Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express a total of 28 different TRP channel proteins, which can be divided into seven subfamilies based on amino acid sequence homology: TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (Polycystin), TRPV (Vanilloid). They are a class of ion channels found in numerous tissues and cell types and are permeable to a wide range of cations such as Ca2+, Mg2+, Na+, K+, and others. TRP channels are responsible for various sensory responses including heat, cold, pain, stress, vision and taste and can be activated by a number of stimuli. Their predominantly location on the cell surface, their interaction with numerous physiological signaling pathways, and the unique crystal structure of TRP channels make TRPs attractive drug targets and implicate them in the treatment of a wide range of diseases. Here, we review the history of TRP channel discovery, summarize the structures and functions of the TRP ion channel family, and highlight the current understanding of the role of TRP channels in the pathogenesis of human disease. Most importantly, we describe TRP channel-related drug discovery, therapeutic interventions for diseases and the limitations of targeting TRP channels in potential clinical applications. 

/pdf/trp-transient-receptor-potential-ion-channel-family-14n1f1ok.pdf

TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases

Chronic inflammatory response plays a prominent role in obesity-related nonalcoholic fatty liver disease (NAFLD). However, the intrahepatic triggering mechanism of inflammation remains obscure. This study aimed to elucidate the role of serum amyloid A1 (SAA1), an acute-phase response protein, in the obesity-induced hepatic inflammation and NAFLD.Male mice were fed a high fat diet (HFD) for 16 weeks, and insulin resistance, hepatic steatosis, and inflammation in mice were monitored. Murine SAA1/2 was genetically manipulated to investigate the role of SAA1 in NAFLD.We found that SAA1 was increased in the NAFLD liver in both humans and mice. Knockout of SAA1/2 or knockdown of hepatic SAA1/2 promoted energy expenditure and alleviated HFD-induced metabolic disorder, hepatic steatosis, and inflammation. Endogenous overexpression of SAA1 in hepatocytes by adeno-associated virus 8 (AAV8) transfection aggravated overnutrition-associated gain of body weight, insulin resistance, hepatic lipid accumulation, and liver injury, which were markedly alleviated by knockout of murine toll-like receptor 4 (TLR4). Mechanistically, SAA1 directly bound with TLR4/myeloid differentiation 2 (MD2) to induce TLR4 internalization, leading to the activation of nuclear factor (NF)-κB signaling and production of both SAA1 and other inflammatory cytokines, including interleukin (IL)-6 and C-C chemokine ligand (CCL2) in hepatocytes. Administration of HFD mice with an AAV8-shRNA-SAA1/2 showed a therapeutic effect on hepatic inflammation and NAFLD progression.These results demonstrate that SAA1 triggers hepatic steatosis and intrahepatic inflammatory response by forming a SAA1/TLR4/NF-κB/SAA1 feedforward regulatory circuit, which, in turn, leads to NAFLD progression. SAA1 may act as a potential target for the disease intervention. 

https://doi.org/10.1016/j.molmet.2022.101462

Serum amyloid A1 exacerbates hepatic steatosis via TLR4-mediated NF-κB signaling pathway

Pretreatment of poplar with eco-friendly levulinic acid to achieve efficient utilization of biomass.

Background/aims This study aimed to explore the therapeutic effects and underlying mechanism of berberine (BBR) on the non-alcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD). Materials and methods Rats were randomly divided into the following 4 groups: control (normal diet), model (HFD), polyene phosphatidylcholine HFD+PPC, and BBR (HFD+BBR) group. The NAFLD models were prepared by feeding with HFD for 12 weeks. The liver tissues were observed by oil red O staining. H-E staining was used to detect pathological changes in the liver tissues. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were detected by an automatic biochemical analyzer. ELISA was performed to observe the inflammatory cytokines (TNF-α, IL-6, and IL-1β) expressions. The levels of TLR4, MyD88, and NF-κB p65 were analyzed using western blot and qRT-PCR, respectively. The nuclear translocation levels of NF-κB in the primary liver cells were measured using flow cytometry. Results BBR could significantly alleviate the liver tissue steatosis and inflammatory cell infiltration; reduce the NAFLD activity scores and serum levels of ALT, AST, TC, and LDL-C; decrease the levels of TNF-α, IL-6, and IL-1β, and reduce the expression of TLR4, MyD88, and NF-κB in the liver tissues. BBR could also reverse the nuclear translocation of NF-κB in the primary liver cells. Conclusion BBR alleviated the progress of NAFLD and liver damage, which might contribute to inhibit the nuclear translocation of NF-κB via the TLR4/MyD88/NF-κB pathway.

Berberine inhibits liver damage in rats with non-alcoholic fatty liver disease by regulating TLR4/MyD88/NF-κB pathway.

Targeting DUSP7 signaling alleviates hepatic steatosis, inflammation and oxidative stress in high fat diet (HFD)-fed mice via suppression of TAK1

TRUSS Exacerbates NAFLD Development by Promoting IκBα Degradation in Mice.

Antiangiogenic tyrosine kinases inhibitors induce hypertension, which may increase the incidents of cardiovascular complications and limit their use. However, the mechanisms by which usage of TKIs results in hypertension have not been fully understood. Here, we report the potential mechanisms of how sunitinib, a widely used TKI, induces hypertension. Male SD rats were randomly divided into control group and sunitinib-administrated group. We show that sunitinib administration for seven days caused a significant increase in artery blood pressure, along with glycerolipid metabolism abnormalities including decreased food intake and low body weight, hypoglycemia, hyperinsulinemia. Sunitinib administration also resulted in a significant increase in the levels of insulin autoantibody (IAA), cyclic adenosine monophosphate and free fatty acid in serum; whereas, sunitinib administration had no effects on serum glucagon levels. Sunitinib led to the decreased insulin sensitivity as determined by insulin tolerance test (ITT) and glucose tolerance test (GTT), reflecting insulin resistance occurred in sunitinib-treated rats. The results obtained from wire myograph assay in the mesenteric arteries show that endothelium-dependent relaxation, but not endothelium-independent relaxation, was impaired by sunitinib. Furthermore, western blot analysis revealed that the expressions levels of phosphorylated IRS-1, Pellino-1, AKT and eNOS were significantly attenuated by sunitinib in rat mesenteric artery tissues and in the sunitinib-treated primary cultured mesenteric artery endothelial cells. The levels of serum and endothelium-derived nitric oxide were also significantly decreased by sunitinib. Moreover, sunitinib-induced decrease in the expression levels of phosphorylated AKT and eNOS was further reduced by knocking down of Pellino-1 in MAECs. Our results suggest that sunitinib causes vascular dysfunction and hypertension, which are associated with insulin resistance- and Pellino-1-mediated inhibition of AKT/eNOS/NO signaling. Our results may provide a rational for preventing and/or treating sunitinib-induced endothelial dysfunction and hypertension.

/pdf/insulin-resistance-and-pellino-1-mediated-decrease-in-the-3lifgbqpgu.pdf

Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to Sunitinib-Induced Hypertension.

Hemicellulose is a major component of the complex biomass recalcitrance structure of fiber cell walls. Even though biomass recalcitrance protects plants, it affects the effective utilization of lignocellulosic biomass resources. Therefore, the separation and extraction of hemicellulose is very important. In this study, an improved two-step alkali pretreatment method was proposed to separate hemicellulose efficiently. Firstly, 16.61% hemicellulose was extracted from bamboo by the weak alkali treatment. Then, the physical freezing and the alkali treatment were carried out by freezing at −20 °C for 12.0 h and thawing at room temperature, heating to 80 °C, and treating with 5.0% sodium hydroxide for 90 min; the extraction yield of hemicellulose reached 73.93%. The total extraction yield of the two steps was 90.54%, and the molecular weight and purity reached 44,865 g·mol–1 and 89.60%, respectively. It provides a new method for breaking the biomass recalcitrance of wood fiber resources and effectively extracting hemicellulose.

/pdf/high-efficiency-and-high-quality-extraction-of-hemicellulose-2y8b94iw.pdf

High-Efficiency and High-Quality Extraction of Hemicellulose of Bamboo by Freeze-Thaw Assisted Two-Step Alkali Treatment

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TRUSS Exacerbates NAFLD Development by Promoting IκBα Degradation in Mice.

Insulin Resistance and Pellino-1 Mediated Decrease in the Activities of Vasodilator Signaling Contributes to Sunitinib-Induced Hypertension.

High-Efficiency and High-Quality Extraction of Hemicellulose of Bamboo by Freeze-Thaw Assisted Two-Step Alkali Treatment