Comprehensive analysis reveals cholesterol metabolism-related signature for predicting prognosis and guiding individualized treatment of glioma.

Objective: Gliomas are the most common intracranial tumors with the highest degree of malignancy. Disturbed cholesterol metabolism is one of the key features of many malignant tumors, including gliomas. This study aimed to investigate the significance of cholesterol metabolism-related genes in prognostic prediction and in guiding individualized treatment of patients with gliomas.

Unravelling the impact of QRICH1 modulation on endoplasmic reticulum stress and neuronal apoptosis in traumatic brain injury.

Background: Traumatic brain injury (TBI) is a major public health concern with high morbidity and mortality rates. Secondary brain injury, marked by inflammatory responses and apoptosis, worsens TBI outcomes. The endoplasmic reticulum stress (ERS) response has been implicated in secondary brain injury, with Glutamine Rich 1 Gene (QRICH1) emerging as a potential mediator.

Enhancing S-nitrosoglutathione reductase decreases S-nitrosylation of ERO1α and reduces neuronal death in secondary traumatic brain injury.

Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, along with high mortality and disability rates. Pathological conversion of excess nitric oxide (NO) to S-nitrosoglutathion (GSNO) after TBI leads to high S-nitrosylation of intracellular proteins, causing nitrative stress. GSNO reductase (GSNOR) plays an important role by regulating GSNO and SNO-proteins (PSNOs) and as a redox regulator of the nervous system.

ARMCX1 inhibits lung adenocarcinoma progression by recruiting FBXW7 for c-Myc degradation.

Background: Armadillo Repeat Containing X-Linked 1 (ARMCX1), a member of the ARM Repeat X-linked protein family, exerts inhibitory function in various tumors. However, its biological role in lung adenocarcinoma (LUAD) and the underlying molecular mechanisms require further exploration.

Methods: LUAD tissue microarrays and bioinformatic databases were used to evaluate the relationship between ARMCX1 and clinicopathological features.

Molecular Mechanism of the βAR Agonist Activity of a β-Blocker.

Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors (βARs). The βAR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of βAR and βAR. Interestingly, several β-blockers, which are antagonists of the βARs and βARs, have been reported to exhibit agonist activity at the βAR.

Metabolome-Wide Mendelian Randomization Assessing the Causal Role of Serum and Cerebrospinal Metabolites in Traumatic Brain Injury.

Previous studies have identified metabolites as biomarkers or potential therapeutic targets for traumatic brain injury (TBI). However, the causal association between them remains unknown. Therefore, we investigated the causal effect of serum metabolites and cerebrospinal fluid (CSF) metabolites on TBI susceptibility through Mendelian randomization (MR).

Ligand efficacy modulates conformational dynamics of the µ-opioid receptor.

The µ-opioid receptor (µOR) is an important target for pain management and molecular understanding of drug action on µOR will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of µOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex.

The role of cardiac microenvironment in cardiovascular diseases: implications for therapy.

Due to aging populations and changes in lifestyle, cardiovascular diseases including cardiomyopathy, hypertension, and atherosclerosis, are the leading causes of death worldwide. The heart is a complicated organ composed of multicellular types, including cardiomyocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, and immune cells. Cellular specialization and complex interplay between different cell types are crucial for the cardiac tissue homeostasis and coordinated function of the heart.

Structural insights into human organic cation transporter 1 transport and inhibition.

The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate.

Dual-task turn velocity - a novel digital biomarker for mild cognitive impairment and dementia.

Background: Disorders associated with cognitive impairment impose a significant burden on both families and society. Previous studies have indicated that gait characteristics under dual-task as reliable markers of early cognitive impairment. Therefore, digital gait detection has great potential for future cognitive screening.

Endoplasmic reticulum stress and the unfolded protein response: emerging regulators in progression of traumatic brain injury.

Traumatic brain injury (TBI) is a common trauma with high mortality and disability rates worldwide. However, the current management of this disease is still unsatisfactory. Therefore, it is necessary to investigate the pathophysiological mechanisms of TBI in depth to improve the treatment options.

Structures of human prostaglandin F receptor reveal the mechanism of ligand and G protein selectivity.

Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH). However, off-target activation of closely related receptors such as the prostaglandin E receptor subtype EP3 (EP3 receptor) by carboprost results in side effects and limits the clinical application.

Stromal cell-derived factor-1 downregulation contributes to neuroprotection mediated by CXC chemokine receptor 4 interactions after intracerebral hemorrhage in rats.

Aim: Stromal cell-derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) have a substantial role in neuronal formation, differentiation, remodeling, and maturation and participate in multiple physiological and pathological events. In this study, we investigated the role of SDF-1/CXCR4 in neural functional injury and neuroprotection after intracerebral hemorrhage (ICH).

Methods: Western blot, immunofluorescence and immunoprecipitation were used to detect SDF-1/CXCR4 expression and combination respectively after ICH.

Armcx1 attenuates secondary brain injury in an experimental traumatic brain injury model in male mice by alleviating mitochondrial dysfunction and neuronal cell death.

Armcx1 is highly expressed in the brain and is located in the mitochondrial outer membrane of neurons, where it mediates mitochondrial transport. Mitochondrial transport promotes the removal of damaged mitochondria and the replenishment of healthy mitochondria, which is essential for neuronal survival after traumatic brain injury (TBI). This study investigated the role of Armcx1 and its potential regulator(s) in secondary brain injury (SBI) after TBI.

Efficacy and tolerability of minocycline in depressive patients with or without treatment-resistant: a meta-analysis of randomized controlled trials.

Background: Minocycline, an antibiotic with anti-inflammatory, antioxidant, and neuroprotective properties, has been used for treating psychiatric disorders in research. This systematic review aimed to evaluate the efficacy and tolerability of minocycline in patients having depression with or without treatment-resistance.

Methods: Electronic databases including Embase, PubMed, and the Cochrane library were searched for relevant studies published up to October 17, 2022.

Structural basis of α-adrenergic receptor activation and recognition by an extracellular nanobody.

The αadrenergic receptor (αAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. αAR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human αAR bound to the endogenous agonist noradrenaline, its selective agonist oxymetazoline, and the antagonist tamsulosin, with resolutions range from 2.

Conformational dynamics of the μ-opioid receptor determine ligand intrinsic efficacy.

The μ-opioid receptor (μOR) is an important target for pain management and the molecular understanding of drug action will facilitate the development of better therapeutics. Here we show, using double electron-electron resonance (DEER) and single-molecule fluorescence resonance energy transfer (smFRET), how ligand-specific conformational changes of the μOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several cytoplasmic receptor conformations interconverting on different timescales, including a pre-activated receptor conformation which is capable of G protein binding, and a fully activated conformation which dramatically lowers GDP affinity within the ternary complex.

Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor.

Advances in structural biology have provided important mechanistic insights into signaling by the transmembrane core of G-protein coupled receptors (GPCRs); however, much less is known about intrinsically disordered regions such as the carboxyl terminus (CT), which is highly flexible and not visible in GPCR structures. The β adrenergic receptor's (βAR) 71 amino acid CT is a substrate for GPCR kinases and binds β-arrestins to regulate signaling. Here we show that the βAR CT directly inhibits basal and agonist-stimulated signaling in cell lines lacking β-arrestins.

Efficacy and safety of levetiracetam versus valproate in patients with established status epilepticus: A systematic review and meta-analysis.

Objective: Status epilepticus (SE) is a common neurological emergency that is defined as a prolonged seizure or a series of seizures which often leads to irreversible damage. Levetiracetam (LEV) and valproate (VPA) are second-line anti-seizure drugs that are frequently used in patients with established SE (ESE). This meta-analysis compared the efficacy and safety of LEV and VPA for the treatment of ESE.

The interconnections between the microtubules and mitochondrial networks in cardiocerebrovascular diseases: Implications for therapy.

Microtubules, a highly dynamic cytoskeleton, participate in many cellular activities including mechanical support, organelles interactions, and intracellular trafficking. Microtubule organization can be regulated by modification of tubulin subunits, microtubule-associated proteins (MAPs) or agents modulating microtubule assembly. Increasing studies demonstrate that microtubule disorganization correlates with various cardiocerebrovascular diseases including heart failure and ischemic stroke.

Therapeutic effects of isosteviol sodium on non-alcoholic fatty liver disease by regulating autophagy via Sirt1/AMPK pathway.

Isosteviol sodium (STVNa) is a beyerane diterpene synthesized via acid hydrolysis of stevioside, which can improve glucose and lipid metabolism in animals with diabetes. However, it remains unknown whether STVNa can exhibit a therapeutic effect on nonalcoholic fatty liver disease (NAFLD) and its underlying mechanism. We hypothesize that autophagic initiation may play a key role in mediating the development of NAFLD.

Isosteviol sodium attenuates high fat/high cholesterol-induced myocardial dysfunction by regulating the Sirt1/AMPK pathway.

A fat-rich diet triggers obesity, and promotes cardiomyocyte injury. Till now, no prior investigations suggested a beneficial role of Isosteviol Sodium (STVNa) in cardiac activity in high fat diet (HFD)-exposed obese rats. However, there is evidence that STVNa accelerates healing of multiple tissue injuries.

Role of hydrogen sulfide in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a common acute and severe disease worldwide, which imposes a heavy burden on families and society. However, the current therapeutic strategies for SAH are unsatisfactory. Hydrogen sulfide (H S), as the third gas signaling molecule after carbon monoxide and nitric oxide, has been widely studied recently.