Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N‐oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora.

Insulin-like growth factor 1 (IGF-1) is implicated in the nociceptive (pain) sensitivity of primary afferent neurons. We found that the IGF-1 receptor (IGF-1R) functionally stimulated voltage-gated T-type Ca(2+) (CaV3) channels in mouse dorsal root ganglia (DRG) neurons through a mechanism dependent on heterotrimeric G protein (heterotrimeric guanine nucleotide-binding protein) signaling. IGF-1 increased T-type channel currents in small-diameter DRG neurons in a manner dependent on IGF-1 concentration and IGF-1R but independent of phosphatidylinositol 3-kinase (PI3K). The intracellular subunit of IGF-1R coimmunoprecipitated with Gαo. Blocking G protein signaling by the intracellular application of guanosine diphosphate (GDP)-β-S or with pertussis toxin abolished the stimulatory effects of IGF-1. Antagonists of protein kinase Cα (PKCα), but not of PKCβ, abolished the IGF-1-induced T-type channel current increase. Application of IGF-1 increased membrane abundance of PKCα, and PKCα inhibition (either pharmacologically or genetically) abolished the increase in T-type channel currents stimulated by IGF-1. IGF-1 increased action potential firing in DRG neurons and increased the sensitivity of mice to both thermal and mechanical stimuli applied to the hindpaw, both of which were attenuated by intraplantar injection of a T-type channel inhibitor. Furthermore, inhibiting IGF-1R signaling or knocking down CaV3.2 or PKCα in DRG neurons abolished the increased mechanical and thermal sensitivity that mice exhibited under conditions modeling chronic hindpaw inflammation. Together, our results showed that IGF-1 enhances T-type channel currents through the activation of IGF-1R that is coupled to a G protein-dependent PKCα pathway, thereby increasing the excitability of DRG neurons and the sensitivity to pain.

BACKGROUND AND PURPOSEEndostatin (ES) is a c-terminal proteolytic fragment of collagen XVIII with promising antitumour properties in several tumour models, including human glioblastoma. We hypothesized that this peptide could interact with plasma membrane ion channels and modulate their functions. EXPERIMENTAL APPROACHUsing cell proliferation and migration assays, patch clamp and Western blot analysis, we studied the effects of ES on the proliferation and migration of human glioblastoma U87 cells, mediated by T-type Ca 2+ channels. KEY RESULTSExtracellular application of ES reversibly inhibited T-type Ca 2+ channel currents (T-currents) in U87 cells, whereas L-type Ca 2+ currents were not affected. This inhibitory effect was associated with a hyperpolarizing shift in the voltage-dependence of inactivation but was independent of G-protein and protein tyrosine kinase-mediated pathways. All three a1 subunits of T-type Ca 2+ channels (CaV3), a1G (CaV3.1), a1H (CaV3.2) and a1I (CaV3.3), were endogenously expressed in U87 cells. Using transfected HEK293 or CHO cells, we showed that only CaV3.1 and CaV3.2, but not CaV3.3 or CaV1.2 (L-type), channel currents were significantly inhibited. More interestingly, ES inhibited the proliferation and migration of U87 cells in a dose-dependent manner. Pretreatment of the cells with the specific T-type Ca 2+ channel blocker mibefradil occluded these inhibitory effects of ES. CONCLUSION AND IMPLICATIONSThis study provides the first evidence that the antitumour effects of ES on glioblastoma cells is through direct inhibition of T-type Ca 2+ channels and gives new insights into the future development of a new class of antiglioblastoma agents that target the proliferation and migration of these cells. LINKED ARTICLEThis article is commented on by Santoni et al., pp. 1244Santoni et al., pp. -1246

Sarcopenia is an age-related geriatric syndrome that is characterized by a progressive loss of muscle mass, strength and function. Chronic heart failure (CHF), the final stage of various cardiovascular diseases, may be closely correlated with the occurrence of sarcopenia. Accumulating evidence has demonstrated that CHF can promote the development of sarcopenia through multiple pathophysiological mechanisms, including malnutrition, inflammation, hormonal changes, oxidative stress, autophagy, and apoptosis. Additionally, CHF can aggravate the adverse outcomes associated with sarcopenia, including falls, osteoporosis, frailty, cachexia, hospitalization, and mortality. Sarcopenia and CHF are mutually interacting clinical syndromes. Patients with these two syndromes seem to endure a double burden, with no particularly effective way to hinder their progression. However, the combination of physical exercise, nutritional supplements, and drug therapy may counteract the development of these maladies. In this review, we will summarize the latest progress in the pathogenesis and treatment of sarcopenia in patients with CHF.

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The escalating proportion of elderly individuals in developed societies has led to a year-on-year increase in geriatric diseases. Improving quality of life for the elderly has thus become a very real problem that society must face. The term "sarcopenia" was first proposed to describe age-related loss of muscle mass and strength by Irwin Rosenberg in 1989. Initially, sarcopenia was generally considered to be a complication of ageing, 1 but was officially included in the ICD-10-MC Diagnosis Code in 2016, marking it as an independent disease, which has since attracted widespread attention worldwide. 2 The effects of ethnicity, environment, age and gender on quantity and quality of skeletal muscle have been investigated, and the definition and diagnosis of sarcopenia are being constantly updated. In 2018, the second European Working Group on Sarcopenia in Older People (EWGSOP2) provided an updated definition of sarcopenia as an age-related disease with a decline in skeletal muscle quantity or quality and a decrease in skeletal muscle strength or physical performance. 3 The extent of muscle atrophy in 65-year-olds is 5-15% and as high as 50% in people over 80 years old, the majority of whom

Summary Higher plants progress through a juvenile and an adult phase of development before they enter the reproductive phase. The transition from the juvenile to the adult phase is referred to as vegetative phase change, and this is signified by the production of trichomes on the abaxial side of leaf blades in Arabidopsis; however, the molecular mechanism underlying this process is poorly understood. We identified a dominant mutation (gl1‐D) in a forward genetic screen that accelerates abaxial trichome production during shoot development. This phenotype is the result of a G‐to‐A substitution in the 3′ noncoding region in the GLABRA1(GL1) gene. We show that TOE1, an AP2‐like transcription factor that acts downstream of the miR156‐SPL pathway, represses GL1 expression by directly binding to this site, and that gl1‐D prevents TOE1 binding. Our work reveals a molecular link between vegetative phase change and abaxial trichome production in Arabidopsis, and answers a long‐standing question of how the vegetative phase change pathway regulates vegetative traits.