAT3 was positively correlated with TASL. Transcription factor STAT3 can directly and positively regulate the expression of TASL through the promoter region binding site. The expression of STAT3, TASL and inflammatory cytokines was elevated, and the change of apoptosis was up-regulated in LPS-stimulated HK2 cells. Inhibition of STAT3 alleviates LPS-stimulated apoptosis and inflammatory response in HK2 cells through transcriptional regulation of TASL. CONCLUSIONS: These findings provide new insights into the transcriptional regulation of TASL and provide new evidence of a direct regulatory relationship between signaling nodes in the lupus signaling network.

4'­O­methylbavachalcone inhibits succinate induced cardiomyocyte hypertrophy via the NFATc4 pathway.

Pathological cardiac hypertrophy is an independent risk factor for complications such as arrhythmia, myocardial infarction, sudden mortality and heart failure. Succinate, an intermediate product of the Krebs cycle, is released into the bloodstream by cells; its levels increase with exacerbations of hypertension, myocardial and other tissue damage and metabolic disease. Succinate may also be involved in several metabolic pathways and mediates numerous pathological effects through its receptor, succinate receptor 1 (SUCNR1; previously known as GPR91). Succinate-induced activation of SUCNR1 has been reported to be related to cardiac hypertrophy, making SUCNR1 a potential target for treating cardiac hypertrophy. Traditional Chinese medicine (TCM) and its active ingredients have served important roles in improving cardiac functions and treating heart failure. The present study investigated whether 4'-O-methylbavachadone (MeBavaC), an active ingredient of the herbal remedy Fructus Psoraleae, which is often used in TCM and has protective effect on myocardial injury and hypertrophy induced by adriamycin, ischemia-reperfusion and sepsis, could ameliorate succinate-induced cardiomyocyte hypertrophy by inhibiting the NFATc4 pathway. Using immunofluorescence staining, reverse transcription-quantitative PCR, western blotting and molecular docking analysis, it was determined that succinate activated the calcineurin/NFATc4 and ERK1/2 pathways to promote cardiomyocyte hypertrophy. MeBavaC inhibited cardiomyocyte hypertrophy, nuclear translocation of NFATc4 and ERK1/2 signaling activation in succinate-induced cardiomyocytes. Molecular docking analysis revealed that MeBavaC interacts with SUCNR1 to form a relatively stable binding and inhibits the succinate-SUCNR1 interaction. The results demonstrated that MeBavaC suppressed cardiomyocyte hypertrophy by blocking SUCNR1 receptor activity and inhibiting NFATc4 and ERK1/2 signaling, which will contribute to the preclinical development of this compound.

Mechanism of tonifying-kidney Chinese herbal medicine in the treatment of chronic heart failure.

According to traditional Chinese medicine (TCM), chronic heart failure has the basic pathological characteristics of "heart-kidney yang deficiency." Chronic heart failure with heart- and kidney-Yang deficiency has good overlap with New York Heart Association (NYHA) classes III and IV. Traditional Chinese medicine classical prescriptions for the treatment of chronic heart failure often take "warming and tonifying kidney-Yang" as the core, supplemented by herbal compositions with functions of "promoting blood circulation and dispersing blood stasis." Nowadays, there are still many classical and folk prescriptions for chronic heart failure treatment, such as Zhenwu decoction, Bushen Huoxue decoction, Shenfu decoction, Sini decoction, as well as Qili Qiangxin capsule. This review focuses on classical formulations and their active constituents that play a key role in preventing chronic heart failure by suppressing inflammation and modulating immune and neurohumoral factors. In addition, given that mitochondrial metabolic reprogramming has intimate relation with inflammation, cardiac hypertrophy, and fibrosis, the regulatory role of classical prescriptions and their active components in metabolic reprogramming, including glycolysis and lipid ß-oxidation, is also presented. Although the exact mechanism is unknown, the classical TCM prescriptions still have good clinical effects in treating chronic heart failure. This review will provide a modern pharmacological explanation for its mechanism and offer evidence for clinical medication by combining TCM syndrome differentiation with chronic heart failure clinical stages.

Erchen Decoction Ameliorates the Metabolic Abnormalities of High-Fat Diet-Fed Rats.

Objective: Brown adipose tissue (BAT) dissipates chemical energy to protect against obesity. In the present study, we aimed to determine the effects of Erchen decoction on the lipolysis and thermogenesis function of BAT in high-fat diet-fed rats. Methods: Sprague-Dawley rats were randomly divided into four groups, which were fed a control diet (C) or a high-fat diet (HF), and the latter was administered with high and low doses of Erchen decoction by gavage once a day, for 12 weeks. Body weight, the serum lipid profile, serum glucose, and insulin levels of the rats were evaluated. In addition, the phosphorylation and protein and mRNA expression of AMP-activated protein kinase (AMPK), adipose triglyceride lipase (ATGL), peroxisome proliferator-activated receptor γ coactivator- (PGC-) 1α, and uncoupling protein 1 (UCP-1) in BAT were measured by immunoblotting and RT-PCR. Results: Erchen decoction administration decreased body weight gain and ameliorated the abnormal lipid profile and insulin resistance index of the high-fat diet-fed rats. In addition, the expression of p-AMPK and ATGL in the BAT was significantly increased by Erchen decoction. Erchen decoction also increased the protein and mRNA expression of PGC-1α and UCP-1 in BAT. Conclusion: Erchen decoction ameliorates the metabolic abnormalities of high-fat diet-fed rats, at least in part via activation of lipolysis and thermogenesis in BAT.

Role of the renin-angiotensin system in NETosis in the coronavirus disease 2019 (COVID-19).

Myocardial infarction and stroke are the leading causes of death in the world. Numerous evidence has confirmed that hypertension promotes thrombosis and induces myocardial infarction and stroke. Recent findings reveal that neutrophil extracellular traps (NETs) are involved in the induction of myocardial infarction and stroke. Meanwhile, patients with severe COVID-19 suffer from complications such as myocardial infarction and stroke with pathological signs of NETs. Due to the extremely low amount of virus detected in the blood and remote organs (e.g., heart, brain and kidney) in a few cases, it is difficult to explain the mechanism by which the virus triggers NETosis, and there may be a different mechanism than in the lung. A large number of studies have found that the renin-angiotensin system regulates the NETosis at multiple levels in patients with COVID-19, such as endocytosis of SARS-COV-2, abnormal angiotensin II levels, neutrophil activation and procoagulant function at multiple levels, which may contribute to the formation of reticular structure and thrombosis. The treatment of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARBs) and neutrophil recruitment and active antagonists helps to regulate blood pressure and reduce the risk of net and thrombosis. The review will explore the possible role of the angiotensin system in the formation of NETs in severe COVID-19.

The ß3 Adrenergic Receptor Agonist CL316243 Ameliorates the Metabolic Abnormalities of High-Fat Diet-Fed Rats by Activating AMPK/PGC-1α Signaling in Skeletal Muscle.

PURPOSE: Skeletal muscle has a major influence on whole-body metabolic homeostasis. In the present study, we aimed to determine the metabolic effects of the ß3 adrenergic receptor agonist CL316243 (CL) in the skeletal muscle of high-fat diet-fed rats. METHODS: Sprague-Dawley rats were randomly allocated to three groups, which were fed a control diet (C) or a high-fat diet (HF), and half of the latter were administered 1 mg/kg CL by gavage once weekly (HF+CL), for 12 weeks. At the end of this period, the serum lipid profile and glucose tolerance of the rats were evaluated. In addition, the phosphorylation and protein and mRNA expression of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, and carnitine palmitoyl transferase (CPT)-1b in skeletal muscle were measured by Western blot analysis and qPCR. The direct effects of CL on the phosphorylation (p-) and expression of AMPK, PGC-1α, and CPT-1b were also evaluated by Western blotting and immunofluorescence in L6 myotubes. RESULTS: CL administration ameliorated the abnormal lipid profile and glucose tolerance of the high-fat diet-fed rats. In addition, the expression of p-AMPK, PGC-1α, and CPT-1b in the soleus muscle was significantly increased by CL. CL (1 µM) also increased the protein expression of p-AMPK, PGC-1α, and CPT-1b in L6 myotubes. However, the effect of CL on PGC-1α protein expression was blocked by the AMPK antagonist compound C, which suggests that CL increases PGC-1α protein expression via AMPK. CONCLUSION: Activation of the ß3 adrenergic receptor in skeletal muscle ameliorates the metabolic abnormalities of high-fat diet-fed rats, at least in part via activation of the AMPK/PGC-1α pathway.

NETosis as a Pathogenic Factor for Heart Failure.

Heart failure threatens the lives of patients and reduces their quality of life. Heart failure, especially heart failure with preserved ejection fraction, is closely related to systemic and local cardiac persistent chronic low-grade aseptic inflammation, microvascular damage characterized by endothelial dysfunction, oxidative stress, myocardial remodeling, and fibrosis. However, the initiation and development of persistent chronic low-grade aseptic inflammation is unexplored. Oxidative stress-mediated neutrophil extracellular traps (NETs) are the main immune defense mechanism against external bacterial infections. Furthermore, NETs play important roles in noninfectious diseases. After the onset of myocardial infarction, atrial fibrillation, or myocarditis, neutrophils infiltrate the damaged tissue and aggravate inflammation. In tissue injury, damage-related molecular patterns (DAMPs) may induce pattern recognition receptors (PRRs) to cause NETs, but whether NETs are directly involved in the pathogenesis and development of heart failure and the mechanism is still unclear. In this review, we analyzed the markers of heart failure and heart failure-related diseases and comorbidities, such as mitochondrial DNA, high mobility box group box 1, fibronectin extra domain A, and galectin-3, to explore their role in inducing NETs and to investigate the mechanism of PRRs, such as Toll-like receptors, receptor for advanced glycation end products, cGAS-STING, and C-X-C motif chemokine receptor 2, in activating NETosis. Furthermore, we discussed oxidative stress, especially the possibility that imbalance of thiol redox and MPO-derived HOCl promotes the production of 2-chlorofatty acid and induces NETosis, and analyzed the possibility of NETs triggering coronary microvascular thrombosis. In some heart diseases, the deletion or blocking of neutrophil-specific myeloperoxidase and peptidylarginine deiminase 4 has shown effectiveness. According to the results of current pharmacological studies, MPO and PAD4 inhibitors are effective at least for myocardial infarction, atherosclerosis, and certain autoimmune diseases, whose deterioration can lead to heart failure. This is essential for understanding NETosis as a therapeutic factor of heart failure and the related new pathophysiology and therapeutics of heart failure.

Effects and Mechanisms of Five Psoralea Prenylflavonoids on Aging-Related Diseases.

During the aging process, senescent cells gradually accumulate in the organs; they secrete proinflammatory cytokines and other factors, collectively known as the senescence-associated secretory phenotype (SASP). SASP secretions contribute to "inflammaging," which is a state of chronic, systemic, sterility, low-grade inflammatory microenvironment and a key risk factor in the development of aging-related diseases. Fructus psoraleae is a traditional Chinese medical herb best known for delaying aging and treating osteoporosis. Prenylflavonoids from fructus psoraleae are the main bioactive compounds responsible for its pharmacological applications, such as beaching, bavachinin, bavachalcone, isobavachalcone, and neobavaisoflavone. In previous decades, there have been some promising studies on the pharmacology of fructus psoraleae. Here, we focus on the anti-inflammatory and antiaging diseases of five psoralea prenylflavonoids, such as cardiovascular protection, diabetes and obesity intervention, neuroprotection, and osteoporosis, and discuss the mechanism of these active ingredients for better understanding the material basis and drug application of fructus psoraleae in Chinese medicine.

Effect of Active Ingredients of Chinese Herbal Medicine on the Rejuvenation of Healthy Aging: Focus on Stem Cells.

Stem cells (SCs) are special types of cells with the ability of self-renewal and multidirectional differentiation. As the organism ages, the ability to maintain homeostasis and regeneration deteriorates and the number and activity of stem cells decline. Theoretically, the restoration of stem cells might reverse aging. However, due to their own aging, donor-derived immune rejection, and difficulties in stem cell differentiation control, a series of problems need to be solved to realize the potential for clinical application of stem cells. Chinese herbal medicine is a nature drug library which is suitable for the long-term treatment of aging-related diseases. Modern pharmacological studies have revealed that many active ingredients of Chinese herbal medicines with the effect of promoting stem cells growth and differentiation mainly belong to "reinforcing herbs." In recent years, exploration of natural active ingredients from Chinese herbal medicines for delaying aging, improving the stem cell microenvironment, and promoting the proliferation and differentiation of endogenous stem cells has attracted substantial attention. This article will focus on active ingredients from Chinese herbs-mediated differentiation of stem cells into particular cell type, like neural cells, endothelial cells, cardiomyocytes, and osteoblasts. We will also discuss the effects of these small molecules on Wnt, Sonic Hedgehog, Notch, eNOS-cGMP, and MAP kinase signal transduction pathways, as well as reveal the role of estrogen receptor α and PPAR γ on selectively promoting or inhibiting stem cells differentiation. This review will provide new insights into the health aging strategies of active ingredients in Chinese herbal medicine in regenerative medicine.

Icariin induces irisin/FNDC5 expression in C2C12 cells via the AMPK pathway.

Backgroud Icariin, a major bioactive pharmaceutical component of the Chinese herbal medicine Epimedii Herba, has demonstrated lipid-lowering and anti-obesity effects. Irisin/ fibronectin type III domain-containing 5 (FNDC5) protects against obesity by inducing browning in white adipose tissue. Objectives This study investigated the effects of icariin on irisin/FNDC5 expression in C2C12 myotubes. Method Cultured murine C2C12 myocytes were used to study the effects of icariin on irisin/FNDC5 expressions by Western-blot, qPCR, Elisa and Immunofluorescence. We also investigated FNDC5 expression in icariin-treated intact mice. Results Icariin increased irisin/FNDC5 protein levels. mRNA levels of irisin/FNDC5 were also increased in C2C12 myocytes after treatment with icariin. Icariin increased peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1α) protein and mRNA levels. Additionally, icariin exposure resulted in phosphorylation of AMP-activated protein kinase (AMPK) in a dose-dependent manner. The regulatory effect of icariin on FNDC5 protein expression was blocked by the AMPK antagonist compound C or silencing of AMPK, suggesting that icariin increased FNDC5 protein expression via the AMPK pathway. In vivo, icariin decreased body weight gain in C57BL/6 mice and increased FNDC5, PGC-1α, and p-AMPK expression levels in skeletal muscle. Conclusions Taken together, our results indicated that icariin induces irisin/FNDC5 expression via the AMPK pathway, indicating that icariin may be promising as an anti-obesity drug.

MicroRNA expression, targeting, release dynamics and early-warning biomarkers in acute cardiotoxicity induced by triptolide in rats.

Tripterygium wilfordii Hook. F. is a plant used in traditional Chinese medicine to treat rheumatoid arthritis, lupus erythematosus, and psoriasis in China. However, its main active substance, triptolide, has toxic effects on the heart, liver, and kidneys, which limit its clinical application. Therefore, determining the mechanism of cardiotoxicity in triptolide and identifying effective early-warning biomarkers is beneficial for preventing irreversible myocardial injury. We observed changes in microRNAs and aryl hydrocarbon receptor (AhR) as potential biomarkers in triptolide-induced acute cardiotoxicity by using techniques such as polymerase chain reaction (PCR) assay. The results revealed that triptolide increased the heart/body ratio and caused myocardial fiber breakage, cardiomyocyte hypertrophy, increased cell gaps, and nuclear dissolution in treated male rats. Real-time PCR array detection revealed a more than 2-fold increase in the expression of 108 microRNA genes in the hearts of the male rats; this not only regulated the signaling pathways of ErbB, FOXO, AMPK, Hippo, HIF-1α, mTOR, and PI3K-Akt but also participated in biological processes such as cell adhesion, cell cycling, action potential, locomotory behavior, apoptosis, and DNA binding. Moreover, triptolide reduced the circulatory and cardiac levels of AhR protein as a target of these microRNAs and the messenger RNA expression of its downstream gene CYP1 A1. However, decreases in myocardial lactate dehydrogenase, creatine kinase MB, catalase, and glutathione peroxidase activity and an increase in circulating cardiac troponin I were observed only in male rats. Moreover, plasma microRNAs exhibited dynamic change. These results revealed that circulating microRNAs and AhR protein are potentially early-warning biomarkers for triptolide-induced cardiotoxicity.

Levistilide A Ameliorates NLRP3 Expression Involving the Syk-p38/JNK Pathway and Peripheral Obliterans in Rats.

BACKGROUND: Inflammation is one of the most important pathogeneses of thromboangiitis obliterans (TAO). The NLRP3 inflammasome plays a vital role in the body's immune response and disease development. It can be activated by numerous types of pathogens or danger signals. As the core of the inflammatory response, the NLRP3 inflammasome may provide a new target for the treatment of various inflammatory diseases. Levistilide A (LA) is a phthalide dimer isolated from umbelliferous plants. Its pharmacological effect is largely unknown. This study revealed the effects of LA on endothelial cell activation, NLRP3, IL-1ß, TNF-α, IL-32, and CCL-2, VCAM-1, MCP-1, and the spleen tyrosine kinase (Syk)--p38/JNK signaling axis and its effect on vasculitis in rats. RESULTS: LA inhibited endothelial activation and the expression of IL-1ß, TNF-α, IL-32, CCL-2, VCAM-1, and MCP-1. LA directly obstructed Syk phosphorylation and activity in a dose-dependent manner, inhibited the activity of p38 and JNK, and reduced the expression of NLRP3 in human umbilical vein endothelial cells and vascular tissue of rats with vasculitis. CONCLUSION: LA suppressed NLRP3 gene expression by blocking the Syk--p38/JNK pathway and reduced damage to the rats' limbs in the thromboangiitis obliterans model.

Natural compound bavachalcone promotes the differentiation of endothelial progenitor cells and neovascularization through the RORα-erythropoietin-AMPK axis.

In cardiovascular diseases, endothelial function is impaired and the level of circulating endothelial progenitor cells (EPCs) is low. This study investigated whether the natural bioactive component bavachalcone (BavaC) induces the differentiation of EPCs and neovascularization in vivo; the underlying mechanisms were also examined. We observed that the treatment of rat bone marrow-derived cells with a very low dose of BavaC significantly promoted EPC differentiation. In our hindlimb ischemia models, low-dose BavaC administered orally for 14 days stimulated the recovery of ischemic hindlimb blood flow, increased circulating EPCs, and promoted capillary angiogenesis. The BavaC treatment of rat bone marrow cells for 24 h initiated the AMP-activated protein kinase (AMPK) activity required for the differentiation of EPCs. Further testing revealed that BavaC and CGP52608, a retinoic acid receptor-related orphan receptor α (RORα) activator, enhanced the activity of RORα1 and EPO luciferase reporter gene. BavaC treatment also elevated EPO mRNA and protein expression in vitro and in vivo and the circulating EPO levels in rats. By contrast, the RORα antagonist VPR66 inhibited BavaC-induced EPO reporter activity, and differentiation of bone marrow cells into endothelial progenitor cells. Overall, this study revealed that BavaC promotes EPC differentiation and neovascularization through a RORα-EPO-AMPK axis. BavaC can be used as a promising angiogenesis agent for enhancing angiogenesis and tissue repair.

Browning of Abdominal Aorta Perivascular Adipose Tissue Inhibits Adipose Tissue Inflammation.

BACKGROUND: Perivascular adipose tissue (PVAT) can regulate vascular homeostasis by secreting various adipokines. This study investigated the effects of PVAT browning on its endocrine function. METHODS: In the first section of our study, male Sprague-Dawley rats were randomly divided into cold exposure (8°C) and 24°C acclimation groups. After cold exposure for 7 days, interscapular brown adipose tissue (iBAT), subcutaneous white adipose tissue, thoracic aortic PVAT, and abdominal aortic PVAT (aPVAT) were harvested for histological and brown marker gene expression analysis. In the second part, male rats were fed a high fat diet (HFD) for 10 weeks. In the 11th week, the rats were treated with or without cold exposure. After 14-day cold exposure, aPVAT was collected for histological, gene, and protein expression analysis. RESULTS: Cold exposure had a browning effect on aPVAT by increasing UCP-1 and PGC-1α expression levels. After HFD feeding for 10 weeks, 14-day cold exposure was still able to induce aPVAT browning. Compared with thermoneutrality acclimation rats, TNF-α, IL-6, and p-p65 expression levels were significantly lower in aPVAT from HFD-fed rats with cold exposure. In contrast, p-AMPK expression levels were increased in aPVAT from HFD-fed rats with cold exposure. CONCLUSIONS: Our study demonstrated that browning of aPVAT in HFD-fed rats lowered the pro-inflammatory adipokine expression levels and activated AMPK.

Higher-Order Chromatin Regulation of Inflammatory Gene Expression.

Whether it is caused by viruses and bacteria infection, or low-grade chronic inflammation of atherosclerosis and cellular senescence, the transcription factor (TF) NF-κB plays a central role in the inducible expression of inflammatory genes. Accumulated evidence has indicated that the chromatin environment is the main determinant of TF binding in gene expression regulation, including the stimulus-responsive NF-κB. Dynamic changes in intra- and interchromosomes are the key regulatory mechanisms promoting the binding of TFs. When an inflammatory process is triggered, NF-κB binds to enhancers or superenhancers, triggering the transcription of enhancer RNA (eRNA), driving the chromatin of the NF-κB-binding gene locus to construct transcriptional factories, and forming intra- or interchromosomal contacts. These processes reveal a mechanism in which intrachromosomal contacts appear to be cis-control enhancer-promoter communications, whereas interchromosomal regulatory elements construct trans-form relationships with genes on other chromosomes. This article will review emerging evidence on the genome organization hierarchy underlying the inflammatory response.

Ilexsaponin A attenuates ischemia-reperfusion-induced myocardial injury through anti-apoptotic pathway.

The protective effects of ilexsaponin A on ischemia-reperfusion-induced myocardial injury were investigated. Myocardial ischemia/reperfusion model was established in male Sprague-Dawley rats. Myocardial injury was evaluated by TTC staining and myocardial marker enzyme leakage. The in vitro protective potential of Ilexsaponin A was assessed on hypoxia/reoxygenation cellular model in neonatal rat cardiomyocytes. Cellular viability and apoptosis were evaluated by MTT and TUNEL assay. Caspase-3, cleaved caspase-3, bax, bcl-2, p-Akt and Akt protein expression levels were detected by western-blot. Ilexsaponin A treatment was able to attenuate the myocardial injury in ischemia/reperfusion model by reducing myocardial infarct size and lower the serum levels of LDH, AST and CK-MB. The in vitro study also showed that ilexsaponin A treatment could increase cellular viability and inhibit apoptosis in hypoxia/reoxygenation cardiomyocytes. Proapoptotic proteins including caspase-3, cleaved caspase-3 and bax were significantly reduced and anti-apoptotic protein bcl-2 was significantly increased by ilexsaponin A treatment in hypoxia/reoxygenation cardiomyocytes. Moreover, Ilexsaponin A treatment was able to increase the expression levels of p-Akt in hypoxia/reoxygenation cellular model and myocardial ischemia/reperfusion animal model. Coupled results from both in vivo and in vitro experiments indicate that Ilexsaponin A attenuates ischemia-reperfusion-induced myocardial injury through anti-apoptotic pathway.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside Promotes Expression of the Longevity Gene Klotho.

The longevity gene klotho has numerous physiological functions, such as regulating calcium and phosphorus levels, delaying senescence, improving cognition, reducing oxidative stress, and protecting vascular endothelial cells. This study tested whether 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), a small molecule with antiaging effects, regulates the expression and physiological effects of klotho. Our results showed that THSG dose-dependently increased the luciferase reporter activity of the klotho gene, reversed the decrease in mRNA and protein expression of klotho which was induced by angiotensin II in NRK-52E renal tubular epithelial cells, and increased klotho mRNA expression in the cerebral cortex, hippocampus, testis, and kidney medulla of spontaneously hypertensive rats. THSG also reduced the number of senescent cells induced by angiotensin II and improved the antioxidant capacity and enhanced the bone strength in vivo. Based on klotho's role in promoting cognition, regulating bone metabolism, and improving renal function, the effect of THSG on klotho expression will be beneficial to the functional improvement or enhancement of the expressed organs or tissues.

Biological Activities of 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-Glucoside in Antiaging and Antiaging-Related Disease Treatments.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG) is active component of the Chinese medicinal plant Polygonum multiflorum Thunb. (THSG). Pharmacological studies have demonstrated that THSG exhibits numerous biological functions in treating atherosclerosis, lipid metabolism, vascular and cardiac remodeling, vascular fibrosis, cardiac-cerebral ischemia, learning and memory disorders, neuroinflammation, Alzheimer and Parkinson diseases, diabetic complications, hair growth problems, and numerous other conditions. This review focuses on the biological effects of THSG in antiaging and antiaging-related disease treatments and discusses its molecular mechanisms.