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Neuroinflammation, mediated by microglia and astrocytes, is an abnormal immune reaction in central nervous system (CNS) disorders. Stimulation of TRPV1 has been found to enhance microglial activation, resulting in a pro-inflammatory response. Natural anthraquinones such as physcion and rhein are commonly found in rhubarb, a medicinal plant recognized for its dual role in culinary and therapeutic applications. The therapeutic potential and mechanisms of these anthraquinones remain largely unexplored. This research aims to examine how anthraquinones protect against neuroinflammation and delineate the underlying mechanisms in lipopolysaccharide (LPS)-mediated cellular and zebrafish models. Among the representative anthraquinone analogs, physcion and rhein showed potent functional inhibitory activity against the TRPV1 channel. The production of nitric oxide (NO) and secretion of pro-inflammatory factors triggered by LPS were significantly reduced in BV-2 cells through regulation of , , , and mRNA expression. Moreover, physcion and rhein inhibited calcium influx and exerted anti-neuroinflammatory effects, which were closely associated with the suppression of Ca /CAMKK2/AKT and the PI3K/AKT-mediated NF-κB activation pathways. Furthermore, physcion and rhein reduced LPS-driven neutrophil recruitment to the brain and ameliorated locomotor deficits in zebrafish larvae, with the restoration of , , and transcript levels to baseline. In conclusion, natural-derived anthraquinones from rhubarb, physcion and rhein, acted as functional inhibitors of TRPV1-mediated calcium dynamics and significantly reduced LPS-mediated neuroinflammation in microglial cells and zebrafish larvae, suggesting promise as therapeutics for neurological disorders.

Background Muscle atrophy and weakness are adverse effects of high dose or the sustained usage of glucocorticoids. Loss of mitochondria and degradation of protein are highly correlated with muscle dysfunction. The deacetylase sirtuin 1 (SIRT1) plays a vital role in muscle remodelling. The current study was designed to identify myricanol as a SIRT1 activator, which could protect skeletal muscle against dexamethasone‐induced wasting. Methods The dexamethasone‐induced atrophy in C2C12 myotubes was evaluated by expression of myosin heavy chain, muscle atrophy F‐box (atrogin‐1), and muscle ring finger 1 (MuRF1), using western blots. The mitochondrial content and oxygen consumption were assessed by MitoTracker staining and extracellular flux analysis, respectively. Muscle dysfunction was established in male C57BL/6 mice (8–10 weeks old, n = 6) treated with a relatively high dose of dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, forced swimming capacity, muscle weight, and muscle histology were assessed. The expression of proteolysis‐related, autophagy‐related, apoptosis‐related, and mitochondria‐related proteins was analysed by western blots or immunoprecipitation. Results Myricanol (10 μM) was found to rescue dexamethasone‐induced muscle atrophy and dysfunction in C2C12 myotubes, indicated by increased expression of myosin heavy chain (0.33 ± 0.14 vs. 0.89 ± 0.21, *P < 0.05), decreased expression of atrogin‐1 (2.31 ± 0.67 vs. 1.53 ± 0.25, *P < 0.05) and MuRF1 (1.55 ± 0.08 vs. 0.99 ± 0.12, **P < 0.01), and elevated ATP production (3.83 ± 0.46 vs. 5.84 ± 0.79 nM/mg protein, **P < 0.01), mitochondrial content (68.12 ± 10.07% vs. 116.38 ± 5.12%, *P < 0.05), and mitochondrial oxygen consumption (166.59 ± 22.89 vs. 223.77 ± 22.59 pmol/min, **P < 0.01). Myricanol directly binds and activates SIRT1, with binding energy of −5.87 kcal/mol. Through activating SIRT1 deacetylation, myricanol inhibits forkhead box O 3a transcriptional activity to reduce protein degradation, induces autophagy to enhance degraded protein clearance, and increases peroxisome proliferator‐activated receptor γ coactivator‐1α activity to promote mitochondrial biogenesis. In dexamethasone‐induced muscle wasting C57BL/6 mice, 5 mg/kg myricanol treatment reduces the loss of muscle mass; the percentages of quadriceps and gastrocnemius muscle in myricanol‐treated mice are 1.36 ± 0.02% and 0.87 ± 0.08%, respectively (cf. 1.18 ± 0.06% and 0.78 ± 0.05% in dexamethasone‐treated mice, respectively). Myricanol also rescues dexamethasone‐induced muscle weakness, indicated by improved grip strength (70.90 ± 4.59 vs. 120.58 ± 7.93 g, **P < 0.01) and prolonged swimming exhaustive time (48.80 ± 11.43 vs. 83.75 ± 15.19 s, **P < 0.01). Myricanol prevents dexamethasone‐induced muscle atrophy and weakness by activating SIRT1, to reduce muscle protein degradation, enhance autophagy, and promote mitochondrial biogenesis and function in mice. Conclusions Myricanol ameliorates dexamethasone‐induced skeletal muscle wasting by activating SIRT1, which might be developed as a therapeutic agent for treatment of muscle atrophy and weakness.

The formyl peptide receptor 1 (FPR1) is primarily responsible for detection of short peptides bearing N-formylated methionine (fMet) that are characteristic of protein synthesis in bacteria and mitochondria. As a result, FPR1 is critical to phagocyte migration and activation in bacterial infection, tissue injury and inflammation. How FPR1 distinguishes between formyl peptides and non-formyl peptides remains elusive. Here we report cryo-EM structures of human FPR1-Gi protein complex bound to S. aureus -derived peptide fMet-Ile-Phe-Leu (fMIFL) and E. coli -derived peptide fMet-Leu-Phe (fMLF). Both structures of FPR1 adopt an active conformation and exhibit a binding pocket containing the R201 5.38 XXXR205 5.42 (RGIIR) motif for formyl group interaction and receptor activation. This motif works together with D106 3.33 for hydrogen bond formation with the N-formyl group and with fMet, a model supported by MD simulation and functional assays of mutant receptors with key residues for recognition substituted by alanine. The cryo-EM model of agonist-bound FPR1 provides a structural basis for recognition of bacteria-derived chemotactic peptides with potential applications in developing FPR1-targeting agents. Detection of invading bacteria is key to immunity. Here, the authors report cryo-electron microscopy structures of agonist-bound formyl peptide receptor 1 (FPR1), that reveal structural basis for recognition of bacteria-derived formyl peptides.

Chemerin is an adipokine with chemotactic activity to a subset of leukocytes. Chemerin binds to 3 G protein-coupled receptors, including chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C chemokine receptor-like 2 (CCRL2). Here, we report that GPR1 is capable of Gi signaling when stimulated with full-length chemerin or its C-terminal nonapeptide (C9, YFPGQFAFS). We present high-resolution cryo-EM structures of Gi-coupled GPR1 bound to full-length chemerin and to the C9 peptide, respectively. C9 insertion into the transmembrane (TM) binding pocket is both necessary and sufficient for GPR1 signaling, whereas the full-length chemerin uses its bulky N-terminal core for interaction with a β-strand located at the N-terminus of GPR1. This interaction involves multiple β-strands of full-length chemerin, forming a β-sheet that serves as a “lid” for the TM binding pocket and is energetically expensive to remove as indicated by molecular dynamics simulations with free energy landscape analysis. Combining results from functional assays, our structural model explains why C9 is an activating peptide at GPR1 and how the full-length chemerin uses a “two-site” model for enhanced interaction with GPR1.

Aging is a process that represents the accumulation of changes in organism overtime. In biological level, accumulations of molecular and cellular damage in aging lead to an increasing risk of diseases like sarcopenia. Sarcopenia reduces mobility, leads to fall‐related injuries, and diminishes life quality. Thus, it is meaningful to find out novel therapeutic strategies for sarcopenia intervention that may help the elderly maintain their functional ability. Oxidative damage‐induced dysfunctional mitochondria are considered as a culprit of muscle wasting during aging. Herein, we aimed to demonstrate whether myricanol (MY) protects aged mice against muscle wasting through alleviating oxidative damage in mitochondria and identify the direct protein target and its underlying mechanism. We discovered that MY protects aged mice against the loss of muscle mass and strength through scavenging reactive oxygen species accumulation to rebuild the redox homeostasis. Taking advantage of biophysical assays, peroxiredoxin 5 was discovered and validated as the direct target of MY. Through activating peroxiredoxin 5, MY reduced reactive oxygen species accumulation and damaged mitochondrial DNA in C2C12 myotubes. Our findings provide an insight for therapy against sarcopenia through alleviating oxidative damage‐induced dysfunctional mitochondria by targeting peroxiredoxin 5, which may contribute an insight for healthy aging. MY was found to protect aged mice against the loss of muscle mass and strength through scavenging ROS accumulation to rebuild the redox homeostasis. Combining biophysical and pharmacological profiles, peroxiredoxin 5 was discovered and validated as the direct target of MY. Furthermore, mechanistic studies showed that MY reduced reactive oxygen species accumulation and damaged mitochondrial DNA in myotubes through activating peroxiredoxin 5.

Objectives To evaluate the safety and clinical efficacy of intra-articular injection of human umbilical cord–derived mesenchymal stem cells (UC-MSCs) for knee osteoarthritis (KOA). Methods This was a randomized, double-blind, placebo-control trial consisting of 3 arms including placebo, hyaluronic acid (HA), and UC-MSCs. 69 individuals were screened, with 55 participants subsequently randomized. The primary endpoint was the safety after injection. The secondary endpoints were improvements in visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Society Clinical Rating System (KSS), EuroQol five-dimensional questionnaire (EQ-5D), and magnetic resonance imaging (MRI) examinations at 6-month after injection. Results Adverse events (AEs) did not demonstrate significant differences among the groups. No serious treatment-related AEs were observed. Compared with placebo and HA, injection of UC-MSCs resulted in a greater improvement in VAS and EQ-5D; however, the differences were not statistically significant. Patients in the UC-MSCs group exhibited significant improvement in synovitis at the 6-month follow-up as compared with the placebo and HA groups (P = 0.003). At 6 months, UC-MSCs injection showed significantly better improvements in VAS (P = 0.011), WOMAC (P = 0.014), and EQ-5D scores (P = 0.049) in patients with KOA incorporating synovitis, particularly those experiencing moderate to severe pain. MRI indicated no significant difference in change of joint structures among the groups, except for the synovium. Conclusions Treatment with UC-MSCs was shown to be a viable therapeutic option for KOA combined with synovitis, showing clinical improvement at the end of follow-up, especially in those with moderate to severe pain. Further phase III clinical trials would be required to confirm the efficacy. Trial registration The trial was registered at chictr.org on October 13, 2020, with the registration number ChiCTR2000039017.

It is generally believed that evapotranspiration at night is too miniscule to be considered. Thus, few studies focus on the nocturnal evapotranspiration (ETN) in alpine region. In this study, based on the half-hour eddy and meteorological data of the growing season (from May to September) in 2019, we quantified the ETN of alpine desert (AD), alpine meadow (AM), alpine meadow steppe (AMS), and alpine steppe (AS) in the Qinghai Lake Basin and clarified the different response of evapotranspiration to climate variables in daytime and nighttime with the variation of elevation. The results show that: (1) ETN accounts for 9.88~15.08% of total daily evapotranspiration and is relatively higher in AMS (15.08%) and AD (12.13%); (2) in the daytime, net radiation (Rn), temperature difference (TD), vapor pressure difference (VPD), and soil moisture have remarkable influence on evapotranspiration, and Rn and VPD are more important at high altitudes, while TD is the main factor at low altitudes; (3) in the nighttime, VPD and wind speed (WS) control ETN at high altitudes, and TD and WS drive ETN at low altitudes. Our results are of great significance in understanding ETN in the alpine regions and provide reference for further improving in the evapotranspiration estimation model.

Venoms from marine animals have been recognized as a new emerging source of peptide-based therapeutics. Several peptide toxins from sea anemone have been investigated as therapeutic leads or pharmacological tools. Venom complexity should be further highlighted using combined strategies of large-scale sequencing and data analysis which integrated transcriptomics and proteomics to elucidate new proteins or peptides to be compared among species. In this work, transcriptomic and proteomic analyses were combined to identify six groups of expressed peptide toxins in Zoanthus natalensis. These include neurotoxin, hemostatic and hemorrhagic toxin, protease inhibitor, mixed function enzymes, venom auxiliary proteins, allergen peptides, and peptides related to the innate immunity. Molecular docking analysis indicated that one expressed Zoanthus Kunitz-like peptide, ZoaKuz1, could be a voltage-gated potassium channels blocker and, hence, it was selected for functional studies. Functional bioassays revealed that ZoaKuz1 has an intrinsic neuroprotective activity in zebrafish model of Parkinson’s disease. Since pharmacological blockade of KV channels is known to induce neuroprotective effects, ZoaKuz1 holds the potential to be developed in a therapeutic tool to control neural dysfunction by slowing or even halting neurodegeneration mediated by ion-channel hyperactivity.

Long non-coding RNAs (lncRNAs) have been shown to play regulatory roles in a diverse range of biological processes and are associated with the outcomes of various diseases. The majority of studies about lncRNAs focus on model organisms, with lessened investigation in non-model organisms to date. Herein, we have undertaken an investigation on lncRNA in two zoanthids (cnidarian): Protolpalythoa varibilis and Palythoa caribaeorum . A total of 11,206 and 13,240 lncRNAs were detected in P . variabilis and P . caribaeorum transcriptome, respectively. Comparison using NONCODE database indicated that the majority of these lncRNAs is taxonomically species-restricted with no identifiable orthologs. Even so, we found cases in which short regions of P . caribaeorum ’s lncRNAs were similar to vertebrate species’ lncRNAs, and could be associated with lncRNA conserved regulatory functions. Consequently, some high-confidence lncRNA-mRNA interactions were predicted based on such conserved regions, therefore revealing possible involvement of lncRNAs in posttranscriptional processing and regulation in anthozoans. Moreover, investigation of differentially expressed lncRNAs, in healthy colonies and colonial individuals undergoing natural bleaching, indicated that some up-regulated lncRNAs in P . caribaeorum could posttranscriptionally regulate the mRNAs encoding proteins of Ras-mediated signal transduction pathway and components of innate immune-system, which could contribute to the molecular response of coral bleaching.

PcActx peptide, identified from the transcriptome of zoantharian Palythoa caribaeorum, was clustered into the phylogeny of analgesic polypeptides from sea anemone Heteractis crispa (known as APHC peptides). APHC peptides were considered as inhibitors of transient receptor potential cation channel subfamily V member 1 (TRPV1). TRPV1 is a calcium-permeable channel expressed in epileptic brain areas, serving as a potential target for preventing epileptic seizures. Through in silico and in vitro analysis, PcActx peptide was shown to be a potential TRPV1 channel blocker. In vivo studies showed that the linear and oxidized PcActx peptides caused concentration-dependent increases in mortality of zebrafish larvae. However, monotreatment with PcActx peptides below the maximum tolerated doses (MTD) did not affect locomotor behavior. Moreover, PcActx peptides (both linear and oxidized forms) could effectively reverse pentylenetetrazol (PTZ)-induced seizure-related behavior in zebrafish larvae and prevent overexpression of c-fos and npas4a at the mRNA level. The excessive production of ROS induced by PTZ was markedly attenuated by both linear and oxidized PcActx peptides. It was also verified that the oxidized PcActx peptide was more effective than the linear one. In particular, oxidized PcActx peptide notably modulated the mRNA expression of genes involved in calcium signaling and γ-aminobutyric acid (GABA)ergic-glutamatergic signaling, including calb1, calb2 , gabra1 , grm1 , gria1b , grin2b, gat1 , slc1a2b, gad1b, and glsa . Taken together, PcActx peptide, as a novel neuroactive peptide, exhibits prominent anti-epileptic activity, probably through modulating calcium signaling and GABAergic-glutamatergic signaling, and is a promising candidate for epilepsy management.