Effects of Kv1.3 knockout on pyramidal neuron excitability and synaptic plasticity in piriform cortex of mice.

Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca2+ imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca2+ influx evoked by high K+ solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca2+ influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.

Comprehensive assembly and comparative examination of the full mitochondrial genome in Castanea mollissima Blume.

The Chinese chestnut, Castanea mollissima Blume, a nut-bearing tree native to China and North Korea, belongs to the Fagaceae family. As an important genetic resource, C. mollissima is vital in enhancing edible chestnut varieties and offers significant insights into the origin and evolution of chestnut species. While the chloroplast genome of C. mollissima has been sequenced, its mitochondrial genome (mitogenome) remains largely uncharted. In this study, we have characterized the C. mollissima mitogenome, assembling it utilizing reads from both BGI and Nanopore sequencing platforms, and conducted a comparative analysis with the mitochondrial genomes of closely related species. The mitogenome of C. mollissima manifests a polycyclic structure consisting of two circular molecules measuring 363,232 bp and 24,806 bp, respectively. This genome encompasses 35 unique protein-coding genes, 19 tRNA genes, and three rRNA genes. A total of 139 SSRs were identified throughout the entire C. mollissima mitogenome. Furthermore, the combined length of homologous fragments between the chloroplast and mitochondrial genomes was 5766 bp, constituting 1.49% of the mitogenome. We also predicted 484 RNA editing sites in C. mollissima, demonstrating C-to-U RNA editing. Phylogenetic analysis of related species' mitogenomes showed that C. mollissima was closely related to Lithocarpus litseifolius (Hance) Chun and Quercus acutissima Carruth. Interestingly, the mitogenome sequences of C. mollissima, L. litseifolius, Q. acutissima, Fagus sylvatica L., and Juglans mandshurica Maxim did not show conservation in their alignments, indicating frequent genome reorganization. This report marks the inaugural study of the C. mollissima mitogenome, serving as a benchmark genome for economically significant plants within the Castanea genus. Moreover, it supplies invaluable information that can guide future molecular breeding efforts and contribute to the broader understanding of chestnut genomics.

Licochalcone Mediates the Pain Relief by Targeting the Voltage-Gated Sodium Channel.

Licorice is a traditional Chinese medicine and recorded to have pain relief effects in national pharmacopoeia, but the mechanisms behind these effects have not been fully explored. Among the hundreds of compounds in licorice, licochalcone A (LCA) and licochalcone B (LCB) are two important components belonging to the chalcone family. In this study, we compared the analgesic effects of these two licochalcones and the molecular mechanisms. LCA and LCB were applied in cultured dorsal root ganglion (DRG) neurons, and the voltage-gated sodium (NaV) currents and action potentials were recorded. The electrophysiological experiments showed that LCA can inhibit NaV currents and dampen excitabilities of DRG neurons, whereas LCB did not show inhibition effect on NaV currents. Because the NaV1.7 channel can modulate Subthreshold membrane potential oscillations in DRG neuron, which can palliate neuropathic pain, HEK293T cells were transfected with NaV1.7 channel and recorded with whole-cell patch clamp. LCA can also inhibit NaV1.7 channels exogenously expressed in HEK293T cells. We further explored the analgesic effects of LCA and LCB on formalin-induced pain animal models. The animal behavior tests revealed that LCA can inhibit the pain responses during phase 1 and phase 2 of formalin test, and LCB can inhibit the pain responses during phase 2. The differences of the effects on NaV currents between LCA and LCB provide us with the basis for developing NaV channel inhibitors, and the novel findings of analgesic effects indicate that licochalcones can be developed into effective analgesic medicines. SIGNIFICANCE STATEMENT: This study found that licochalcone A (LCA) can inhibit voltage-gated sodium (NaV) currents, dampen excitabilities of dorsal root ganglion neurons, and inhibit the NaV1.7 channels exogenously expressed in HEK293T cells. Animal behavior tests showed that LCA can inhibit the pain responses during phase 1 and phase 2 of formalin test, whereas licochalcone B can inhibit the pain responses during phase 2. These findings indicate that licochalcones could be the leading compounds for developing NaV channel inhibitors and effective analgesic medicines.

Mechanisms Underlying the Inhibition of KV1.3 Channel by Scorpion Toxin ImKTX58.

Voltage-gated KV1.3 channel has been reported to be a drug target for the treatment of autoimmune diseases, and specific inhibitors of Kv1.3 are potential therapeutic drugs for multiple diseases. The scorpions could produce various bioactive peptides that could inhibit KV1.3 channel. Here, we identified a new scorpion toxin polypeptide gene ImKTX58 from the venom gland cDNA library of the Chinese scorpion Isometrus maculatus Sequence alignment revealed high similarities between ImKTX58 mature peptide and previously reported KV1.3 channel blockers-LmKTX10 and ImKTX88-suggesting that ImKTX58 peptide might also be a KV1.3 channel blocker. By using electrophysiological recordings, we showed that recombinant ImKTX58 prepared by genetic engineering technologies had a highly selective inhibiting effect on KV1.3 channel. Further alanine scanning mutagenesis and computer simulation identified four amino acid residues in ImKTX58 peptide as key binding sites to KV1.3 channel by forming hydrogen bonds, salt bonds, and hydrophobic interactions. Among these four residues, 28th lysine of the ImKTX58 mature peptide was found to be the most critical amino acid residue for blocking KV1.3 channel. SIGNIFICANCE STATEMENT: In this study, we discovered a scorpion toxin gene ImKTX58 that has not been reported before in Hainan Isometrus maculatus and successfully used the prokaryotic expression system to express and purify the polypeptides encoded by this gene. Electrophysiological experiments on ImKTX58 showed that ImKTX58 has a highly selective blocking effect on KV1.3 channel over Kv1.1, Kv1.2, Kv1.5, SK2, SK3, and BK channels. These findings provide a theoretical basis for designing highly effective KV1.3 blockers to treat autoimmune and other diseases.

Biosorption of lead ions from aqueous solution by Clostridium tyrobutyricum immobilized in macroporous Ca-alginate-lignin beads.

AIMS: The adsorption of lead ions from aqueous solution by macroporous Ca-alginate-lignin (MCAL) beads immobilized with Clostridium tyrobutyricum and free strains was evaluated. METHODS AND RESULTS: The effects of different factors including pH, adsorption time, adsorbent dosage and initial concentration of lead ions were explored. Different characterization methods were used to evaluate the adsorption process of lead ions. Meanwhile, the adsorption kinetics models and adsorption isotherm models were applied. The fitting results showed that the adsorption behaviour of C. tyrobutyricum immobilized in MCAL beads and free strains was better described by the pseudo-second-order kinetic model and the adsorption process followed the Langmuir isotherm model. The maximum biosorption of lead ions by C. tyrobutyricum immobilized in MCAL beads and free strains was 144.9 and 106.4 mg/g respectively. CONCLUSIONS: The C. tyrobutyricum immobilized in MCAL beads proved to be practicable and had better adsorption effects on lead ions compared with the free strains. SIGNIFICANCE AND IMPACT OF THE STUDY: The paper demonstrated a new insight and strategy for the effective treatment of lead ions from aqueous solutions by the novel function of C. tyrobutyricum.

Can a multitiered copayment system affect people's healthcare-seeking behavior? A case study of Wenzhou, China.

BACKGROUND: Facilitating the primary health care (PHC) system and maintaining people's reasonable healthcare-seeking behavior are key to establishing a sustainable healthcare system. China has employed a multitiered copayment system/medical insurance differentiated payment policies to incentivize the public to utilize PHC services through its hierarchical medical care system; however, most people still prefer visiting tertiary care hospitals. We question whether the quality gap in healthcare services reduces the effect of the multitiered copayment system, which is considered an important factor in the lack of reform in the Chinese healthcare system. Thus, we explore the effect and influencing factors of the multitiered copayment system that drives primary healthcare-seeking behavior under the current situation with a large quality gap. We also consider the hypothetical situation of a reduced gap in the future. METHODS: This study used the hypothetical quality improvement scenario to elicit people's hypothetical behaviors, and a multistage stratified cluster random sampling method. This preliminary study was conducted in 2016 using 1829 individuals from four regions of Wenzhou in Zhejiang Province: Ouhai, Ruian, Yongjia, and Taishun. A descriptive statistical analysis, chi-square analysis, Fisher's exact test, and multinomial logistic regression model were performed to introduce the effect of the multitiered copayment system, and to explore the factors affecting the selection of PHC institutions at pre- and post-change phases. RESULT: The results show that compared with the large quality gap phase, the number of respondents who believed the multitiered copayment system had an effect on their selection of PHC institutions after the equalization of healthcare services quality increased threefold (from 14.0% to 50.8%). Moreover, the main determinants in people's selection of PHC institutions changed from age and needs variables (self-rated health status) to age, needs variables (self-rated health status) and enabling variables (distance to a medical care facility). CONCLUSION: The results indicate limited initial effects of the multitiered copayment system. However, they become more pronounced after the equalization of healthcare services quality. This study confirms that changes in the quality gap in healthcare services influence the effect of the multitiered copayment system. Hence, reducing this gap can help achieve the intended outcome of the tiered healthcare insurance schedule.

Neuritin improves the neurological functional recovery after experimental intracerebral hemorrhage in mice.

Stroke is one of the leading causes of death worldwide, with intracerebral hemorrhage (ICH) being the most lethal subtype. Neuritin (Nrn) is a neurotropic factor that has been reported to have neuroprotective effects in acute brain and spinal cord injury. However, whether Nrn has a protective role in ICH has not been investigated. In this study, ICH was induced in C57BL/6 J mice by injection of collagenase VII, while the overexpression of Nrn in the striatum was induced by an adeno-associated virus serotype 9 (AAV9) vector. We found that compared with GFP-ICH mice, Nrn-ICH mice showed improved performance in the corner, cylinder and forelimb tests after ICH, and showed less weight loss and more rapid weight recovery. Overexpression of Nrn reduced brain lesions, edema, neuronal death and white matter and synaptic integrity dysfunction caused by ICH. Western blot results showed that phosphorylated PERK and ATF4 were significantly inhibited, while phosphorylation of Akt/mammalian target of rapamycin was increased in the Nrn-ICH group, compared with the GFP-ICH group. Whole cell recording from motor neurons indicated that overexpression of Nrn reversed the decrease of spontaneous excitatory postsynaptic currents (sEPSCs) and action potential frequencies induced by ICH. These data show that Nrn improves neurological deficits in mice with ICH by reducing brain lesions and edema, inhibiting neuronal death, and possibly by increasing neuronal connections.

Complete Genome Sequence of Janibacter melonis M714, a Janus-Faced Bacterium with Both Human Health Impact and Industrial Applications.

Janibacter, a member of the Intrasporangiaceae family of Actinobacteria, is a Janus-faced bacterium that has both antibiotic resistance/pathogenicity and the ability to degrade pollutants, with significant research value. Here, we isolated the novel strain Janibacter melonis M714 from an irradiated area in Xinjiang Uygur Autonomous Region, China. J. melonis M714 contains one circular chromosome of 3,426,637 bp with a GC content of 72.98% and one plasmid of 54,436 bp with a GC content of 67.80%. The genome of J. melonis M714 contains 2,859 CDSs, 47 tRNA genes, and 6 rRNA genes. Genome assembly and annotation indicated that strain M714 has a high GC content and contains multiple notable functional genes, including a beta-lactam resistance gene and dioxygenase gene, which may be the key determinants of the strain's antibiotic resistance and xenobiotic degradation ability, respectively. The whole genome sequences of J. melonis M714 provide information that is useful for its potential applications in the degradation of pollutants and environmental remediation.

Draft Genome Sequence of a Potential Organic Phosphorus-Degrading Bacterium Brevibacterium frigoritolerans GD44, Isolated from Radioactive Soil in Xinjiang, China.

Brevibacterium frigoritolerans, a strain quite potential use in environmental pollution, is also able to degrade the pesticide phorate. Here, we report a strain isolated from radioactive soil in the Xinjiang Uygur Autonomous Region of China. The genome of strain GD44 encompasses 5,471,331 base pairs with a GC content of 40.42%. The sequence was assembled into 1985 open reading frames (ORFs) encoding 5053 proteins. Sequence analysis identified the genes encoding enzymes related to the degradation of organophosphorus compounds such as esterase, phosphotransferase, C-P lyase, and alkaline phosphatase. The nitrate reductase gene was also found in GD44, which was associated with biosynthesis of silver nanoparticles used for bacteriostat. In addition, Antibiotic Resistance Ontology (ARO) genes accounted for 10.6%, including the vancomycin resistance gene cluster. Therefore, the whole-genome sequence of B. frigoritolerans GD44 will be beneficial for identifying and analyzing genes utilized for soil remediation and antibacterial agent, which will provide genetic evaluation for potential application in the future.

Molecularly Engineered Macrophage-Derived Exosomes with Inflammation Tropism and Intrinsic Heme Biosynthesis for Atherosclerosis Treatment.

Atherosclerosis (AS) is a major contributor to cardiovascular diseases worldwide, and alleviating inflammation is a promising strategy for AS treatment. Here, we report molecularly engineered M2 macrophage-derived exosomes (M2 Exo) with inflammation-tropism and anti-inflammatory capabilities for AS imaging and therapy. M2 Exo are derived from M2 macrophages and further electroporated with FDA-approved hexyl 5-aminolevulinate hydrochloride (HAL). After systematic administration, the engineered M2 Exo exhibit excellent inflammation-tropism and anti-inflammation effects via the surface-bonded chemokine receptors and the anti-inflammatory cytokines released from the anti-inflammatory M2 macrophages. Moreover, the encapsulated HAL can undergo intrinsic biosynthesis and metabolism of heme to generate anti-inflammatory carbon monoxide and bilirubin, which further enhance the anti-inflammation effects and finally alleviate AS. Meanwhile, the intermediate protoporphyrin IX (PpIX) of the heme biosynthesis pathway permits the fluorescence imaging and tracking of AS.

Expression of soluble epoxide hydrolase in renal tubular epithelial cells regulates macrophage infiltration and polarization in IgA nephropathy.

Tubulointerstitial inflammatory cell infiltration and activation contribute to kidney inflammation and fibrosis. Epoxyeicosatrienoic acids (EETs), which are rapidly metabolized to dihydroxyeicosatrienoic acids by the soluble epoxide hydrolase (sEH), have multiple biological functions, including vasodilation, anti-inflammatory action, and others. Inhibition of sEH has been demonstrated to attenuate inflammation in many renal disease models. However, the relationship between sEH expression and macrophage polarization in the kidney remains unknown. In this study, we investigated the relationships between the level of sEH and clinical and pathological parameters in IgA nephropathy. The level of sEH expression positively correlated with proteinuria and infiltration of macrophages. sEH-positive tubules were found to be surrounded by macrophages. Furthermore, we found that incubation of immortalized human proximal tubular HK-2 cells with total urinary protein and overexpression of sEH promoted inflammatory factor production, which was associated with M1 polarization. We also exposed RAW264.7 mouse leukemic monocytes/macrophages to different HK-2 cell culture media conditioned by incubation with various substances affecting sEH amount or activity. We found that the upregulation of sEH promoted M1 polarization. However, pharmacological inhibition of sEH and supplementation with EETs reversed the conditioning effects of urinary proteins by inhibiting M1 polarization through the NF-κB pathway and stimulating M2 polarization through the phosphatidylinositol 3-kinase pathway. These data suggest that inhibition of sEH could be a new strategy to prevent the progression of inflammation and to attenuate renal tubulointerstitial fibrosis.

Neuritin promotes neurite and spine growth in rat cerebellar granule cells via L-type calcium channel-mediated calcium influx.

Neuritin is a neurotrophic factor that is activated by neural activity and neurotrophins. Its major function is to promote neurite growth and branching; however, the underlying mechanisms are not fully understood. To address this issue, this study investigated the effects of neuritin on neurite and spine growth and intracellular Ca2+ concentration in rat cerebellar granule neurons (CGNs). Incubation of CGNs for 24 h with neuritin increased neurite length and spine density; this effect was mimicked by insulin and abolished by inhibiting insulin receptor (IR) or mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) activity. Calcium imaging and western blot analysis revealed that neuritin enhanced the increase in intracellular Ca2+ level induced by high K+ , and stimulated the cell surface expression of CaV 1.2 and CaV 1.3 α subunits of the L-type calcium channel, which was suppressed by inhibition of IR or mitogen-activated protein kinase kinase/ERK. Treatment with inhibitors of L-type calcium channels, calmodulin, and calcineurin (CaN) abrogated the effects of neuritin on neurite length and spine density. A similar result was obtained by silencing nuclear factor of activated T cells c4, which is known to be activated by neuritin in CGNs. These results indicate that IR and ERK signaling as well as the Ca2+ /CaN/nuclear factor of activated T cells c4 axis mediate the effects of neuritin on neurite and spine growth in CGNs. OPEN PRACTICES: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/ Cover Image for this issue: doi: 10.1111/jnc.14195.

Functions and the related signaling pathways of the neurotrophic factor neuritin.

Neuritin is a member of the neurotrophic factor family, which is activated by neural activity and neurotrophins, and promotes neurite growth and branching. It has shown to play an important role in neuronal plasticity and regeneration. It is also involved in other biological processes such as angiogenesis, tumorigenesis and immunomodulation. Thus far, however, the primary mechanisms of neuritin, including whether or not it acts through a receptor or which downstream signals might be activated following binding, are not fully understood. Recent evidence suggests that neuritin may be a potential therapeutic target in several neurodegenerative diseases. This review focuses on the recent advances in studies regarding the newly identified functions of neuritin and the signaling pathways related to these functions. We also discuss current hot topics and difficulties in neuritin research.

Neuritin Up-regulates Kv4.2 α-Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway.

Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca(2+)/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca(2+) and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4(-/-) mice but not in Nfatc2(-/-) mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4(-/-) mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions.

Modification of starch metabolism in transgenic Arabidopsis thaliana increases plant biomass and triples oilseed production.

We have identified a novel means to achieve substantially increased vegetative biomass and oilseed production in the model plant Arabidopsis thaliana. Endogenous isoforms of starch branching enzyme (SBE) were substituted by either one of the endosperm-expressed maize (Zea mays L.) branching isozymes, ZmSBEI or ZmSBEIIb. Transformants were compared with the starch-free background and with the wild-type plants. Each of the maize-derived SBEs restored starch biosynthesis but both morphology and structure of starch particles were altered. Altered starch metabolism in the transformants is associated with enhanced biomass formation and more-than-trebled oilseed production while maintaining seed oil quality. Enhanced oilseed production is primarily due to an increased number of siliques per plant whereas oil content and seed number per silique are essentially unchanged or even modestly decreased. Introduction of cereal starch branching isozymes into oilseed plants represents a potentially useful strategy to increase biomass and oilseed production in related crops and manipulate the structure and properties of leaf starch.

Development and in vitro-in vivo evaluation of a water-in-oil microemulsion formulation for the oral delivery of troxerutin.

OBJECTIVE: The main objective of this study was to develop and evaluate a W/O microemulsion formulation of troxerutin to improve its oral bioavailability. METHODS: The W/O microemulsion was optimized using a pseudo-ternary phase diagram and evaluated for physical properties. In vitro MDCK cell permeability studies were carried out to evaluate the permeability enhancement effect of microemulsion, and in vivo absorption of troxerutin microemulsion in the intestine was compared with that of solution after single-dose administration (56.7 mg/kg) in male Wistar rats. RESULTS: The optimal formulation consisted of lecithin, ethanol, isopropyl myristate and water (23.30/11.67/52.45/12.59 w/w) was physicochemical stable and the mean droplet size was about 50.20 nm. In vitro study, the troxerutin-loaded microemulsion showed higher intestinal membrane permeability across MDCK monolayer when compared with the control solution. The W/O microemulsion can significantly promote the intestinal absorption of troxerutin in rats in vivo, and the relative bioavailability of the microemulsion was about 205.55% compared to control solution. CONCLUSION: These results suggest that novel W/O microemulsion could be used as an effective formulation for improving the oral bioavailability of troxerutin.

Melatonin protects rat cerebellar granule cells against electromagnetic field-induced increases in Na(+) currents through intracellular Ca(2+) release.

Although melatonin (MT) has been reported to protect cells against oxidative damage induced by electromagnetic radiation, few reports have addressed whether there are other protective mechanisms. Here, we investigated the effects of MT on extremely low-frequency electromagnetic field (ELF-EMF)-induced Nav activity in rat cerebellar granule cells (GCs). Exposing cerebellar GCs to ELF-EMF for 60 min. significantly increased the Nav current (INa ) densities by 62.5%. MT (5 µM) inhibited the ELF-EMF-induced INa increase. This inhibitory effect of MT is mimicked by an MT2 receptor agonist and was eliminated by an MT2 receptor antagonist. The Nav channel steady-state activation curve was significantly shifted towards hyperpolarization by ELF-EMF stimulation but remained unchanged by MT in cerebellar GC that were either exposed or not exposed to ELF-EMF. ELF-EMF exposure significantly increased the intracellular levels of phosphorylated PKA in cerebellar GCs, and both MT and IIK-7 did not reduce the ELF-EMF-induced increase in phosphorylated PKA. The inhibitory effects of MT on ELF-EMF-induced Nav activity was greatly reduced by the calmodulin inhibitor KN93. Calcium imaging showed that MT did not increase the basal intracellular Ca(2+) level, but it significantly elevated the intracellular Ca(2+) level evoked by the high K(+) stimulation in cerebellar GC that were either exposed or not exposed to ELF-EMF. In the presence of ruthenium red, a ryanodine-sensitive receptor blocker, the MT-induced increase in intracellular calcium levels was reduced. Our data show for the first time that MT protects against neuronal INa that result from ELF-EMF exposure through Ca(2+) influx-induced Ca(2+) release.

MG53: A new protagonist in the precise treatment of cardiomyopathies.

Cardiomyopathies (CMs) are highly heterogeneous progressive heart diseases characterised by structural and functional abnormalities of the heart, whose intricate pathogenesis has resulted in a lack of effective treatment options. Mitsugumin 53 (MG53), also known as Tripartite motif protein 72 (TRIM72), is a tripartite motif family protein from the immuno-proteomic library expressed primarily in the heart and skeletal muscle. Recent studies have identified MG53 as a potential cardioprotective protein that may play a crucial role in CMs. Therefore, the objective of this review is to comprehensively examine the underlying mechanisms mediated by MG53 responsible for myocardial protection, elucidate the potential role of MG53 in various CMs as well as its dominant status in the diagnosis and prognosis of human myocardial injury, and evaluate the potential therapeutic value of recombinant human MG53 (rhMG53) in CMs. It is expected to yield novel perspectives regarding the clinical diagnosis and therapeutic treatment of CMs.

Intracellular and extracellular Cyclophilin a promote cardiac fibrosis through TGF-ß signaling in response to angiotensin â ¡.

Cardiac fibrosis is characterized by abnormal proliferation of cardiac fibroblasts (CFs) and ventricular remodeling, which finally leads to heart failure. Inflammation and oxidative stress play a central role in the development of cardiac fibrosis. CyPA (Cyclophilin A) is a main proinflammatory cytokine secreted under the conditions of oxidative stress. The mechanisms by which intracellular and extracellular CyPA interact with CFs are unclear. Male C57BL/6 J mice received angiotensin Ⅱ (Ang Ⅱ) or vehicle for 4 weeks. Inhibition of CyPA significantly reversed Ang Ⅱ-induced cardiac hypertrophy and fibrosis. Mechanically, TGF-ß (Transforming growth factor-ß) signaling was found to be an indispensable downstream factor of CyPA-mediated myofibroblast differentiation and proliferation. Furthermore, intracellular CyPA and extracellular CyPA activate TGF-ß signaling through NOD-like receptor protein 3 (NLRP3) inflammasome and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, respectively. Pharmacological inhibition of CyPA and its receptor CD147 implemented by Triptolide also attenuated the expression of TGF-ß signaling and cardiac fibrosis in Ang Ⅱ-model. These studies elucidate a novel mechanism by which CyPA promotes TGF-ß and its downstream signaling in CFs and identify CyPA (both intracellular and extracellular) as plausible therapeutic targets for preventing or treating cardiac fibrosis induced by chronic Ang Ⅱ stimulation.

Types of Home and Community-Based Physical Activity and Their Effects on the Older Adults' Quality of Life: A Systematic Review and Meta-Analysis.

Home and community-based physical activity (HCBPA) has been extensively utilized among older adults. Nevertheless, the varying types of HCBPA, including different duration, intensity, and frequency, have sparked controversy regarding their impact on the quality of life in older adults. This study aims to explore the effects of HCBPA on QoL in older adults. We conducted a systematic review and retrieved studies published from January 2000 to April 2023 from multiple databases (PubMed, Embase, Cochrane, and the Web of Science Library). Seventeen articles met the inclusion criteria for this study. Long-term HCBPA interventions may have a more pronounced positive impact on older adults' quality of life than short-term ones, with the intervention's intensity and frequency playing a key role in its effectiveness. The results of the meta-analyses showed significant differences in PCS but not in MCS, both with low certainty of evidence. Policymakers should prioritize the importance of promoting HCBPA interventions with appropriate duration, intensity, and frequency to create a more age-inclusive society.