Search

Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.

Abstract Background Periostin is an extracellular matrix protein that plays a critical role in cell fate determination and tissue remodeling, but the underlying role and mechanism of periostin in diabetic cardiomyopathy (DCM) are far from clear. Thus, we aimed to clarify the mechanistic participation of periostin in DCM. Methods The expression of periostin was examined in DCM patients, diabetic mice and high glucose (HG)-exposed cardiac fibroblasts (CF). Gain- and loss-of-function experiments assessed the potential role of periostin in DCM pathogenesis. RNA sequencing was used to investigate the underlying mechanisms of periostin in DCM. Results A mouse cytokine antibody array showed that the protein expression of periostin was most significantly upregulated in diabetic mouse heart, and this increase was also observed in patients with DCM or HG-incubated CF. Periostin-deficient mice were protected from diabetes-induced cardiac dysfunction and myocardial damage, while overexpression of periostin held the opposite effects. Hyperglycemia stimulated the expression of periostin in a TGF-β/Smad-dependent manner. RNA sequencing results showed that periostin upregulated the expression of nucleosome assembly protein 1-like 2 (NAP1L2) which recruited SIRT3 to deacetylate H3K27ac on the promoters of the branched-chain amino acid (BCAA) catabolism-related enzymes BCAT2 and PP2Cm, resulting in BCAA catabolism impairment. Additionally, CF-derived periostin induced hypertrophy, oxidative injury and inflammation in primary cardiomyocytes. Finally, we identified that glucosyringic acid (GA) specifically targeted and inhibited periostin to ameliorate DCM. Conclusion Overall, manipulating periostin expression may function as a promising strategy in the treatment of DCM.

Introduction: Meteorin-like hormone (Metrnl) is ubiquitously expressed in skeletal muscle, heart, and adipose with beneficial roles in obesity, insulin resistance, and inflammation. Metrnl is found to protect against cardiac hypertrophy and doxorubicin-induced cardiotoxicity. However, its role in diabetic cardiomyopathy (DCM) is undefined. Objectives: We aimed to elucidate the potential roles of Metrnl in DCM. Methods: Gain- and loss-of-function experiments were utilized to determine the roles of Metrnl in the pathological processes of DCM. Results: We found that plasma Metrnl levels, myocardial Metrnl protein and mRNA expressions were significantly downregulated in both streptozotocin (STZ)-induced (T1D) mice and leptin receptor deficiency (db/db) (T2D) mice. Cardiac-specific overexpression (OE) of Metrnl markedly ameliorated cardiac injury and dysfunction in both T1D and T2D mice. In sharp contrast, specific deletion of Metrnl in the heart had the opposite phenotypes. In parallel, Metrnl OE ameliorated, whereas Metrnl downregulation exacerbated high glucose (HG)-elicited hypertrophy, apoptosis and oxidative damage in primary neonatal rat cardiomyocytes. Antibody-induced blockade of Metrnl eliminated the effects of benefits of Metrnl in vitro and in vivo. Mechanistically, Metrnl activated the autophagy pathway and inhibited the cGAS/STING signaling in a LKB1/AMPK/ULK1-dependent mechanism in cardiomyocytes. Besides, Metrnl-induced ULK1 phosphorylation facilitated the dephosphorylation and mitochondrial translocation of STING where it interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2), a scaffold protein and E3 ubiquitin ligase that was responsible for ubiquitination and degradation of STING, rendering cardiomyocytes sensitive to autophagy activation. Conclusion: Thus, Metrnl may be an attractive therapeutic target or regimen for treating DCM.

Abstract Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known molecule that participates in cellular defense against oxidative stress. Utilizing luciferase reporter assay from 379 natural products, we reported here that Ginsenoside Rb1 played a dual role in inhibiting Kelch-like ECH-associated protein 1 (Keap1) and p47phox luciferase reporter activities. In endothelial cells (ECs), Rb1 pretreatment enhanced cell viability, reduced oxidative stress, inflammation, endothelial-mesenchymal transition (EndMT), and apoptosis, as well as ameliorated mitochondrial quality following oxidized low-density lipoprotein (ox-LDL) plus high glucose (HG) challenge. Rb1 directly bound to Keap1 and promoted its ubiquitination and proteasomal degradation dependent on lysine residues (K108, K323, and K551) by recruiting the E3 ligase synovial apoptosis inhibitor 1 (SYVN1), leading to Nrf2 dissociation from Keap1, Nrf2 nuclear translocation, Nrf2/PGC-1α complex formation. We further identified that Rb1 could bind to p47phox and reduce its phosphorylation and membrane translocation, thereby disrupting the assembly of the NOX2 complex. Importantly, Rb1-mediated preservation of cytoplasmic p47phox stabilized and contributed to Nrf2 activation. Additionally, we revealed that Rb1 reduced aortic atherosclerotic plaque formation along with reductions in oxidative stress and inflammatory response in streptozotocin (STZ)-induced ApoE−/− mice, but not in ApoE−/− mice with deficiency of Nrf2 and PGC-1α. Collectively, we demonstrated that Rb1, which directly targeted Keap1 and p47phox in ECs, may be an attractive candidate for the treatment of atherosclerosis in diabetes.

Due to their high prevalence and incidence, diabetes and atherosclerosis are increasingly becoming global public health concerns. Atherosclerosis is one of the leading causes of morbidity and disability in type 1 and/or type 2 diabetes patients. Atherosclerosis risk in diabetic patients is obviously higher than that of non-diabetic individuals. Diabetes-related glycolipid metabolism disorder has been shown to play a central role in atherosclerosis development and progression. Hyperglycemia and dyslipidemia increase the risks for atherosclerosis and plaque necrosis through multiple signaling pathways, such as a prolonged increase in reactive oxygen species (ROS) and inflammatory factors in cardiovascular cells. Notwithstanding the great advances in the understanding of the pathologies of diabetes-accelerated atherosclerosis, the current medical treatments for diabetic atherosclerosis hold undesirable side effects. Therefore, there is an urgent demand to identify novel therapeutic targets or alternative strategies to prevent or treat diabetic atherosclerosis. Burgeoning evidence suggests that plant and herbal medicines are closely linked with healthy benefits for diabetic complications, including diabetic atherosclerosis. In this review, we will overview the utilization of plant and herbal medicines for the treatment of diabetes-accelerated atherosclerosis. Furthermore, the underlying mechanisms of the ethnopharmacological therapeutic potentials against diabetic atherosclerosis are gathered and reviewed. It is foreseeable that the natural constituents from medicinal plants might be a new hope for the treatment of diabetes-accelerated atherosclerosis.

Growing evidence suggests that hypertension is one of the leading causes of cardiovascular morbidity and mortality since uncontrolled high blood pressure increases the risk of myocardial infarction, aortic dissection, hemorrhagic stroke, and chronic kidney disease. Impaired vascular homeostasis plays a critical role in the development of hypertension-induced vascular remodeling. Abnormal behaviors of vascular cells are not only a pathological hallmark of hypertensive vascular remodeling, but also an important pathological basis for maintaining reduced vascular compliance in hypertension. Targeting vascular remodeling represents a novel therapeutic approach in hypertension and its cardiovascular complications. Phytochemicals are emerging as candidates with therapeutic effects on numerous pathologies, including hypertension. An increasing number of studies have found that curcumin, a polyphenolic compound derived from dietary spice turmeric, holds a broad spectrum of pharmacological actions, such as antiplatelet, anticancer, anti-inflammatory, antioxidant, and antiangiogenic effects. Curcumin has been shown to prevent or treat vascular remodeling in hypertensive rodents by modulating various signaling pathways. In the present review, we attempt to focus on the current findings and molecular mechanisms of curcumin in the treatment of hypertensive vascular remodeling. In particular, adverse and inconsistent effects of curcumin, as well as some favorable pharmacokinetics or pharmacodynamics profiles in arterial hypertension will be discussed. Moreover, the recent progress in the preparation of nano-curcumins and their therapeutic potential in hypertension will be briefly recapped. The future research directions and challenges of curcumin in hypertension-related vascular remodeling are also proposed. It is foreseeable that curcumin is likely to be a therapeutic agent for hypertension and vascular remodeling going forwards.

The composition of anthocyanins in cultivated Lycium ruthenicum Murray (CLM) before and after in vitro gastrointestinal digestion was determined using an HPLC system coupled with an electrospray ionization-time of flight mass spectrometry. The antioxidant activity and α-glucosidase inhibition of the anthocyanins before and after digestion were also studied. The results showed that most of the anthocyanins in CLM were found in glycosylated form, containing glycoside ligands. After digestion, the glycosylated anthocyanins were transformed to anthocyanidins (without glycol-ligands) which exhibited higher antioxidant activity comparatively. Interestingly, although the inhibitory activity of anthocyanins against α-glucosidase was increased by in vitro gastrointestinal digestion, as suggested by IC50 value, the binding affinity of the anthocyanidins to α-glucosidase remained stable, as demonstrated by fluorescence quenching constant. This suggested that the anthocyanidins might have formed the anthocyanidin-α-glucosidase-substrate tertiary complex. Conclusively, in vitro gastrointestinal digestion may enhance the biological activities of CLM anthocyanins, regarding the antioxidant activity and α-glucosidase inhibition.

The present work was aimed at developing and characterizing biodegradable citrus pectin films incorporated with young apple polyphenols (YAPs). Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy analysis (SEM) and X-ray diffraction (XRD) analysis were performed to get acquaintance with the structure of the pectin/YAP films. An increase of tensile strength (TS) and elastic modulus (EM) accompanied with a decrease in elongation at break (% EB) was observed with YAP. FTIR spectrometry exhibited the emergence of new absorbance peak at 1520 cm−1, suggesting some interactions between both constituents of films. An increase in thermal stability of films was also observed by the inclusion of YAP into the film. Moreover, SEM analysis revealed that YAPs were homogenously distributed across pectin matrix. The antioxidant potential of the films was amplified by incorporating YAP. The microbiological assessment of the films confirmed the antimicrobial efficiency of newly developed films against three major food-borne pathogens.

Let \Omega be a set of unsatisfiable clauses, an implicit resolution refutation of \Omega is a circuit \beta with a resolution proof {\alpha} of the statement "\beta describes a correct tree-like resolution refutation of \Omega". We show that such system is p-equivalent to Extended Frege. More generally, let {\tau} be a tautology, a [P, Q]-proof of {\tau} is a pair (\alpha,\beta) s.t. \alpha is a P-proof of the statement "\beta is a circuit describing a correct Q-proof of \tau". We prove that [EF,P] \leq p [R,P] for arbitrary Cook-Reckhow proof system P.