Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis.

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.

Characterization of the physicochemical properties of Lipu Colocasia esculenta (L.) Schott starch: A potential new food ingredient.

The physicochemical properties of Lipu taro starch (LTS), cassava starch (CS) and wheat starch (WS) were analyzed. These starches exhibited a comparable starch content (86 %). However, LTS had a significantly lower amylose content (15.93 %) compared to CS (26.62 %) and WS (33.53 %). Moreover, LTS demonstrated an irregular polygonal cubic morphology with a smaller particle size of 2.55 µm while possessed an A-type crystal structure with high crystallinity at 25.07 %. In contrast, CS and WS had larger particle sizes of 13.33 µm and 16.68 µm, respectively, with lower crystallinities of 22.52 % and 20.33 %. Due to these physicochemical properties, LTS exhibited superior emulsification properties with a higher emulsifying activity index of 8.63 m2/g and an emulsion stability index of 69.18 min, whereas CS and WS had values of 2.35 m2/g and 25.15 min, and 0.37 m2/g and 11.48 min, respectively. LTS also demonstrated enhanced thermal stability, characterized by higher gelatinization temperature (indicated by To, Tp, Tc, and ΔT) and reduced paste viscosity (indicated by PV, TV, FV, SBV, and BDV) compared to CS. However, the mechanical strength of the gel made from LTS (indicated by hardness, adhesiveness, springiness, gumminess, and chewiness) was comparatively inferior to those from CS and WS.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Disrupted cardiac fibroblast BCAA catabolism contributes to diabetic cardiomyopathy via a periostin/NAP1L2/SIRT3 axis.

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-ß/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.

Divergent and Selective Light Alkene Cross-Coupling.

Light olefins are abundantly manufactured in the petroleum industry and thus represent ideal starting materials for modern chemical synthesis. Selective and divergent transformations of feedstock light olefins to value-added chemicals are highly sought-after but remain challenging. Herein we report an exceptionally regioselective carbonickelation of light alkenes followed by in situ trapping with three types of nucleophiles, namely a reductant, base, or Grignard reagent. This protocol enables efficient 1,2-hydrofunctionalization, dicarbofunctionalization, and branched-selective Heck-type cross-coupling of light alkenes with aryl and alkenyl reagents to streamline access to diverse alkyl arenes and complex alkenes. Harnessing bulky N-heterocyclic carbene ligands with acenaphthyl backbones for nickel catalysts is crucial to attain high reactivity and selectivity. This strategy provides a rare, modular, and divergent platform for upgrading feedstock alkenes and is expected to find broad applications in medicinal chemistry and industrial processes.

A Rehmannia glutinosa caffeic acid O-methyltransferase functional identification: Reconstitution of the ferulic acid biosynthetic pathway in Saccharomyces cerevisiae using Rehmannia glutinosa enzymes.

Rehmannia glutinosa produces many pharmacological natural components, including ferulic acid (FA) which is also an important precursor of some medicinal ingredients, so it is very significant to explore FA biosynthesis for enhancing the production of FA and its derivations. This study aimed to determine and reconstitute the R. glutinosa FA biosynthetic pathway from phenylalanine (Phe) metabolism in Saccharomyces cerevisiae as a safe host for the biosynthesis of plant-derived products. Although plant caffeic acid O-methyltransferases (COMTs) are thought to be a vital catalytic enzyme in FA biosynthesis pathways, to date, none of the RgCOMTs in R. glutinosa has been characterized. This study identified an RgCOMT and revealed its protein enzymatic activity for FA production in vitro. The RgCOMT overexpression in R. glutinosa significantly increased FA yield, suggesting that its molecular function is involved in FA biosynthesis. Heterologous expression of the RgCOMT and reported R. glutinosa genes, RgPAL2 (encoding phenylalanine ammonia-lyase [PAL] protein), RgC4H (cinnamate 4-hydroxylase [C4H]), and RgC3H (p-coumarate-3-hydroxylase [C3H]), in S. cerevisiae confirmed their catalytic abilities in the reaction steps for the FA biosynthesis. Importantly, in this study, these genes were introduced into S. cerevisiae and coexpressed to reconstitute the R. glutinosa FA biosynthetic pathway from Phe metabolism, thus obtaining an engineered strain that produced an FA titer of 148.34 mg L-1 . This study identified the functional activity of RgCOMT and clarified the R. glutinosa FA biosynthesis pathway in S. cerevisiae, paving the way for the efficient production of FA and its derivatives.

Unsymmetric N-heterocyclic carbene ligand enabled nickel-catalysed arylation of bulky primary and secondary amines.

The arylation of sterically hindered amines represents one of the long-standing challenges in synthetic chemistry. Herein, we report a highly efficient Ni-catalysed arylation of sterically hindered primary and secondary amines with aryl chlorides or phenol derivatives enabled by an unsymmetric N-heterocyclic carbene (NHC) ligand. The protocol provides general, efficient, and scalable access to various sterically demanding anilines in excellent yields under mild conditions. A wide range of functional groups and heterocycles are compatible (>50 examples), including those present in biologically relevant molecules. Computational studies suggest that the unsymmetric bulky and flexible NHC ligand was critical to balance the oxidative addition and reductive elimination elementary steps, thus promoting this challenging transformation.

DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice.

BACKGROUND: Na+/K+-ATPase (NKA), an ion pumping enzyme ubiquitously expressed in various cells, is critically involved in cellular ion homeostasis and signal transduction. However, the role of NKA in hepatic lipid homeostasis has yet to be fully characterized. METHODS: The activity of NKA and NKAα1 expression were determined in steatotic cells, mice and patients. The roles of NKAα1 in hepatosteatosis were detected using hepatocyte knockout or specific overexpression of NKAα1 in mice. RESULTS: Herein, we demonstrated that the expression and activity of α1 subunit of NKA (NKAα1) were lowered in the livers of nonalcoholic fatty liver disease (NAFLD) patients, high-fat diet (HFD)-induced obese mice, and genetically obese (ob/ob, db/db) mice, as well as oleic acid-induced hepatocytes. Hepatic deficiency of NKAα1 exacerbated, while adeno-associated virus-mediated liver specific overexpression of NKAα1 alleviated hepatic steatosis through regulation of fatty acid oxidation (FAO) and lipogenesis. Mechanistically, we revealed that NKAα1 upregulated sirtuin 1 (SIRT1) via interacting with ubiquitin specific peptidase 22 (USP22), a deubiquitinating enzyme for the stabilization and deubiquitination of SIRT1, thus activating the downstream autophagy signaling. Blockade of the SIRT1/autophagy signaling pathway eliminated the protective effects of NKAα1 against lipid deposition in hepatocytes. Importantly, we found that an antibody against the DR region (897DVEDSYGQQWTYEQR911) of NKAα1 subunit (DR-Ab) ameliorated hepatic steatosis through maintaining the membrane density of NKAα1 and inducing its activation. CONCLUSIONS: Collectively, this study renews the functions of NKAα1 in liver lipid metabolism and provides a new clue for gene therapy or antibody treatment of hepatic lipid metabolism disturbance by targeting NKAα1.

Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy.

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- andloss-of-function experimentswere 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.

Hydrogen Sulfide in Diabetic Complications Revisited: The State of the Art, Challenges, and Future Directions.

Significance: Diabetes and its related complications are becoming an increasing public health problem that affects hundreds of millions of people globally. Increased disability and mortality rate of diabetic individuals are closely associated with various life-threatening complications, such as atherosclerosis, nephropathy, retinopathy, and cardiomyopathy. Recent Advances: Conventional treatments for diabetes are still limited because of undesirable side effects, including obesity, hypoglycemia, and hepatic and renal toxicity. Studies have shown that hydrogen sulfide (H2S) plays a critical role in the modulation of glycolipid metabolism, pancreatic ß cell functions, and diabetic complications. Critical Issues: Preservation of endogenous H2S systems and supplementation of H2S donors are effective in attenuating diabetes-induced complications, thus representing a new avenue to treat diabetes and its associated complications. Future Directions: This review systematically recapitulates and discusses the most recent updates regarding the therapeutic effects of H2S on diabetes and its various complications, with an emphasis on the molecular mechanisms that underlie H2S-mediated protection against diabetic complications. Furthermore, current clinical trials of H2S in diabetic populations are highlighted, and the challenges and solutions to the clinical transformation of H2S-derived therapies in diabetes are proposed. Finally, future research directions of the pharmacological actions of H2S in diabetes and its related complications are summarized. Antioxid. Redox Signal. 38, 18-44.