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BackgroundMajor depressive disorder (MDD) has emerged as the fifth leading cause of years lived with disability, with a high prevalent, affecting nearly 4% of the global population. While available evidence suggests that intradermal acupuncture may enhance the effectiveness of antidepressants, whether its efficacy is a specific therapeutic effect or a placebo effect has not been reported. Moreover, the cerebral mechanism of intradermal acupuncture as a superficial acupuncture (usually subcutaneous needling to a depth of 1–2 mm) for MDD remains unclear.MethodsA total of 120 participants with MDD will be enrolled and randomized to the waiting list group, sham intradermal acupuncture group and active intradermal acupuncture group. All 3 groups will receive a 6-week intervention and a 4-week follow-up. The primary outcome will be measured by the Hamilton Depression Rating Scale-17 and the secondary outcome measures will be the Self-Rating depression scale and Pittsburgh sleep quality index. Assessments will be conducted at baseline, 3 weeks, 6 weeks, and during the follow-up period. In addition, 20 eligible participants in each group will be randomly selected to undergo head magnetic resonance imaging before and after the intervention to explore the effects of intradermal acupuncture on brain activity in MDD patients.DiscussionIf the intradermal acupuncture is beneficial, it is promising to be included in the routine treatment of MDD.Clinical Trial RegistrationClinicaltrials.gov, NCT05720637.

In the development and study of antimicrobial peptides (AMPs), researchers have kept a watchful eye on peptides from the brevinin family because of their extensive antimicrobial activities and anticancer potency. In this study, a novel brevinin peptide was isolated from the skin secretions of the Wuyi torrent frog, Amolops wuyiensis (A. wuyiensisi), named B1AW (FLPLLAGLAANFLPQIICKIARKC). B1AW displayed anti-bacterial activity against Gram-positive bacteria Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA), and Enterococcus faecalis (E. faecalis). B1AW-K was designed to broaden the antimicrobial spectrum of B1AW. The introduction of a lysine residue generated an AMP with enhanced broad-spectrum antibacterial activity. It also displayed the ability to inhibit the growth of human prostatic cancer PC-3, non-small lung cancer H838, and glioblastoma cancer U251MG cell lines. In molecular dynamic (MD) simulations, B1AW-K had a faster approach and adsorption to the anionic membrane than B1AW. Therefore, B1AW-K was considered a drug prototype with a dual effect, which deserves further clinical investigation and validation.

Background The study was designed to explore the correlation of the asymmetric regulation between periaqueductal gray (PAG) and bilateral trigeminal nucleus caudalis (TNC) in migraine rats through studying the changes of metabolites in pain regulatory pathway of acute migraine attack. Methods Thirty male Sprague–Dawley (SD) rats were randomly divided into three groups: blank, control, model groups. Then, blank group was intraperitoneally injected with ultrapure water, while control group injected with saline and model group injected with Glyceryl Trinitrate (GTN). Two hours later, PAG and bilateral TNC were removed respectively, and metabolite concentrations of PAG, Left-TNC, Right-TNC were obtained. Lastly, the differences of metabolite among three brain tissues were compared. Results The relative concentrations of rNAA, rGlu, rGln, rTau, rMI in PAG or bilateral TNC had interaction effects between groups and sites. The concentration of rLac of three brain tissues increased in migraine rats, however, the rLac of LTNC and RTNC increased more than that of PAG. Besides, the concentrations of rNAA and rGln increased in RTNC, while rGABA decreased in RTNC. Conclusions There is correlation between PAG, LTNC and RTNC in regulation of pain during acute migraine attack, and the regulation of LTNC and RTNC on pain is asymmetric.

Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are four primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 angstrom via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over opioid receptor. According to the structure analysis, we revealed that MRGPRX1 shares common features of the Gq-mediated receptor activation mechanism of MRGPRX family members. However, the variable residues in orthosteric pocket of MRGPRX1 exhibits the unique agonist recognition pattern, which may facilitate to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.

Testis-specifically expressed genes are important for male reproduction according to their unique expression patterns. However, the functions of most of these genes in reproduction are unclear. Here, we showed that mouse 4930590J08Rik was a testis-specifically expressed gene. 4930590J08Rik knockout mice exhibited a delay in the first wave of spermatogenesis and a reduction of cauda epididymal sperm. Furthermore, knockout spermatozoa exhibited defective acrosome reactions and decreased progressive motility, which led to impaired in vivo fertilization. Transcriptome analysis of testes revealed that most of the differentially expressed genes in knockout testes were associated with metabolic processes. 4930590J08Rik knockout sperm exhibited oxidative phosphorylation deficiency and were highly dependent on increased anaerobic glycolysis to compensate for ATP demands. Taken together, the 4930590J08Rik-disrupted mouse partially mimics the phenotypes of human asthenospermia and oligozoospermia, which provides a new model for further understanding the pathogenesis of idiopathic male infertility.

International audience; Since its discovery in Wuhan, China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread over the world, having a huge impact on people’s lives and health. The respiratory system is often targeted in people with the coronavirus disease 2019 (COVID-19). The virus can also infect many organs and tissues in the body, including the reproductive system. The consequences of the SARS-CoV-2 infection on fertility and pregnancy in hosts are poorly documented. Available data on other coronaviruses, such as severe acute respiratory syndrome (SARS-CoV) and Middle Eastern Respiratory Syndrome (MERS-CoV) coronaviruses, identified pregnant women as a vulnerable group with increased pregnancy-related complications. COVID-19 was also shown to impact pregnancy, which can be seen in either the mother or the fetus. Pregnant women more likely require COVID-19 intensive care treatment than non-pregnant women, and they are susceptible to giving birth prematurely and having their newborns admitted to the neonatal intensive care unit. Angiotensin converting enzyme 2 (ACE2), a key player of the ubiquitous renin-angiotensin system (RAS), is the principal host cellular receptor for SARS-CoV-2 spike protein. ACE2 is involved in the regulation of both male and female reproductive systems, suggesting that SARS-CoV-2 infection and associated RAS dysfunction could affect reproduction. Herein, we review the current knowledge about COVID-19 consequences on male and female fertility, pregnant women, and their fetuses. Furthermore, we describe the effects of COVID-19 vaccination on reproduction.

Human NaV1.9 (hNaV1.9), encoded by SCN11A, is preferentially expressed in nociceptors, and its mutations have been linked to pain disorders. NaV1.9 could be a promising drug target for pain relief. However, the modulation of NaV1.9 activity has remained elusive. Here, we identified a new candidate NaV1.9-interacting partner, protein arginine methyltransferase 7 (PRMT7). Whole-cell voltage-clamp recordings showed that coelectroporation of human SCN11A and PRMT7 in dorsal root ganglion (DRG) neurons of Scn11a-/- mice increased the hNaV1.9 current density. By contrast, a PRMT7 inhibitor (DS-437) reduced mNaV1.9 currents in Scn11a+/+ mice. Using the reporter molecule CD4, we observed an increased distribution of hLoop1 on the cell surface of PRMT7-overexpressing HKE293T cells. Furthermore, we found that PRMT7 mainly binds to residues 563 to 566 within the first intracellular loop of hNaV1.9 (hLoop1) and methylates hLoop1 at arginine residue 519. Moreover, overexpression of PRMT7 increased the number of action potential fired in DRG neurons of Scn11a+/+ mice but not Scn11a-/- mice. However, DS-437 significantly inhibited the action potential frequency of DRG neurons and relieved pain hypersensitivity in Scn11aA796G/A796G mice. In summary, our observations revealed that PRMT7 modulates neuronal excitability by regulating NaV1.9 currents, which may provide a potential method for pain treatment.

Purpose To investigate whether preoperative histogram parameters of dynamic contrast‐enhanced MRI (DCE‐MRI) can assess the expression of Ki‐67 in prostate cancer (PCa). Materials and methods A consecutive series of 76 patients with pathology‐proven PCa who underwent routine DCE‐MRI scans were retrospectively recruited. Quantitative parameters including the volume transfer constant (Ktrans), rate contrast (Kep), extracellular‐extravascular volume fraction (Ve), and plasma volume (Vp) by outlining the three‐dimensional volume of interest (VOI) of all lesions were processed. Then, the histogram analyses of these quantitative parameters were performed. The Spearman rank correlation analysis was used to evaluate the correlation of these parameters and Ki‐67 expression of PCa. Receiver operating characteristic (ROC) curve analysis was adopted to evaluate the efficacy of these quantitative histogram parameters in identifying high Ki‐67 expression from low Ki‐67 expression of PCa. Results Eighty‐eight PCa lesions were enrolled in this study, including 31 lesions with high Ki‐67 expression and 57 lesions with low Ki‐67 expression. The median, mean, 75th percentile, and 90th percentile derived from Ktrans and Kep had a moderately positive correlation with Ki‐67 expression (r = 0.361–0.450, p, In this work, we found that the median, mean, 75th percentile, and 90th percentile derived from Ktrans and Kep had a moderately positive correlation with Ki‐67 expression. We also chose the histogram quantitative parameters with an r value ≥0.4 to discriminate high Ki‐67 expression from low Ki‐67 expression in PCa. And six histogram parameters derived from Ktrans and Kep were selected, in which the AUC of mean for Ktrans was the highest (0.826).

Novel degraded potassium channel-modulatory peptides were recently found in thermally processed scorpions, but their pharmacological properties remain unclear. Here, we identified a full-length scorpion toxin (i.e., BmKcug2) and its four truncated analogs (i.e., BmKcug2-P1, BmKcug2-P2, BmKcug2-P3 and BmKcug2-P4) with three conserved disulfide bonds in processed scorpion medicinal material by mass spectrometry. The pharmacological experiments revealed that the recombinant BmKcug2 and BmKcug2-P1 could selectively inhibit the human Kv1.2 and human Kv1.3 potassium channels, while the other three analogs showed a much weaker inhibitory effect on potassium channels. BmKcug2 inhibited hKv1.2 and hKv1.3 channels, with IC50 values of 45.6 ± 5.8 nM and 215.2 ± 39.7 nM, respectively, and BmKcug2-P1 inhibited hKv1.2 and hKv1.3, with IC50 values of 89.9 ± 9.6 nM and 1142.4 ± 64.5 nM, respectively. The chromatographic analysis and pharmacological properties of BmKcug2 and BmKcug2-P1 boiled in water for different times further strongly supported their good thermal stability. Structural and functional dissection indicated that one amino acid, i.e., Tyr36, determined the differential affinities of BmKcug2 and four BmKcug2 analogs. Altogether, this research investigated the different pharmacological properties of BmKcug2 and its truncated analogs, and the findings highlighted the diversity of K+ channel blockers from various scorpion species through thermal processing.

Thermally processed Buthus martensii Karsch scorpion is an important traditional Chinese medical material that has been widely used to treat various diseases in China for over one thousand years. Our recent work showed that thermally processed Buthus martensii Karsch scorpions contain many degraded peptides; however, the pharmacological activities of these peptides remain to be studied. Here, a new degraded peptide, BmTX4-P1, was identified from processed Buthus martensii Karsch scorpions. Compared with the venom-derived wild-type toxin peptide BmTX4, BmTX4-P1 missed some amino acids at the N-terminal and C-terminal regions, while containing six conserved cysteine residues, which could be used to form disulfide bond-stabilized α-helical and β-sheet motifs. Two methods (chemical synthesis and recombinant expression) were used to obtain the BmTX4-P1 peptide, named sBmTX4-P1 and rBmTX4-P1. Electrophysiological experimental results showed that sBmTX4-P1 and rBmTX4-P1 exhibited similar activities to inhibit the currents of hKv1.2 and hKv1.3 channels. In addition, the experimental electrophysiological results of recombinant mutant peptides of BmTX4-P1 indicated that the two residues of BmTX4-P1 (Lys22 and Tyr31) were the key residues for its potassium channel inhibitory activity. In addition to identifying a new degraded peptide, BmTX4-P1, from traditional Chinese scorpion medicinal material with high inhibitory activities against the hKv1.2 and hKv1.3 channels, this study also provided a useful method to obtain the detailed degraded peptides from processed Buthus martensii Karsch scorpions. Thus, the study laid a solid foundation for further research on the medicinal function of these degraded peptides.

Three highly oxygenated norbisabolane sesquiterpenoid glycosides (glochiwilsonosides A-C), five benzofuran lignans (glochiwilsonises A-E) and a phenolic glycoside (glochiwilsophe-noside), together with forty-one known compounds, were isolated from the roots of Glochidion wilsonii Hutch. The chemical structures of the compounds were identified by spectroscopic methods and previous literature data. Glochiwilsonoside A displayed anti-proliferative activity on A-549 and RAW 264.7 cell lines with an IC

The hypothalamus plays a central role in the pathophysiology of migraine and is considered to be the "migraine generator." It participates in initiating a migraine attack through its connectivity to regions of the brain involved in processing and modulating pain. However, the underlying mechanisms of hypothalamic effective functional connectivity that bring about migraines remain unclear. This study investigated the hypothalamus-based directional effective connectivity in migraine without aura patients and assessed associations among the clinical characteristics.Seven patients with migraine without aura during the attack (MWoA-DA) (four with photophobia (MWoA-DAWP) and three without photophobia (MWoA-DAWoP)), twenty-seven patients with migraine without aura during the interictal period (MWoA-DI), and twenty-nine healthy controls (HC) were included in this study. Granger causality analysis (GCA) was used to investigate the directional effective connectivity between the hypothalamus and other brain regions.MWoA-DA patients exhibited decreased outflow from the bilateral hypothalamus to the visual cortex compared with the MWoA-DI patients and HCs. The MWoA-DAWP group primarily contributed to this result. The MWoA-DA patients showed decreased outflow from the bilateral hypothalamus to the right inferior parietal gyrus compared with the HCs. The visual analogue scale (VAS) was negatively correlated with abnormal effective functional connectivity from the right hypothalamus to the right inferior parietal gyrus in the MWoA-DA group.These data provide evidence that the hypothalamus might serve as a central component of a multisystem network implicated in migraine and ictal photophobia, which includes hypothalamus and the visual and trigeminovascular systems.

COVID-19 has expanded across the world since its discovery in Wuhan (China) and has had a significant impact on people’s lives and health. Long COVID is a term coined by the World Health Organization (WHO) to describe a variety of persistent symptoms after acute SARS-CoV-2 infection. Long COVID has been demonstrated to affect various SARS-CoV-2-infected persons, independently of the acute disease severity. The symptoms of long COVID, like acute COVID-19, consist in the set of damage to various organs and systems such as the respiratory, cardiovascular, neurological, endocrine, urinary, and immune systems. Fatigue, dyspnea, cardiac abnormalities, cognitive and attention impairments, sleep disturbances, post-traumatic stress disorder, muscle pain, concentration problems, and headache were all reported as symptoms of long COVID. At the molecular level, the renin-angiotensin system (RAS) is heavily involved in the pathogenesis of this illness, much as it is in the acute phase of the viral infection. In this review, we summarize the impact of long COVID on several organs and tissues, with a special focus on the significance of the RAS in the disease pathogenesis. Long COVID risk factors and potential therapy approaches are also explored.

Increasing number of resistant bacteria have emerged with the overuse of antibiotics, which indicates that the bacterial infection has become a global challenge. Furthermore, the pollution of antibiotics to the environment has become a serious threat to public health. It is known that toxins produced by bacteria are the main cause of bacterial infections. Photothermal therapy is an effective antibacterial approach. However, the photothermal reagents cannot eliminate bacterial toxins, and even some anti-bacterial materials are toxic. Here, we synthesized a biomimetic recycled nanoparticle, red blood cell (RBC) membrane-coated Fe3O4 nanoparticles (RBC@Fe3O4), as an antibacterial agent. The RBC@Fe3O4 nanoparticles act as nano-sponges to trap toxins and then kill them all with a photothermal effect. We can describe this process simply as a battle between two armies. Our strategy is to disarm the "enemy" so that we can easily kill the "enemy" who has no power, which results in enhancing the bactericidal efficacy. The toxin of methicillin-resistant Staphylococcus aureus (MRSA) was absorbed by RBC@Fe3O4in vitro. In addition, in vivo studies proved that the RBC@Fe3O4 nanoparticles confer obvious survival benefits against toxin-induced lethality by absorbing the toxin of MRSA. Furthermore, using a mouse model of MRSA wound infection, the RBC@Fe3O4 nanoparticles with laser irradiation were found to have a superior wound-healing effect. Simultaneously, the RBC@Fe3O4 nanoparticles could be recycled in a simple way without affecting the bactericidal efficacy. The highly biocompatible and recyclable RBC@Fe3O4 biomimetic nanoparticles based on photothermal therapy and bacterial toxin adsorption strategy are promising for treating bacterial infections.

Clinical fungal infections always cause a negative impact on human health. Moreover, during the interaction of pathogenic fungi with the environment and host, many biologically active substances are produced. Here, we report a new toxin-like defensin of purlisin derived from a clinical pathogenic isolate of Purpureocillium lilacinum. The analysis of its genomic and mRNA sequences revealed an open reading frame of 444 bp without introns. The deduced precursor peptide was composed of 147 amino acids, and the mature peptide were identified at protein level by LC-ESI-Q-TOF-MS/MS. After posttranslational processing, the precursor peptide of purlisin was split into two independent peptides. The two mature defensins, purlisin-NT and purlisin-CT, are consisting of 36 and 38 amino acid residues, which can form three and four intramolecular disulfide bonds, respectively. The results of circular dichroism and homology modeling revealed that they adopted a representative cysteine-stabilized α-helical and β-sheet motif. The purlisin-NT showed a dose-dependent selective inhibition of immune-related hKv1.3 target channel with IC50 value of 0.2 ± 0.04 μM but no obvious antibacterial activity, while the purlisin-CT displayed antimicrobial activities against gram-positive bacteria as well as clinical isolates of MRSA and low affinities for potassium channels. Our findings suggest that purlisin-NT with immunosuppressive effects and purlisin-CT possessing antibacterial activities are adapted to the survival and pathogenicity of clinical P lilacinumis. Moreover, they can also be used as templates for the design of novel antibacterial peptide and immunosuppressive agents.

Arthropods maintain ecosystem balance while also contributing to the spread of disease. Plant-derived natural repellents represent an ecological method of pest control, but their direct molecular targets in arthropods remain to be further elucidated. Occupying a critical phylogenetic niche in arthropod evolution, scorpions retain an ancestral genetic profile. Here, using a behavior-guided screening of the Mesobuthus martensii genome, we identified a scorpion transient receptor potential (sTRP1) channel that senses Cymbopogon-derived natural repellents, while remaining insensitive to the synthetic chemical pesticide DEET. Scrutinizing orthologs of sTRP1 in Drosophila melanogaster, we further demonstrated dTRPγ ion channel as a chemosensory receptor of natural repellents to mediate avoidance behavior. This study sheds light on arthropod molecular targets of natural repellents, exemplifying the arthropod–plant adaptation. It should also help the rational design of insect control strategy and in conserving biodiversity.

International audience; The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its downregulation, which subsequently leads to the dysregulation of the renin–angiotensin system (RAS) in favor of the ACE–angiotensin II (Ang II)–angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II–AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.

To investigate the value of diffusion weighted imaging (DWI) in predicting the clinical progression of perforator artery cerebral infarction.The magnetic resonance imaging (MRI) data of patients with perforator artery cerebral infarction hospitalized in our hospital from October 2015 to February 2022 were analyzed retrospectively. Then we compared the differences of apparent diffusion coefficient (ADC) value, maximal size, location of cerebral infarction, clinical data and treatment plan between the two groups.A total of 81 patients with perforating artery cerebral infarction were included, with 33 patients in the progressive cerebral infarction (PCI) group and 48 patients in the non-progressive cerebral infarction (NPCI) group. The ADC value in the progressive group was lower than that in the non-progressive group (P 0.001), and ADC value was an independent factor influencing the clinical progression (OR = 0.974, 95 %CI = 0.960-0.989, P = 0.001); The average area of cerebral infarction in the progressive group was larger than that in the non-progressive group (P = 0.004). There was no difference between the two groups (P 0.05) in terms of clinical data and treatment plan.The ADC value and maximal size of infarction were correlated with the clinical Progression. ADC value was an independent factor influencing the clinical progression of perforating artery cerebral infarction, which could be used for the prediction of clinical progress and provide guidance for the development of individualized treatment.

Background: Hemangioblastoma is a benign tumor occurring in the central nervous system. As known, the most common sites are the cerebellum and spinal cord with the typical appearance which is a nodule with a cyst and contrast-enhanced scan demonstrates the obvious enhancement of the nodule and the local cyst wall. However, it’s difficult to diagnose the hemangioblastoma when it occurs in the lateral ventricle, due to the rare incidence of hemangioblastoma in the lateral ventricle.Case presentation: A 28-year-old man with a 1-month history of recurrent headache accompanied by slight dizziness, then the computed tomography (CT) and magnetic resonance imaging (MRI) of brain showed the cystic solid tumor with obvious enhancement in the parenchymal part and local cystic wall, also, there was abnormal dilated blood vessel in the parenchymal part which was considered as the hemangioblastoma in the lateral ventricle.Conclusions: Total resection of the tumor was performed under neuronavigation, then the tumor was pathologically confirmed to be hemangioblastoma which was the Grade WHOI. Based on this study, we have increased the understanding of hemangioblastoma in the differential diagnosis of tumors located in the lateral ventricle and provide a new method of resection of the tumor.

Mas-related G protein-coupled receptors (Mrgprs) are a newly discovered class of G protein-coupled receptors consisting of more than 50 members in recent years. MRGPRX1 can be activated by bovine adrenal medulla peptide 8-22 (BAM8-22), triggering Ca

The coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, is a current pandemic that has resulted in nearly 250 million cases and over 5 million deaths. While vaccines have been developed to prevent infection, and most COVID-19 cases end up being fairly light, there are severe cases of COVID-19 that may end up in death, even with adequate healthcare treatment. New options to combat this disease's effects, therefore, could prove to be invaluable in saving lives. Adamalysins are proteins that have several roles in regulating different functions in the human body but are also known to have functions in inflammation. They are also known to have roles in several different diseases, including COVID-19, where ADAM17, in particular, is now well-known to have a prominent role, but also several diseases which include comorbidities that may worsen cases of COVID-19. Therefore, investigating the functions of adamalysins in disease may give us clues to the molecular workings of COVID-19 as well as potentially new therapeutic targets. Understanding these molecular mechanisms may also allow for an understanding of the mechanisms behind the rare severe side effects that occur in response to current COVID-19 vaccines, which may lead to better monitoring measures for people who may be more at risk of developing these side effects. This review investigates the known roles and functions of adamalysins in disease, including what is currently known of their involvement in COVID-19, and how these functions might be involved.

Background. Resting-state functional MRI is widely used in migraine research. However, the pathophysiology and imaging markers specific for migraine pathologies are not well understood. In this study, we combined both structural and functional images to explore the concurrence and process of migraines. Methods. Thirty-four patients with a history of migraine without aura presenting during the interictal period (MwoA-DI), 10 patients with migraine without aura presenting during the acute attack (MwoA-DA), and 32 healthy controls (HCs) were recruited in this study. All participants underwent scanning via MRI. Voxel-based morphometry (VBM) and seed-based resting-state functional connectivity (rs-FC) analysis were used to detect the brain structural and associated brain functional connectivity. Results. In VBM analysis, a decrease of gray matter volume (GMV) in the middle frontal cortex was found in MwoA patients compared with HCs. The GMV of the middle frontal cortex had a negative correction with the duration of disease. In rs-FC analysis, the left middle frontal cortex (lower, VBM result) in both the MwoA-DA and the HC groups showed significantly increased functional connectivity with the left middle frontal cortex (upper) and left superior frontal cortex compared with MwoA-DI. The left middle frontal cortex (lower) in the MwoA-DI group also showed decreased functional connectivity in the left posterior cingulate cortex (PCC) compared with the HC group. The left middle frontal cortex (lower) in the MwoA-DA group demonstrated significantly increased functional connectivity in the left cerebellum lobule VI compared with the HC group. Conclusions. Our results demonstrated that the middle frontal cortex may serve as an important target in the frequency and severity of migraines due to its role in pain regulation through the default mode network, especially in the PCC. In addition, the cerebellum may modulate the pathophysiology of migraines by serving as a communication point between the cortex and the brainstem.

This study was designed to explore the potential mechanisms of electroacupuncture (EA) in treating inflammatory bowel disease- (IBD-) related anxiety and mood disorders. A colitis model was induced in rats with 2, 4, 6-trinitrohydrosulfonic acid (TNBS), followed by ST36 and SP6 targeted therapy by EA or sham EA treatment. The elevated plus maze (EPM) and open-field test (OFT) were performed to assess the state of anxiety and depression-like behavior. Tests were carried out by 16S rDNA amplification sequence, 1H nuclear magnetic resonance (1H NMR) spectroscopy, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). The analyses detailed metabolic alterations and the Toll-like receptor 4 (TLR4) signaling pathway/NOD-like receptor protein 3 (NLRP3) inflammasome in rats’ hippocampal region. Furthermore, the activity of the hypothalamic-pituitary adrenal (HPA) axis and gut microbiome was assessed. As a result of treatment, EA significantly improved in the behavioral tests and altered the composition of the gut microbiome through a significant increase in the density of short chain fatty acids (SCFAs) producers mainly including Ruminococcaceae, Phascolarctobacterium, and Akkermansiaceae. EA upregulated the metabolites of the hippocampus mainly containing l-glutamine and gamma-aminobutyric acid (GABA), as well as ZO-1 expression. Whereas the treatment blocked the TLR4/nuclear factor- kappa B (NF-κB) signaling pathways and NLRP3 inflammasomes, along with downregulating the interleukin- (IL-) 1β level. The hyperactivity of the HPA axis was also diminished. In conclusion, EA at ST36 and SP6 attenuated anxiety and depression-like behavior in colitis model rats through their effects on the gut microbiome by modulating the hippocampal inflammatory response and metabolic disorders, as well as the HPA axis. This study provides evidence for clinical application of EA to serve as an adjunctive treatment for IBD-related anxiety and depression.

Viruses completely rely on the energy and metabolic systems of host cells for life activities. Viral infections usually lead to cytopathic effects and host diseases. To date, there are still no specific clinical vaccines or drugs against most viral infections. Therefore, understanding the molecular and cellular mechanisms of viral infections is of great significance to prevent and treat viral diseases. A variety of viral infections are related to the p38 MAPK signalling pathway, and p38 is an important host factor in virus-infected cells. Here, we introduce the different signalling pathways of p38 activation and then summarise how different viruses induce p38 phosphorylation. Finally, we provide a general summary of the effect of p38 activation on virus replication. Our review provides integrated data on p38 activation and viral infections and describes the potential application of targeting p38 as an antiviral strategy.

Transient receptor potential mucolipin 2 and 3 (TRPML2 and TRPML3), as key channels in the endosomal-lysosomal system, are associated with many different cellular processes, including ion release, membrane trafficking and autophagy. In particular, they can also facilitate viral entry into host cells and enhance viral infection. We previously identified that two selective TRPML agonists, ML-SA1 and SN-2, that showed antiviral activities against dengue virus type 2 (DENV2) and Zika virus (ZIKV) in vitro, but their antiviral mechanisms are still elusive. Here, we reported that ML-SA1 could inhibit DENV2 replication by downregulating the expression of both TRPML2 and TRPML3, while the other TRPML activator, SN-2, suppressed DENV2 infection by reducing only TRPML3 expression. Consistently, the channel activities of both TRPML2 and TRPML3 were also found to be associated with the antiviral activity of ML-SA1 on DENV2 and ZIKV, but SN-2 relied only on TRPML3 channel activity. Further mechanistic experiments revealed that ML-SA1 and SN-2 decreased the expression of the late endosomal marker Rab7, dependent on TRPML2 and TRPML3, indicating that these two compounds likely inhibit viral infection by promoting vesicular trafficking from late endosomes to lysosomes and then accelerating lysosomal degradation of the virus. As expected, neither ML-SA1 nor SN-2 inhibited herpes simplex virus type I (HSV-1), whose entry is independent of the endolysosomal network. Together, our work reveals the antiviral mechanisms of ML-SA1 and SN-2 in targeting TRPML channels, possibly leading to the discovery of new drug candidates to inhibit endocytosed viruses.

Phosphorus is a necessary component of all living organisms. This nutrient is mainly transported from the maternal blood to the fetus via the placenta, and insufficient phosphorus availability via the placenta disturbs the normal development of the fetus, especially fetal bone formation in late gestation. Key proteins (phosphate transporters and exporters) that are responsible for the maintenance of placental-fetal phosphorus homeostasis have been identified. A deficiency in the phosphate transporter Pit2 has been shown to result in placental calcification and the retardation of fetal development in mice. What roles does XPR1 (the only known phosphate exporter) play in maintaining placental-fetal phosphorus homeostasis? In this study, we found that Xpr1 expression is strong in the murine placenta and increases with age during gestation. We generated a global Xpr1 knockout mouse and found that heterozygous (Xpr1+/- ) and homozygous (Xpr1-/- ) fetuses have lower inorganic phosphate (Pi) levels in amniotic fluid and serum and a decreased skeletal mineral content. Xpr1-deficient placentas show abnormal Pi exchange during gestation. Therefore, Xpr1 deficiency in the placenta disrupts placental-fetal Pi homeostasis. We also discovered that the placentas of the Xpr1+/- and Xpr1-/- embryos are severely calcified. Mendelian inheritance statistics for offspring outcomes indicated that Xpr1-deficient embryos are significantly reduced in late gestation. In addition, Xpr1-/- mice die perinatally and a small proportion of Xpr1+/- mice die neonatally. RNA sequence (RNA-Seq) analysis of placental mRNA revealed that many of the transcripts are significantly differentially expressed due to Xpr1 deficiency and are linked to dysfunction of the placenta. This study is the first to reveal that XPR1 plays an important role in maintaining placental-fetal Pi homeostasis, disruption of which causes severe placental calcification, delays normal placental function, and restricts fetal growth. © 2019 American Society for Bone and Mineral Research.

Scorpion fluorescence under ultraviolet light is a well-known phenomenon, and its change is also a known biological feature during the scorpion moulting process. However, the synthesis and transport of fluorescent substances during the moulting stage remain unclear. In this study, in-depth investigations on the global fluorescence changes from the exoskeleton, fluorescence layer, coelomic fluid, and abdomen to the digestive glands indicated that the digestive glands, which occupy most of the space in the abdomen of the scorpion mesosoma segment, were responsible for synthesizing the fluorescent substances. More importantly, these fluorescent substances were produced in advance, before the moulting process, which contributed to the recovery of the fluorescent exoskeleton as early as possible. The synthesized fluorescent substances first entered the coelomic fluid, then successively passed through the inherent epithelial cell layer and two new formed endocuticle and exocuticle layers, and ultimately reached and became enriched in the new formed fluorescent layer, which was protected by the new epicuticle layer. These four new layers were the first to illustrate the structural features of the fluorescent exoskeleton. Due to the very soft body and the inability of the newly moulted scorpion to resist attacks from the predator, this special synthesis and transport strategy of the fluorescent substances could guarantee the rapid formation of the integrated fluorescent exoskeleton during the 24 h after ecdysis, which would be a novel biological feature during the scorpion evolution.

Thermally processed Buthus martensii Karsch scorpions are a traditional Chinese medical material for treating various diseases. However, their pharmacological foundation remains unclear. Here, a new degraded peptide of scorpion toxin was identified in Chinese scorpion medicinal material by proteomics. It was named BmK86-P1 and has six conserved cysteine residues. Homology modeling and circular dichroism spectra experiments revealed that BmK86-P1 not only contained representative disulfide bond-stabilized α-helical and β-sheet motifs but also showed remarkable stability at test temperatures from 20–95 °C. Electrophysiology experiments indicated that BmK86-P1 was a highly potent and selective inhibitor of the hKv1.2 channel with IC50 values of 28.5 ± 6.3 nM. Structural and functional dissection revealed that two residues of BmK86-P1 (i.e., Lys19 and Ile21) were the key residues that interacted with the hKv1.2 channel. In addition, channel chimeras and mutagenesis experiments revealed that three amino acids (i.e., Gln357, Val381 and Thr383) of the hKv1.2 channel were responsible for BmK86-P1 selectivity. This research uncovered a new bioactive peptide from traditional Chinese scorpion medicinal material that has desirable thermostability and Kv1.2 channel-specific activity, which strongly suggests that thermally processed scorpions are novel peptide resources for new drug discovery for the Kv1.2 channel-related ataxia and epilepsy diseases.

Scorpion venom is a mixture of bioactive peptides, among which neurotoxins and antimicrobial peptides serve especially vital functions. Scorpion venom peptides in Buthidae species have been well described, but toxic peptides from non-Buthidae species have been under-investigated. Here, an antimicrobial peptide gene, Ctri9594, was cloned and functionally identified from the venom of the scorpion Chaerilus tricostatus. The precursor nucleotide sequence of Ctri9594 is 199 nt in length, including a 43 nt 5′ UTR, 115 nt 3′ UTR and 210 nt ORF. The ORF encodes 69 amino acid residues, containing a 21 aa signal peptide, 14 aa mature peptide, 3 aa C-terminal posttranslational processing signal and 31 aa propeptide. Multiple sequence alignment and evolutionary analyses show that Ctri9594 is an antimicrobial peptide in scorpion venom. The mature peptide of Ctri9594 was chemically synthesized with a purity greater than 95% and a molecular mass of 1484.4 Da. Minimum inhibitory concentrations (MICs) indicate that the synthesized mature peptide of Ctri9594 has inhibitory activity against Gram-positive bacteria (Bacillus thuringensis, Bacillus subtilis, Staphylococcus aureus and Micrococcus luteus) but not Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) or a fungus (Candida albicans). The antimicrobial mechanism of Ctri9594 is inferred to be related to its amphiphilic α-helix structure.

Background: Although there have been many magnetic resonance spectroscopy (MRS) studies of migraine, few have focused on migraines during an attack. Here, we aimed to assess metabolite changes in the brain of patients with migraine, both during an attack and in the interictal phase.Methods: Six patients (one man and five women, mean age: 39 ± 10 years) with migraine without aura during the attack (MWoA-DA), 13 patients (three men and 10 women, mean age: 31 ± 9 years) with migraine without aura during the interictal period (MWoA-DI), and 13 healthy controls (HC) (four men and nine women, mean age: 31 ± 9 years) were studied. All subjects underwent an MRS examination focusing on the occipital lobe. Metabolite changes were investigated among three groups.Results: The MWoA-DA patients had lower glutathione/total creatine ratio (GSH/tCr) than the MWoA-DI patients and HC. Furthermore, MWoA-DI patients showed lower total choline/total creatine ratio (tCho/tCr) than those in the other two groups. The GSH/tCr ratio was positively correlated with attack frequency in the MWoA-DI group. The tCho/tCr ratio was positively correlated with attack frequency and Migraine Disability Assessment Scale (MIDAS) scores in the MWoA-DA group.Conclusion: The present study suggests the existence of distinct pathophysiological states between the MWoA-DA and MWoA-DI groups. Neuronal dysfunction is a possible predisposing factor for migraine attack onset, along with oxidative stress and inflammation.

The scorpion venom system plays a critical role in capturing prey and defending against predators. In this study, the rapid developmental process of the first instar telson was first presented. The small amount of venom in the first instar could be stored well by the distorted and blocked venom ducts, which disappeared in the older scorpions. This special developmental process of the first instar telson revealed the notable survival ability of scorpions.

Background Primary familial brain calcification (PFBC) is a rare inheritable neurodegenerative disease characterized by bilateral calcification in different brain regions and by a range of neuropsychiatric symptoms. Six causative genes of PFBC (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified. Methods Sanger sequencing was used to identify the causative genes associated with PFBC in this study. Results We describe the first PFBC case with both SLC20A2 and PDGFRB heterozygous mutations. Notably, this patient with the digenic mutation (who was only 5 years old) showed severe brain calcification and migraine, whereas the patient's parents, who each carried a heterozygous mutation in SLC20A2 or PDGFRB, exhibited varying degrees of brain calcification but were clinically asymptomatic. Conclusion This case highlights the digenic influences on the characteristics of PFBC patients., We report a family in which the members have various genetic states and manifestations of PFBC. Notably, the proband carrying the SLC20A2 and PDGFRB heterozygous mutations showed more severe brain calcification and earlier onset age of clinical symptoms than her family members, highlighting digenic influences on the characteristics of PFBC patients.

International audience; Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to more than 150 million infections and about 3.1 million deaths up to date. Currently, drugs screened are urgently aiming to block the infection of SARS-CoV-2. Here, we explored the interaction networks of kinase and COVID-19 crosstalk, and identified phosphoinositide 3-kinase (PI3K)/AKT pathway as the most important kinase signal pathway involving COVID-19. Further, we found a PI3K/AKT signal pathway inhibitor capivasertib restricted the entry of SARS-CoV-2 into cells under non-cytotoxic concentrations. Lastly, the signal axis PI3K/AKT/FYVE finger-containing phosphoinositide kinase (PIKfyve)/PtdIns(3,5)P2 was revealed to play a key role during the cellular entry of viruses including SARS-CoV-2, possibly providing potential antiviral targets. Altogether, our study suggests that the PI3K/AKT kinase inhibitor drugs may be a promising anti-SARS-CoV-2 strategy for clinical application, especially for managing cancer patients with COVID-19 in the pandemic era.

Author(s): Cao, Zhijian; Wang, Jing-Lin; McNutt, Patrick Michael; Utkin, Yuri N; Shahbazzadeh, Delavar; Wulff, Heike; Kovacic, Herve; Sabatier, Jean-Marc

Novel degraded potassium channel-modulatory peptides were recently found in thermally processed scorpions, but their pharmacological properties remain unclear. Here, we identified a full-length scorpion toxin (i.e., BmKcug2) and its four truncated analogs (i.e., BmKcug2-P1, BmKcug2-P2, BmKcug2-P3 and BmKcug2-P4) with three conserved disulfide bonds in processed scorpion medicinal material by mass spectrometry. The pharmacological experiments revealed that the recombinant BmKcug2 and BmKcug2-P1 could selectively inhibit the human Kv1.2 and human Kv1.3 potassium channels, while the other three analogs showed a much weaker inhibitory effect on potassium channels. BmKcug2 inhibited hKv1.2 and hKv1.3 channels, with IC

Background and purpose Chronic itch is one of the most common irritating sensations, yet its mechanisms have not been fully elucidated. Although some studies have revealed relationships between itching and brain function, the structural changes in the brain induced by chronic itching, such as those accompanying chronic spontaneous urticaria (CSU), remain unclear. In this study, we aimed to explore the potential changes in brain structure and the associated functional circuitry in CSU patients to generate insights to aid chronic itch management. Methods Forty CSU patients and forty healthy controls (HCs) were recruited. Seven-day urticaria activity score (UAS7) values were collected to evaluate clinical symptoms. Voxel-based morphometry (VBM) and seed-based resting-state functional connectivity (rs-FC) analysis were used to assess structural changes in the brain and associated changes in functional circuitry. Results Compared with HCs, CSU patients had significantly increased grey matter (GM) volume in the right premotor cortex, left fusiform cortex, and cerebellum. UAS7 values were positively associated with GM volume in the left fusiform cortex. In CSU patients relative to HCs, the left fusiform cortex as extracted by VBM analysis demonstrated decreased functional connectivity with the right orbitofrontal cortex, medial prefrontal cortex (mPFC), premotor cortex, primary motor cortex (MI), and cerebellum and increased functional connectivity with the right posterior insular cortex, primary somatosensory cortex (SI), and secondary somatosensory cortex (SII). The left cerebellum as extracted from VBM analysis demonstrated decreased functional connectivity with the right supplementary motor area (SMA) and MI in CSU patients relative to HCs. Conclusions Our findings indicate that patients suffering from chronic itching conditions, such as CSU, are likely to demonstrate altered GM volume in some brain regions. These changes may affect not only the sensorimotor area but also brain regions associated with cognitive function.

Highlights • Vitamin D may mitigate COVID-19 through its effects on gene expression. • Increased vitamin D concentration is associated with better prognosis in COVID-19 cases. • The benefits of vitamin D supplementation in COVID-19 patients remain to be determined. • The use of vitamin D supplements as an adjuvant treatment for COVID-19 needs to be examined urgently., Using Hill's methodology for exploring causality, we aimed to determine in early May 2020 whether evidence supports vitamin D as a biological determinant of COVID-19 outcomes. Vitamin D is a secosteroid hormone theoretically able to reduce COVID-19 risk through regulation of (i) the renin-angiotensin system, (ii) cellular innate and adaptive immunity, and (iii) physical barriers. Inverse associations were found between 25-hydroxyvitamin D concentrations and COVID-19 incidence and mortality. Randomized controlled trials testing vitamin D supplementation in the treatment of COVID-19 are in progress. Positive results in such studies would encourage the use of vitamin D supplements as an adjuvant treatment in COVID-19.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), manifests with a wide spectrum of presentations. Most reports of COVID-19 highlight fever and upper respiratory symptoms as the dominant initial presentations, consistent with the World Health Organization guidelines regarding suspected SARS-CoV-2 infection. However, atypical presentations of this disease have been evolving since the initial outbreak of the pandemic in December 2019. We report a case of an older male patient who presented at our hospital with an unusual manifestation of COVID-19.Brief report.A university hospital in Saudi Arabia.A 73-year-old man who presented with confusion in the absence of any respiratory symptoms or fever.The patient was initially admitted with delirium and underwent a further work-up.Given his recent history of domestic travel and the declaration of a global COVID-19 pandemic status, the patient was administered a swab test for SARS-CoV-2.The patient's positive test led to a diagnosis of COVID-19. Although he began to experience a spiking fever and mild upper respiratory symptoms, he recovered rapidly with no residual sequela.The recognition of atypical presentations of COVID-19 infection, such as delirium, is critical to the timely diagnosis, provision of appropriate care, and avoidance of outbreaks within healthcare facilities during this pandemic. J Am Geriatr Soc 68:1382-1384, 2020.

ObjectiveTo investigate the correlation between changes of the brain’s default mode network (DMN) activity and clinical scale scores in patients with depression after breast cancer surgery using resting-state functional magnetic resonance imaging (rs-fMRI) based on the amplitude of low frequency fluctuations (ALFF) and the regional homogeneity (ReHo), to explore whether activity changes of the DMN can be an indicator of women’s depression after breast cancer surgery.MethodsThe institutional Ethics Committee has approved this prospective study. Twenty-three patients were followed after breast cancer surgery, including 12 cases with postoperative depression and 11 cases without depression. All patients underwent rs-fMRI. The ALFF and ReHo values were obtained and converted to Z values for statistical analysis. Pearson and Spearman correlation analysis were performed to correlate the clinical scale scores with ALFF value and ReHo value. A two sample T-test was conducted for ALFF and ReHo values of patients in two groups.ResultsThe ALFF value of the right precuneus was negatively correlated with the Hamilton anxiety scale (HAMA) score (r = -0.43, P < 0.05). The full-scale attention quotient (FSAQ) score was positively correlated with the ALFF value of the left angular gyrus (r = 0.44, P < 0.05) and the right supramarginal gyrus (r = 0.50, P < 0.05). The ReHo value of the right angular gyrus was positively correlated with self-rating depression scale (SDS) score (r = 0.45, P < 0.05) and HAMA score (r = 0.49, P < 0.05). There were significant correlations between the clinical scale scores and the ALFF values and ReHo values of the DMN regions in patients after breast cancer surgery, but no statistical difference in ALFF and ReHo values between patients with and without depression after breast cancer surgery.ConclusionsActivity changes of the DMN in patients were closely related to the attention deficit in depressive disorder and anxiety in patients who had recently undergone breast cancer surgery. Meanwhile, the change of neuronal synchronization in the right angular gyrus may be closely associated with the pathophysiology of anxiety. Rs-fMRI can help to better detect and evaluate depression in patients after breast cancer surgery.

Rationale: Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study. Methods: The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. In vitro kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication. Results: HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2. Conclusion: Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.

International audience