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The involvement of academic research in drug discovery is consistently growing. However, academic projects seldom advance to clinical trials. Here, we assess the landscape of drug discovery within the National Centre of Competence in Research (NCCR) TransCure launched by the Swiss National Science Foundation to foster basic research and early-stage drug discovery on membrane transporters. This included transporters in central nervous system (CNS) disorders, which represent a huge unmet medical need. While idea championship, sustainable funding, collaborations between disciplines at the interface of academia and industry are important for translational research, Popperian falsifiability, strong intellectual property and a motivated startup team are key elements for innovation. This is exemplified by the NCCR TransCure spin-off company Synendos Therapeutics, a clinical stage biotech company developing the first selective endocannabinoid reuptake inhibitors (SERIs) as novel treatment for neuropsychiatric disorders. We provide a perspective on the challenges related to entering an uncharted druggable space and bridging the often mentioned "valley of death". The high attrition rate of drug discovery projects in the CNS field within academia is often due to the lack of meaningful animal models that can provide pharmacological proof-of-concept for potentially disruptive technologies at the earliest stages, and the absence of solid intellectual property., (© 2024 The Author(s). ChemBioChem published by Wiley-VCH GmbH.)

Opioid use disorder is a public health problem that includes symptoms such as withdrawal syndrome and opioid-induced hyperalgesia. Currently, drugs to treat side effects of opioids also have undesirable effects, which lead to limitations. This study investigated the effect of a treatment with cannabidiol in morphine-induced hyperalgesia and withdrawal behavior in morphine-dependent rats. Male and female rats were submitted to a morphine-induced physical dependence protocol consisting of a twice daily treatment with morphine (filtered solution, dose of 7.89 mg/kg, 1 ml/kg, s.c.) for 10 days. Nociception was measured using the hot plate test and morphine-induced thermal hyperalgesia was equally achieved following 7-10 days of morphine administration in male and female rats. Repeated treatment with cannabidiol (30 mg/kg) was sufficient to prevent thermal hyperalgesia in male and female rats. Subsequently, rats received an acute administration of naloxone (2 mg/kg. s.c.), 90 min after the morphine treatment on day 11, the number of withdrawal behaviors was scored. Rats that received treatment exclusively with morphine presented significant withdrawal behaviors compared to control (Water). Morphine-dependent female rats showed a prevalent stereotyped behavior of rearing, whereas male rats had teeth chattering behavior as the most preeminent. Treatment with cannabidiol on day 11 partially attenuated withdrawal behavior in morphine-dependent male rats, with mild effects in female rats (high withdrawal responders only). Altogether, our data provide evidence of an anti-hyperalgesic effect of cannabidiol in rats. Male and female rats treated chronically with morphine exhibited withdrawal behaviors in different ratios, and cannabidiol treatment attenuated withdrawal behavior in a sex-dependent manner., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques and tau tangles, leading to cognitive decline and dementia. Insulin-like Growth Factor-1 (IGF-1) is similar in structure to insulin and is crucial for cell growth, differentiation, and regulating oxidative stress, synaptic plasticity, and mitochondrial function. IGF-1 exerts its physiological effects by binding to the IGF-1 receptor (IGF-1R) and activating PI3K/Akt pathway. In addition to the physiological activities in the brain, numerous studies point to a potential protective role of the IGF-1 pathway in the pathogenesis of neurodegenerative diseases, such as AD. Interestingly, patients with AD often exhibit altered insulin and IGF-1 levels, along with an inadequate insulin response. Dysregulation of IGF-1 signaling contributes to hyperphosphorylation of tau, NFT accumulation, increased β- and γ-secretase activity, elevated Aβ production, and impaired Aβ clearance, highlighting the need to explore the role of this signaling for potential therapeutic targets of AD. This review explores the role of IGF signaling in AD pathology, highlighting IGF-1 as a promising therapeutic target due to its significant involvement in disease mechanisms. Modulating IGF-1 activity could help mitigate neurodegeneration and preserve cognitive function in AD. A comprehensive understanding of the mechanisms underlying IGF-1 dysregulation is crucial for developing targeted therapeutic strategies to address the complex and multifaceted nature of AD., Competing Interests: Declarations. Conflict of interest: The authors assert that they do not have any known financial interests or personal relationships that could be perceived as influencing the work reported in this paper. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The Homo sapiens Na + /H + antiporter NHA2 (SLC9B2) transports Na + or Li + in exchange for protons across cell membranes, and its dysfunction results in various pathologies. The activity of HsNHA2 is specifically inhibited by the flavonoid phloretin. Using bioinformatic modeling, we predicted two amino acids (R177 and S178) as being important for the binding of phloretin to the HsNHA2 molecule. Functional expression of HsNHA2 in Saccharomyces cerevisiae and its site-directed mutagenesis revealed that while the R177T mutation resulted in an antiporter that was less sensitive to phloretin, the S178T mutation enhanced the inhibitory effect of phloretin on HsNHA2. Our data corroborate the transport properties of HsNHA2 and its interactions with an inhibitor and can be helpful for the development of new therapeutics targeting this antiporter and its pleiotropic physiological functions., (© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The pandemic COVID-19 (coronavirus disease 2019) is caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), which devastated the global economy and healthcare system. The infection caused an unforeseen rise in COVID-19 patients and increased the mortality rate globally. This study gives an overall idea about host-pathogen interaction, immune responses to COVID-19, recovery status of infection, targeted organs and complications associated, and comparison of post-infection immunity in convalescent subjects and non-infected individuals. The emergence of the variants and episodes of COVID-19 infections made the situation worsen. The timely introduction of vaccines and precautionary measures helped control the infection's severity. Later, the population that recovered from COVID-19 grew significantly. However, understanding the impact of healthcare issues resulting after infection is paramount for improving an individual's health status. It is now recognised that COVID-19 infection affects multiple organs and exhibits a broad range of clinical manifestations. So, post COVID-19 infection creates a high risk in individuals with already prevailing health complications. The identification of post-COVID-19-related health issues and their appropriate management is of greater importance to improving patient's quality of life. The persistence, sequelae and other medical complications that normally last from weeks to months after the recovery of the initial infection are involved with COVID-19. A multi-disciplinary approach is necessary for the development of preventive measures, techniques for rehabilitation and strategies for clinical management when it comes to long-term care., Competing Interests: Declarations. Ethical Approval: This is a review article. Appropriate approval/ethical approval is already taken. Consent to Participate: The consent part from the subject is not applicable to this review article. Consent or Publication: All the authors agreed to submit the manuscript to the journal. The same has been approved by the parent Institute. Conflict of Interest: The authors declare no competing interests., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic pain and opioid use disorder (OUD) are major public health problems, with rising opioid-related overdose deaths linked to increased opioid prescriptions for pain management. Novel treatment approaches for these commonly comorbid disorders are needed. Growing evidence supports a role for glial activation for both chronic pain and substance use disorders, including OUD. This review provides an overview of glial modulators as a novel treatment approach for comorbid pain and OUD. We aim to synthesize clinical studies investigating the efficacy of glial modulators in treating these comorbid disorders. We conducted a literature search of PubMed and Google Scholar databases in October 2023 to identify relevant clinical trials. The included studies varied in terms of patient population, study methodology and outcomes assessed, and were often limited by small sample sizes and other methodological issues. Additionally, several glial modulators have yet to be studied for chronic pain and OUD. Despite these limitations, these studies yielded positive signals that merit further investigation. Both chronic pain and OUD remain significant public health problems, with many treatment challenges. Glial modulators continue to hold promise as novel therapeutics for comorbid pain and OUD, given positive indications that they can improve pain measures, and reduce addiction-related outcomes. As our understanding of the mechanisms underlying the contributions of glial modulators to pain and addiction behaviours deepens, we will be better equipped to identify more specific therapeutic targets for chronic pain and OUD., (© 2024 British Pharmacological Society.)

Growth hormone-releasing hormone (GHRH) is primarily produced by the hypothalamus and stimulates the release of growth hormone (GH) in the anterior pituitary gland, which subsequently regulates the production of hepatic insulin-like growth factor-1 (IGF-1). GH and IGF-1 have potent effects on promoting cell proliferation, inhibiting cell apoptosis, as well as regulating cell metabolism. In central nerve system (CNS), GHRH/GH/IGF-1 promote brain development and growth, stimulate neuronal proliferation, and regulate neurotransmitter release, thereby participating in the regulation of various CNS physiological activities. In addition to hypothalamus-pituitary gland, GHRH and GHRH receptor (GHRH-R) are also expressed in other brain cells or tissues, such as endogenous neural stem cells (NSCs) and tumor cells. Alternations in GHRH/GH/IGF-1 axis are associated with various CNS diseases, for example, Alzheimer's disease, amyotrophic lateral sclerosis and emotional disorders manifest GHRH, GH or IGF-1 deficiency, and GH or IGF-1 supplementation exerts beneficial therapeutic effects on these diseases. CNS tumors, such as glioma, can express GHRH and GHRH-R, and activating this signaling pathway promotes tumor cell growth. The synthesized GHRH antagonists have shown to inhibit glioma cell growth and may hold promising as an adjuvant therapy for treating glioma. In addition, we have shown that GHRH agonist MR-409 can improve neurological sequelae after ischemic stroke by activating extrapituitary GHRH-R signaling and promoting endogenous NSCs-derived neuronal regeneration. This article reviews the involvement of GHRH/GH/IGF-1 in CNS diseases, and potential roles of GHRH agonists and antagonists in treating CNS diseases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Na + /H + antiporters facilitate the exchange of Na + for H + across the cytoplasmic membrane in prokaryotic and eukaryotic cells. These transporters are crucial to maintain the homeostasis of sodium ions, consequently pH, and volume of the cells. Therefore, sodium/proton antiporters are considered promising therapeutic targets in humans. The Na + /H + antiporter in Escherichia coli (Ec-NhaA), a prototype of cation-proton antiporter (CPA) family, transports two protons and one sodium (or Li + ) in opposite direction. Previous mutagenesis experiments on Ec-NhaA have proposed Asp164, Asp163, and Asp133 amino acids with the significant implication in functional and structural integrity and create site for ion-binding. However, the mechanism and the sites for the binding of the two protons remain unknown and controversial which could be critical for pH regulation. In this study, we have explored the role of Glu78 in the regulation of pH by Ec-NhaA. Although we have created various mutants, E78C has shown a considerable effect on the stoichiometry of NhaA and presented comparable phenotypes. The ITC experiment has shown the binding of ~ 5 protons in response to the transport of one lithium ion. The phenotype analysis on selective medium showed a significant expression compared to WT Ec-NhaA. This represents the importance of Glu78 in transporting the H + across the membrane where a single mutation with Cys amino acid alters the number of H + significantly maintaining the activity of the protein., (© 2024. European Biophysical Societies' Association.)

Biophysicochemical rhizosheath properties play a vital role in plant drought adaptation. However, their integration into the framework of plant drought response is hampered by incomplete mechanistic understanding of their drought responsiveness and unknown linkage to intraspecific plant-soil drought reactions. Thirty-eight Zea mays varieties were grown under well-watered and drought conditions to assess the drought responsiveness of rhizosheath properties, such as soil aggregation, rhizosheath mass, net-rhizodeposition, and soil organic carbon distribution. Additionally, explanatory traits, including functional plant trait adaptations and changes in soil enzyme activities, were measured. Drought restricted soil structure formation in the rhizosheath and shifted plant-carbon from litter-derived organic matter in macroaggregates to microbially processed compounds in microaggregates. Variety-specific functional trait modifications determined variations in rhizosheath drought responsiveness. Drought responses of the plant-soil system ranged among varieties from maintaining plant-microbial interactions in the rhizosheath through accumulation of rhizodeposits, to preserving rhizosheath soil structure while increasing soil exploration through enhanced root elongation. Drought-induced alterations at the root-soil interface may hold crucial implications for ecosystem resilience in a changing climate. Our findings highlight that rhizosheath soil properties are an intrinsic component of plant drought response, emphasizing the need for a holistic concept of plant-soil systems in future research on plant drought adaptation., (© 2024 The Authors New Phytologist © 2024 New Phytologist Foundation.)

Huntington's disease is a rare autosomal dominant disorder presenting with chorea, rigidity, hypo-/akinesia, cognitive decline, and psychiatric disturbances. Numerous risk factors have been defined in the onset of this disease. However, the number of CAG repeats in the genes are the most crucial factor rendering patients susceptible to the disease. Studies have shown significant differences in onset and disease presentation among the sexes, which prompts analysis of the impact of different sexes on disease etiology and progression. This article therefore discusses the evidence-based role of sex in aspects of symptomatology, pathogenesis, biomarkers, progression, and prognosis of Huntington's disease, with a secondary review of sex-linked differences in Alzheimer's and Parkinson's disease., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, ein Teil von Springer Nature.)

Adolescence is one of the most critical periods for brain development, and exposure to morphine during this period can have long-life effects on pain-related behaviors. The opioid system in the periaqueductal gray (PAG) is highly vulnerable to drug exposure. However, the impact of adolescent morphine exposure (AME) on the endogenous opioid system in the PAG is currently unknown. This study aims to investigate the long-lasting effects of AME on the endogenous opioid system and its involvement in altering nociceptive behaviors. Adolescent rats were given escalating doses of morphine (2.5-25 mg/kg, subcutaneous) or an equal volume of saline twice daily for 10 consecutive days (PND 31-40). After a 30-day washout period, adult rats underwent formalin tests following microinjection of morphine, naloxone, or saline into the ventrolateral PAG (vlPAG) region. The results indicated that morphine microinjection into the vlPAG of the adolescent morphine-treated group significantly reduced the nociceptive score. However, the analgesic response to morphine in this group was significantly lower compared to the saline-treated group during adolescence. Additionally, the nociceptive score significantly increased following naloxone but not saline microinjection into the vlPAG of the saline-treated group during adolescence, rather than the morphine-treated one. These findings indicate that AME has long-lasting effects on the endogenous opioid system in the vlPAG, which can consequently alter behaviors related to inflammatory pain in adulthood., (© 2023 Wiley Periodicals LLC.)

Pain is characterized by the unpleasant sensory and emotional sensation associated with actual or potential tissue damage, whereas nociception refers to the mechanism by which noxious stimuli are transmitted from the periphery to the CNS. The main drugs used to treat pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, which have side effects that limit their use. Therefore, in the search for new drugs with potential antinociceptive effects, essential oils have been studied, whose constituents (monoterpenes) are emerging as a new therapeutic possibility. Among them, linalool and its metabolites stand out. The present study aims to investigate the antinociceptive potential of linalool and its metabolites through a screening using an in silico approach. Molecular docking was used to evaluate possible interactions with important targets involved in antinociceptive activity, such as α 2 -adrenergic, GABAergic, muscarinic, opioid, adenosinergic, transient potential, and glutamatergic receptors. The compounds in the investigated series obtained negative energies for all enzymes, representing satisfactory interactions with the targets and highlighting the multi-target potential of the L4 metabolite. Linalool and its metabolites have a high likelihood of modulatory activity against the targets involved in nociception and are potential candidates for future drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Glutamate decarboxylase (GAD) is a Ca 2+ -calmodulin-activated, cytosolic enzyme that produces γ-aminobutyrate (GABA) as the committed step of the GABA shunt. This pathway bypasses the 2-oxoglutarate to succinate reactions of the tricarboxylic acid (TCA) cycle. GABA also accumulates during many plant stresses. We tested the hypothesis that AtGAD1 (At5G17330) facilitates Arabidopsis acclimation to Pi deprivation. Quantitative RT-PCR and immunoblotting revealed that AtGAD1 transcript and protein expression is primarily root-specific, but inducible at lower levels in shoots of Pi-deprived (-Pi) plants. Pi deprivation reduced levels of the 2-oxoglutarate dehydrogenase (2-OGDH) cofactor thiamine diphosphate (ThDP) in shoots and roots by > 50%. Growth of -Pi atgad1 T-DNA mutants was significantly attenuated relative to wild-type plants. This was accompanied by: (i) an > 60% increase in shoot and root GABA levels of -Pi wild-type, but not atgad1 plants, and (ii) markedly elevated anthocyanin and reduced free and total Pi levels in leaves of -Pi atgad1 plants. Treatment with 10 mM GABA reversed the deleterious development of -Pi atgad1 plants. Our results indicate that AtGAD1 mediates GABA shunt upregulation during Pi deprivation. This bypass is hypothesized to circumvent ThDP-limited 2-OGDH activity to facilitate TCA cycle flux and respiration by -Pi Arabidopsis., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Background: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials., Methods: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24., Results: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia., Conclusions: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.)., (Copyright © 2023 Massachusetts Medical Society.)

Chronic pain is a prevalent neurological complication among individuals living with human immunodeficiency virus (PLHIV) in the post-combination antiretroviral therapy (cART) era. These individuals experience malfunction in various cellular and molecular pathways involved in pain transmission and modulation, including the neuropathology of the peripheral sensory neurons and neurodegeneration and neuroinflammation in the spinal dorsal horn. However, the underlying etiologies and mechanisms leading to pain pathogenesis are complex and not fully understood. In this review, we aim to summarize recent progress in this field. Specifically, we will begin by examining neuropathology in the pain pathways identified in PLHIV and discussing potential causes, including those directly related to HIV-1 infection and comorbidities, such as antiretroviral drug use. We will also explore findings from animal models that may provide insights into the molecular and cellular processes contributing to neuropathology and chronic pain associated with HIV infection. Emerging evidence suggests that viral proteins and/or antiretroviral drugs trigger a complex pathological cascade involving neurons, glia, and potentially non-neural cells, and that interactions between these cells play a critical role in the pathogenesis of HIV-associated pain., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Significance Statement: Thiazide diuretics (thiazides) are among the most widely prescribed drugs worldwide, but their use is associated with glucose intolerance and new-onset diabetes mellitus. The molecular mechanisms remain elusive. Our study reveals that thiazides attenuate insulin secretion through inhibition of the mitochondrial carbonic anhydrase isoform 5b (CA5b) in pancreatic β cells. We furthermore discovered that pancreatic β cells express only one functional carbonic anhydrase isoform, CA5b, which is critical in replenishing oxaloacetate in the mitochondrial tricarboxylic acid (TCA) cycle (anaplerosis). These findings explain the mechanism for thiazide-induced glucose intolerance and reveal a fundamental role of CA5b in TCA cycle anaplerosis and insulin secretion in β cells., Background: Thiazide diuretics are associated with glucose intolerance and new-onset diabetes mellitus. Previous studies demonstrated that thiazides attenuate insulin secretion, but the molecular mechanisms remain elusive. We hypothesized that thiazides attenuate insulin secretion via one of the known molecular thiazide targets in β cells., Methods: We performed static insulin secretion experiments with islets of wild-type, Sodium/chloride co-transporter (NCC) (SLC12A3), and sodium-driven chloride/bicarbonate exchanger (NDCBE) (SLC4A8) knock-out (KO) mice and with murine Min6 cells with individual knockdown of carbonic anhydrase (CA) isoforms to identify the molecular target of thiazides in β cells. CA isoform 5b (CA5b) KO mice were then used to assess the role of the putative thiazide target CA5b in β -cell function and in mediating thiazide sensitivity in vitro and in vivo ., Results: Thiazides inhibited glucose- and sulfonylurea-stimulated insulin secretion in islets and Min6 cells at pharmacologically relevant concentrations. Inhibition of insulin secretion by thiazides was CO 2 /HCO 3- -dependent, not additive to unselective CA inhibition with acetazolamide, and independent of extracellular potassium. By contrast, insulin secretion was unaltered in islets of mice lacking the known molecular thiazide targets NCC or NDCBE. CA expression profiling with subsequent knockdown of individual CA isoforms suggested mitochondrial CA5b as a molecular target. In support of these findings, thiazides significantly attenuated Krebs cycle anaplerosis through reduction of mitochondrial oxaloacetate synthesis. CA5b KO mice were resistant to thiazide-induced glucose intolerance, and thiazides did not alter insulin secretion in CA5b KO islets., Conclusions: Thiazides attenuate insulin secretion via inhibition of the mitochondrial CA5b isoform in β cells of mice., (Copyright © 2023 by the American Society of Nephrology.)

In this work, we demonstrate how important it is to investigate not only on-target activity but to keep antibiotic activity against critical pathogens in mind. Since antimicrobial resistance is spreading in bacteria such as Mycobacterium tuberculosis, investigations into new targets are urgently needed. One promising new target is 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) of the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. We have recently solved the crystal structure of truncated M. tuberculosis DXPS and used it to perform a virtual screening in collaboration with Atomwise Inc. using their deep convolutional neural network-based AtomNet® platform. Of 94 virtual hit compounds only one showed interesting results in binding and activity studies. We synthesized 30 close derivatives using a straightforward synthetic route that allowed for easy derivatization. However, no improvement in activity was observed for any of the derivatives. Therefore, we tested them against a variety of pathogens and found them to be good inhibitors against Escherichia coli., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Vanilloids, including capsaicin and eugenol, are ligands of transient receptor potential channel vanilloid subfamily member 1 (TRPV1). Prolonged treatment with vanilloids triggered the desensitization of TRPV1, leading to analgesic or antinociceptive effects. Caenorhabditis elegans (C. elegans) is a model organism expressing vanilloid receptor orthologs (e.g., OSM-9 and OCR-2) that are associated with behavioral and physiological processes, including sensory transduction. We have shown that capsaicin and eugenol hamper the nocifensive response to noxious heat in C. elegans. The objective of this study was to perform proteomics to identify proteins and pathways responsible for the induced phenotype and to identify capsaicin and eugenol targets using a thermal proteome profiling (TPP) strategy. The results indicated hierarchical differences following Reactome Pathway enrichment analyses between capsaicin- and eugenol-treated nematodes. However, both treated groups were associated mainly with signal transduction pathways, energy generation, biosynthesis and structural processes. Wnt signaling, a specific signal transduction pathway, is involved following treatment with both molecules. Wnt signaling pathway is noticeably associated with pain. The TPP results show that capsaicin and eugenol target OCR-2 but not OSM-9. Further protein-protein interaction (PPI) analyses showed other targets associated with enzymatic catalysis and calcium ion binding activity. The resulting data help to better understand the broad-spectrum pharmacological activity of vanilloids., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Opioids are often first-line analgesics in pain therapy. However, prolonged use of opioids causes paradoxical pain, termed "opioid-induced hyperalgesia (OIH)." The infralimbic medial prefrontal cortex (IL-mPFC) has been suggested to be critical in inflammatory and neuropathic pain processing through its dynamic output from layer V pyramidal neurons. Whether OIH condition induces excitability changes of these output neurons and what mechanisms underlie these changes remains elusive. Here, with combination of patch-clamp recording, immunohistochemistry, as well as optogenetics, we revealed that IL-mPFC layer V pyramidal neurons exhibited hyperexcitability together with higher input resistance. In line with this, optogenetic and chemogenetic activation of these neurons aggravates behavioral hyperalgesia in male OIH rats. Inhibition of these neurons alleviates hyperalgesia in male OIH rats but exerts an opposite effect in male control rats. Electrophysiological analysis of hyperpolarization-activated cation current (Ih) demonstrated that decreased Ih is a prerequisite for the hyperexcitability of IL-mPFC output neurons. This decreased Ih was accompanied by a decrease in HCN1, but not HCN2, immunolabeling, in these neurons. In contrast, the application of HCN channel blocker increased the hyperalgesia threshold of male OIH rats. Consequently, we identified an HCN-channel-dependent hyperexcitability of IL-mPFC output neurons, which governs the development and maintenance of OIH in male rats., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The study is to investigate the neuroprotective effect of different doses of Maresin1 pretreatment in aged rats after anesthesia/surgery and the related mechanisms., Methods: Aged male rats were randomly divided into a control group, an anesthesia/surgery group, and low, medium, and high-dose Maresin1 pretreatment groups, and the hippocampus was taken for study. The Morris water maze was performed to detect the cognitive ability of rats. Western blot and immunofluorescence were used to detect the expression of glial fibrillary acidic protein (GFAP) and central nervous system-specific protein (S100β). The ultrastructure of astrocytes was observed by a transmission electron microscope. Quantitative real-time PCR was used to detect the relative expression of IL-1β, IL-6, and TNF-α mRNA., Results: Compared with the control group, the cognition of rats in the anesthesia/surgery group was significantly reduced. The expression of astrocyte markers (GFAP and S100β) in the hippocampus of rats in the anesthesia/surgery group was increased. The levels of hippocampal inflammatory cytokines (TNF-α, IL-1β, and IL-6) were also higher in the anesthesia/surgery group than in the control group. After pretreatment with different doses of Maresin1, the cognitive impairment of rats was alleviated to varying degrees. Maresin1 pretreatment decreased the expression of astrocyte markers and inflammatory factors in the hippocampus of rats after anesthesia/surgery, and improve the microstructures of activated astrocytes, especially in the medium-dose group., Conclusion: Pretreatment with Maresin1 (especially at medium-dose) showed neuroprotective effects in aged rats after anesthesia/surgery, which may be related to the inhibition of astrocyte activation., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Monoclonal antibodies have been successfully incorporated into the current therapeutical landscape of lung cancer in the last decades. Recently, with technological advances, bispecific antibodies (bsAbs) have also shown robust efficacy in the treatment of malignant cancers, including lung cancer. These antibodies target two independent epitopes or antigens and have been extensively explored in translational and clinical studies in lung cancer. Here, we outline the mechanisms of action of bsAbs, related clinical data, ongoing clinical trials, and potent novel compounds of various types of bsAbs in clinical studies, especially in lung cancer. We also propose future directions for the clinical development of bsAbs, which might bring a new era of treatment for patients with lung cancer., (Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Transient receptor potential (TRP) channels are cation channels that regulate key physiological and pathological processes in response to a broad range of stimuli. Moreover, they systemically regulate the release of hormones, metabolic homeostasis, and complications of diabetes, which positions them as promising therapeutic targets to combat metabolic disorders. Nevertheless, there are significant challenges in the design of TRP ligands with high potency and durability. Herein we summarize the four challenges as hydrophobicity, selectivity, mono-target therapy, and interspecies discrepancy. We present 1134 TRP ligands with diversified modes of TRP-ligand interaction and provide a detailed discussion of the latest strategies, especially cryogenic electron microscopy (cryo-EM) and computational methods. We propose solutions to address the challenges with a critical analysis of advances in membrane partitioning, polypharmacology, biased agonism, and biochemical screening of transcriptional modulators. They are fueled by the breakthrough from cryo-EM, chemoinformatics and bioinformatics. The discussion is aimed to shed new light on designing next-generation drugs to treat obesity, diabetes and its complications, with optimal hydrophobicity, higher mode selectivity, multi-targeting and consistent activities between human and rodents., (© 2022 Wiley-VCH GmbH.)

Abstract: Long-term opioid use in patients with chronic noncancer pain (CNCP) can lead to opioid use disorder (OUD) and has been associated with hyperalgesia and reduced quality of life (QoL). Studies suggest antihyperalgesic properties of buprenorphine, and buprenorphine or naloxone (BuNa) has shown beneficial effects on QoL in patients with OUD without CNCP. This study investigated the added value of BuNa in patients with CNCP with OUD on self-reported pain, pain thresholds, pain tolerance, and QoL. In the current study, 43 outpatients with CNCP and OUD were included for inpatient conversion from full μ-receptor agonist opioids to BuNa. Self-reported pain, pain thresholds, pain tolerance, and QoL were determined at baseline and after 2 months of follow-up, using, respectively, a Visual Analogue Scale (VAS-pain and VAS-QoL), quantitative sensory testing, and EuroQol-5 dimensions. In total, 37 participants completed the protocol, and their data were analyzed. The mean VAS-pain score decreased from 51.3 to 37.2 (27.5%, F = 3.3; P = 0.044), whereas the pressure pain threshold and electric pain threshold or tolerance increased after substitution (F = 7.8; P = 0.005 and F = 44.5; P < 0.001, respectively), as well as QoL (EuroQol-5 dimensions questionnaire: F = 10.4; P = 0.003 and VAS-QoL: F = 4.4; P = 0.043). We found that conversion of full μ-receptor agonists to BuNa, in patients with CNCP with OUD, was accompanied with lower self-reported pain, higher pain thresholds, higher pain tolerance, and improved QoL. Despite several study limitations, these data suggest that BuNa might be of value in patients with CNCP with OUD. Future studies should investigate long-term effects of BuNa in randomized trials., (Copyright © 2021 International Association for the Study of Pain.)

Morphine is generally used to treat chronic pain in clinic. But long-term use of morphine can inevitably induce analgesic tolerance and hyperalgesia. Caveolin-1 is reported to affect morphine-mediated signaling transduction. However, the action mechanism of morphine-induced analgesic tolerance is still unknown. In this study, morphine-induced analgesic tolerance model was established in Sprague-Dawley rats. The effects of Caveolin-1 blocking on neuroinflammation and ERK/c-JUN pathway were then explored. Morphine can remarkably elevate the expression level of Caveolin-1. Based on paw withdrawal latency behavior test, we found that Caveolin-1 blocking can effectively attenuate morphine-induced analgesic tolerance and neuroinflammation. Activation of ERK/c-JUN significantly reversed the above influences caused by Caveolin-1 blocking. Taken together, blocking of Caveolin-1 can attenuate morphine-induced inflammation and analgesic tolerance through inhibiting NLRP3 inflammasome and ERK/c-JUN pathway., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Case: We present an adolescent contact-sport athlete presenting with hip pain after a traumatic in-play event. After delayed clinical improvement, a magnetic resonance arthrogram (MRA) revealed a posterior acetabular labral tear and the patient was referred for arthroscopic repair. However, subsequent critical interpretation of the MRA demonstrated a missed concomitant posterior acetabular wall fracture, which was later confirmed with computed tomography., Conclusion: Despite the low incidence of acetabular fractures in adolescents, this case report highlights the importance of maintaining clinical suspicion in young athletes after a traumatic injury, recognizing the association with labral tears, and acknowledging the limitations of certain imaging modalities., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B843)., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

Roots anchor plants to the soil, providing them with nutrients and water while creating a defence network and facilitating beneficial interactions with a multitude of living organisms and climatological conditions. To facilitate morphological and molecular studies, root research has been conducted using in vitro systems. However, under natural conditions, roots grow in the dark, mainly in the absence of illumination, except for the relatively low illumination of the upper soil surface, and this has been largely ignored. Here, we discuss the results found over the last decade on how experimental exposure of roots to light may bias root development and responses through the alteration of hormonal signalling, cytoskeleton organization, reactive oxygen species or the accumulation of flavonoids, among other factors. Illumination alters the uptake of nutrients or water, and also affects the response of the roots to abiotic stresses and root interactions with the microbiota. Furthermore, we review in vitro systems created to maintain roots in darkness, and provide a comparative analysis of root transcriptomes obtained with these devices. Finally, we identify other experimental variables that should be considered to better mimic soil conditions, whose improvement would benefit studies using in vitro cultivation or enclosed ecosystems., (© 2021 The Authors. New Phytologist © 2021 New Phytologist Foundation.)

Abstract: Opioids are the frontline analgesics in pain management. However, chronic use of opioid analgesics causes paradoxical pain that contributes to the decrease of their efficacy in pain control and the escalation of dose in long-term management of pain. The underling pathogenic mechanism is not well understood. Microglia have been commonly believed to play a critical role in the expression of opioid-induced hyperalgesia in animal models. We performed microglial ablation experiments using either genetic (CD11b-diphtheria toxin receptor transgenic mouse) or pharmacological (colony-stimulating factor-1 receptor inhibitor PLX5622) approaches. Surprisingly, ablating microglia using these specific and effective approaches did not cause detectable impairment in the expression of hyperalgesia induced by morphine. We confirmed this conclusion with a behavioral test of mechanical and thermal hyperalgesia, in male and female mice, and with different species (mouse and rat). These findings raise caution about the widely assumed contribution of microglia to the development of opioid-induced hyperalgesia., (Copyright © 2021 International Association for the Study of Pain.)

In many regions across Africa, agriculture is largely based on low-input and small-holder farming systems that use little inorganic fertilisers and have limited access to irrigation and mechanisation. Improving agricultural practices and developing new cultivars adapted to these environments, where production already suffers from climate change, is a major priority for food security. Here, we illustrate how breeding for specific root traits could improve crop resilience in Africa using three case studies covering very contrasting low-input agroecosystems. We first review how greater basal root whorl number and longer and denser root hairs increased P acquisition efficiency and yield in common bean in South East Africa. We then discuss how water-saving strategies, root hair density and deep root growth could be targeted to improve sorghum and pearl millet yield in West Africa. Finally, we evaluate how breeding for denser root systems in the topsoil and interactions with arbuscular mycorrhizal fungi could be mobilised to optimise water-saving alternate wetting and drying practices in West African rice agroecosystems. We conclude with a discussion on how to evaluate the utility of root traits and how to make root trait selection feasible for breeders so that improved varieties can be made available to farmers through participatory approaches., (© 2022 John Wiley & Sons Ltd.)

A synergy between the rumen microbiota and the host genetics has created a symbiotic relationship, beneficial to the host's health. In this study, the association between the host genetics and rumen microbiome of Damara and Meatmaster sheep was investigated. The composition of rumen microbiota was estimated through the analysis of the V3-V4 region of the 16S rRNA gene, while the sheep blood DNA was genotyped with Illumina OvineSNP50 BeadChip and the genome-wide association (GWA) was analyzed. Sixty significant SNPs dispersed in 21 regions across the Ovis aries genome were found to be associated with the relative abundance of seven genera: Acinetobacter, Bacillus, Clostridium, Flavobacterium, Prevotella, Pseudomonas, and Streptobacillus. A total of eighty-four candidate genes were identified, and their functional annotations were mainly associated with immunity responses and function, metabolism, and signal transduction. Our results propose that those candidate genes identified in the study may be modulating the composition of rumen microbiota and further indicating the significance of comprehending the interactions between the host and rumen microbiota to gain better insight into the health of sheep., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Invasive pneumococcal disease (IPD) is responsible for substantial mortality and morbidity worldwide. We aimed to identify host and bacterial factors associated with 30-day mortality in 18-year-old patients hospitalized with IPD in France from 2013 to 2015., Methods: This study analyzed data collected from consecutives IPD cases included in two parallel multi-center cohort studies: COMBAT study (280 patients with pneumococcal community-acquired bacterial meningitis) and SIIP study (491 patients with non-meningitis IPD). Factors associated with 30-day mortality were identified using logistic regression., Results: Among the 771 enrolled patients (median age 66 years, IQR [52.0-79.7]), 592/767 (77.2%) had at least one chronic disease. Patients with meningitis were younger (60.2 vs 70.9 years; p < 0.001) and had fewer chronic diseases than those with non-meningitis IPD (73.3% vs 79.4%; p = 0.05). Non-vaccine serotypes were more frequent in meningitis patients than in those with other IPD (36.1% vs 23.1%; p < 0.001). The overall 30-day mortality was 16.7% and patients with concurrent meningitis and extra-cerebral IPD had the highest 30-day mortality rate (26.5%). On multivariate analyses, older age, history of malignant solid tumor, meningeal IPD and serotypes previously identified with high mortality potential were independently associated with 30-day mortality. Of the serotypes with high mortality potential, 80% were included in licensed (PCV13 or PPV23) vaccines., Conclusion: We observed an effect of both host factors and pneumococcal serotypes on 30-day mortality in IPD. This highlights the need for a focused strategy to vaccinate at-risk patients., Clinical Trial: ClinicalTrial. Gov identification number: NCT01730690., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

A major challenge in medicine is developing potent pain therapies without the adverse effects of opiates. Neuroinflammation and in particular microglial activation have been shown to contribute to these effects. However, the implication of the microglial mu opioid receptor (MOR) is not known. We developed a novel conditional knockout (cKO) mouse line, wherein MOR is deleted in microglia. Morphine analgesic tolerance was delayed in both sexes in cKO mice in the hot plate assay. Opioid-induced hyperalgesia (OIH) as measured in the tail immersion assay was abolished in male cKO mice, and physical dependence to morphine as assessed by naloxone-induced withdrawal was attenuated in female cKO mice. Our results show a sex-dependent contribution of microglial MOR in morphine analgesic tolerance, OIH, and physical dependence. In conclusion, our data suggest that blockade of microglial MOR could represent a therapeutic target for opiate analgesia without the opiate adverse effects., (© 2020 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

The kappa opioid receptor (KOR) is expressed on a number of hematopoietic cell populations, based on both protein binding analysis and the detection of kappa opioid receptor gene (Oprk1) transcripts. There are prominent Oprk1 splice variants that are expressed in the mouse and human brain cells and leukocytes. The activation of KOR results in reduced antibody production, an inhibition of phagocytic cell activity, an inhibition of T cell development, alterations in the production of various pro-inflammatory cytokines, chemokines, and the receptors for these mediators. Finally, the activation of KOR also leads to the regulation of receptor functional activity of chemokine receptors through the process of heterologous desensitization. The functional activity of KOR is important for the regulation of inflammatory responses and may provide opportunities for the development of therapeutics for the treatment of inflammatory disease states., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objectives: Central nervous system depressant medications (CNSD) including benzodiazepines, z-hypnotics and opioids are regularly prescribed for the older patient. These medications are linked to dependence and associated with severe side effects in some older patients. Consensus recommendations for this group suggest limiting their use. We have recently described a high proportion of long-term CNSD use and dependence among older in-hospital patients. In this study, we aim to investigate factors associated with pain intensity and presentation of pain among older adults with long-term use of CNSDs compared to non-users., Methods: Two hundred and forty six elderly hospitalised patients were recruited consecutively in a cross-sectional study. Data was collected from patients and electronic health records (EHR). Independent variables were sex, age, education, emotional symptoms (hospital anxiety and depression scale [HADS]), cognitive function (Mini-mental State Examination test [MMSE]), comorbidity (cumulative illness rating score - geriatrics [CIRS-G]), loneliness (the six-item De Jong Gierveld Loneliness Scale) and prolonged (≥4 weeks) use of any CNSDs or prolonged use of opioids (≥4 weeks). All variables, including pain intensity, were collected at one time point consistent with the cross-sectional study design. Statistical analyses included descriptive statistics and linear regression models using the above mentioned variables and pain intensity (visual analogue scale for pain intensity [VAS] pain 0-100) as outcome. Additional information regarding pain presentation was extracted from the patients' EHR., Results: Mean pain intensity VAS (SD) was 35.2 (30.4) and 18.1 (24.2) respectively, for patients with vs. without prolonged use of CNSDs. In the multivariable linear regression analysis, prolonged use of CNSDs and opioids were positively associated with pain intensity (VAS) (regression coefficient (95% CI) 20.7 (11.0; 30.3), p<0.001, and 19.8 (5.7; 33.8), p=0.006, respectively), while sex, age, education, MMSE, HADS, CIRS-G and loneliness scores were not. Pain related to back (23.2%) and lower extremities (23.2%) were most common pain sites, and those with one or more pain sites reported overall higher pain intensity compared to those with no reported pain sites (p<0.006)., Conclusions: Prolonged use of CNSD medications as well as prolonged use of opioids are both positively associated with pain intensity. The results may have implications for treatment and long-term pain management for older patients., (© 2021 Maria Torheim Bjelkarøy et al., published by De Gruyter, Berlin/Boston.)

Background: Adolescent idiopathic scoliosis (AIS) surgery is associated with significant postoperative pain. Remifentanil is a short-acting opioid that is often used as a component of total intravenous anesthesia. Remifentanil has been implicated in acute opioid tolerance and opioid-induced hyperalgesia, resulting in increased postoperative pain and opioid consumption. This retrospective study sought to investigate the relationship between the dose of intraoperative remifentanil and cumulative postoperative opioid consumption through 72 hours following surgery for pediatric AIS patients., Methods: We performed a retrospective chart review of adolescent patients undergoing posterior spine instrumentation under total intravenous general anesthesia at a single major pediatric center between January 2015 and October 2017. The relationship between intraoperative cumulative weight-adjusted remifentanil dose and logarithmic transformation of cumulative weight-adjusted opioid consumption through 72 hours following surgery was examined by regression analysis. A priori determined potential confounding variables were collected, including demographic data, perioperative analgesic agents (ie, ketamine, dexmedetomidine, and acetaminophen), surgical duration, vertebrae instrumented, and blood transfusion. Multivariable linear regression analysis was used to adjust for these possible confounding variables., Results: Eighty-nine patients met inclusion criteria, of which 78 had complete data for analysis. Univariable linear regression analysis revealed no association between remifentanil dose and opioid consumption through 72 hours following surgery (slope = 0.79 [95% confidence interval [CI], 0.61-0.98; R2 = 0.0039; P = .588]). After adjustment for possible confounding factors, no relationship between remifentanil dose (regression coefficient (coeff.) -0.08; 95% CI, -1.59 to 1.43; P = .912) and opioid consumption through 72 hours was found (slope =0.90 [95% CI, -0.65 to 2.46]; R2 = 0.1634). Similar results were obtained when the model was repeated for opioid consumption in postanesthesia care unit (PACU)., Conclusions: In this study examining adolescent patients undergoing surgery for idiopathic scoliosis, no association was found between the dose of intraoperative remifentanil and postoperative opioid consumption in the context of a propofol-based total intravenous anesthetic and multimodal analgesia. These results provide direction for future prospective controlled studies to further evaluate this relationship., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Objectives: The most notable adverse side effects of chronic morphine administration include tolerance and hyperalgesia. This study investigated the involvement of dorsal root ganglion (DRG) protein kinase Cɛ (PKCɛ) expression during chronic morphine administration and also considered the relationship between DRG PKCɛ expression and the substance P- neurokinin1 receptor ( SP- NK1R) activity., Methods: Thirty-six animals were divided into six groups (n=6) in this study. In the morphine and sham groups, rats received 10 µg intrathecal (i.t.) morphine or saline for eight consecutive days, respectively. Behavioral tests were performed on days 1 and 8 before and after the first injections and then 48 h after the last injection (day 10). In the treatment groups, rats received NK1R antagonist (L-732,138, 25 µg) daily, either alone or 10 min before a morphine injection, Sham groups received DMSO alone or 10 min before a morphine injection. Animals were sacrificed on days 8 and 10, and DRG PKCɛ and SP expression were analyzed by western blot and immunohistochemistry techniques, respectively., Results: Behavioral tests indicated that tolerance developed following eight days of chronic morphine injection. Hyperalgesia was induced 48 h after the last morphine injection. Expression of SP and PKCɛ in DRG significantly increased in rats that developed morphine tolerance on day 8 and hyperalgesia on day 10, respectively. NK1R antagonist (L-732,138) not only blocked the development of hyperalgesia and the increase of PKCɛ expression but also alleviated morphine tolerance., Conclusions: Our results provide evidence that DRG PKCɛ and SP-NK1R most likely participated in the generation of morphine tolerance and hyperalgesia. Pharmacological inhibition of SP-NK1R activity in the spinal cord suggests a role for NK1R and in restricting some side effects of chronic morphine. All experiments were performed by the National Institute of Health (NIH) Guidelines for the Care and Use of Laboratory Animals (NIH Publication No. 80-23, revised1996) and were approved by the Animal Ethics Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.MSP.REC.1396.130)., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

The high plasticity of root morphology, physiology, and function influences root-associated microbiomes. However, the variation in root-associated microbiome diversity and structures in response to root diameter at different root depths remains poorly understood. Here, we selected black locust (Robinia pseudoacacia L.) as a model plant to investigate the selection and network interactions of rhizospheric and root endophytic bacterial microbiomes associated with roots of different diameters (1, 1-2, and > 2 mm) among root depths of 0-100 cm via the Illumina sequencing of the 16S rRNA gene. The results showed that the alpha diversity of the root-associated bacterial communities decreased with increasing root diameters among different root depths; fewer orders with higher relative abundance, especially in the endosphere, were enriched in association with coarse roots (> 2 mm) than fine roots among root depths. Furthermore, the variation in the enriched bacterial orders associated with different root diameters was explained by bulk soil properties. Higher co-occurrence network complexity and stability emerged in the rhizosphere microbiomes of fine roots than those of coarse roots, in contrast to the situation in the endosphere microbiomes. In particular, the endosphere of roots with a diameter of 1-2 mm exhibited the lowest network complexity and stability and a high proportion of keystone taxa (e.g., Cytophagia, Flavobacteriia, Sphingobacteriia, β-Proteobacteria, and γ-Proteobacteria), suggesting a keystone taxon-reliant strategy in this transitional stage. In summary, this study indicated that root diameter at different root depths differentially affects rhizospheric and endophytic bacterial communities, which implies a close relationship between the bacterial microbiome, root function, and soil properties., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Ferroptosis is a newly identified regulated form of cell death, which is thought to play a major role in neurodegenerative diseases. In this review, we discuss recent studies elucidating the molecular mechanisms involved in the regulation and execution of ferroptotic cell death and also its role in the brain. Ferroptosis is regulated mainly via iron homeostasis, glutathione metabolism, and lipid peroxidation. Ferroptotic cell death and pro-ferroptotic factors are correlated with the etiopathogenesis of Parkinson's disease (PD) and Alzheimer's disease (AD). Ferroptosis and etiological factors act synergistically in PD and AD pathogenesis. Furthermore, several preclinical and clinical studies targeting ferroptosis in PD and AD have also shown positive results. Evidence of ferroptosis in the brain thus gives new insights into understanding neurodegenerative diseases. Ferroptosis studies in the brain are still in their infancy, but the existing pieces of evidence suggest a strong correlation between ferroptotic cell death and neurodegenerative diseases. Thus, ferroptosis might be a promising target for treating neurodegenerative diseases., (© 2021 Wiley Periodicals LLC.)

Background: Currently, opioids are the standard of care for postoperative pain management. Avoiding unnecessary opioid exposure in patients is of current interest because of widespread abuse., Methods: This is a prospective cohort study in which wide-awake, local anesthesia, no-tourniquet (WALANT) technique was used for 94 hand/upper extremity surgical patients and compared to patient cohorts undergoing similar procedures under monitored anesthesia care. Patients were not prescribed opioids postoperatively but were instead directed to use over-the-counter pain relievers. Pain scores on a visual analogue scale were collected from patients preoperatively, and on postoperative days 1 and 14. WALANT visual analogue scale scores were compared to those of the two patient cohorts who either did or did not receive postoperative opioids after undergoing similar procedures under monitored anesthesia care. Electronic medical records and New York State's prescription monitoring program, Internet System for Tracking Over-Prescribing, were used to assess prescription opioid-seeking. Information on sex, age, comorbidity burden, previous opioid exposure, and insurance coverage was also collected., Results: Decreased pain was reported by WALANT patients 14 days postoperatively compared to preoperatively and 1 day postoperatively, with a total group mean pain score of 0.37. This is lower than mean scores of monitored anesthesia care patients with and without postoperative opioids. Only two WALANT patients (2.1 percent) sought opioid prescriptions from outside providers. There was little evidence suggesting factors including sex, age, comorbidity burden, previous opioid exposure, or insurance status alter these results., Conclusion: WALANT may be a beneficial technique hand surgeons may adopt to mitigate use of postoperative opioids and reduce risk of abuse in patients., Clinical Question/level of Evidence: Therapeutic, II., (Copyright © 2021 by the American Society of Plastic Surgeons.)

The clinical features and neurobiology of pain and opioid use disorder (OUD) are inextricably linked. Despite emerging evidence supporting the negative impact of ongoing pain in the treatment of OUD, the pharmacological management of pain in the presence of OUD has received limited attention. We sought to systematically review the studies investigating pharmacotherapies for pain among persons with OUD. Eligible studies had participants with OUD and outcomes including evoked or spontaneous pain. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Out of 1,097 studies that met the search criteria, 12 studies provided data relevant to the research question-five laboratory studies and seven clinical trials. Random effects pooled estimates suggested no significant difference between groups at baseline but a response favoring the active treatment group over placebo, with nonsignificant heterogeneity between studies. Findings from these studies provide preliminary evidence for analgesic and antihyperalgesic effects of gabapentin, GABA agonists, and NMDA antagonists among persons with OUD. To establish the tradeoffs between the analgesic effects and abuse liability of these compounds, further well-controlled clinical trials are required among persons with OUD. This review also underscores the need for methodological enhancement in drug development for pain in OUD. Future research should address the clinical and neurobiological overlap between pain- and addiction-related phenomena. Transdisciplinary approaches may identify biomarkers of these shared phenomena and their neural substrates. The development of novel therapeutics for pain in OUD may be accelerated by such integration of pain and addiction research., (© 2020 Society for the Study of Addiction.)

Chimeric peptide MCRT (YPFPFRTic-NH 2 ) was a multifunctional ligand of opioid and neuropeptide FF (NPFF) receptors and reported to be potentially antalgic in acute tail-flick test. Here, we developed spared nerve injury (SNI) model to explore its efficacy in chronic neuropathic pain. Analgesic tolerance, opioid-induced hyperalgesia and gastrointestinal transit were measured for safety evaluation. Intracerebroventricular (i.c.v.) and intraplantar (i.pl.) injections were conducted as central and peripheral routes, respectively. Results demonstrated that MCRT alleviated neuropathic pain effectively and efficiently, with the ED 50 values of 4.93 nmol/kg at the central level and 3.11 nmol/kg at the peripheral level. The antagonist blocking study verified the involvement of mu-, delta-opioid and NPFF receptors in MCRT produced anti-allodynia. Moreover, the separation of analgesia from unwanted effects was preliminarily achieved and that MCRT caused neither analgesic tolerance nor hyperalgesia after chronic i.c.v. administration, nor constipation after i.pl. administration. Notably, the local efficacy of MCRT in SNI mice was about one thousandfold higher than morphine and ten thousandfold higher than pregabalin, indicating a great promise in the future treatment of neuropathic pain., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Spinocerebellar ataxia type 2 is a progressive neurodegenerative disorder due to an unstable expansion of a CAG repeat in the ATXN2 gene. Although weight loss has been associated with disease progression in several neurodegenerative conditions, it has been barely assessed in patients with spinocerebellar ataxia type 2., Objective: The objective of this study was to test whether body mass index is altered in patients with spinocerebellar ataxia type 2 with varying expansion sizes from early to late disease stages., Methods: A cross-sectional case-control study was performed, which included 222 clinically and molecularly diagnosed patients and 214 sex- and age-matched healthy individuals. ATXN2 genotypes and sex were considered as risk factors. Clinical outcomes included the body mass index, age at onset, disease duration, Scale for the Assessment and Rating of Ataxia score, disease stage, dysphagia, and progression rate. Multiple linear regression models were generated., Results: Body mass index was significantly decreased in male patients, but not in female patients, relative to control subjects. In addition to sex, body mass index was significantly associated with age at onset and progression rate. Conversely, body mass index, along with repeat length in ATXN2 expanded alleles and disease duration, was associated with Scale for the Assessment and Rating of Ataxia score. In addition, body mass index, along with the age at onset and the repeat length in ATXN2 normal and expanded alleles, has a significant influence on progression rate., Conclusions: Body mass index might be a useful biomarker of disease severity, particularly in male patients with spinocerebellar ataxia type 2 in the context of nutritional interventions or clinical trials assessing the efficacy of promising new drugs. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Medication overuse headache (MOH), the development or worsening of chronic headache resulting from frequent and excessive intake of medications used for acute treatment of headache, is a common secondary headache disorder and is associated with significant personal and societal burdens. The plausible physiologic mechanism is that chronic exposure to acute care migraine treatment leads to suppression of endogenous antinociceptive systems, consequently facilitating the trigeminal nociceptive process via up-regulation of the calcitonin gene-related peptide (CGRP) system. Recognizing and preventing its development is an integral aspect of migraine management, as medication overuse is a modifiable risk factor in the progression from episodic to chronic migraine. Over the years, MOH has been difficult to treat and has generated much controversy. Ongoing debates exist over the diagnostic criteria and treatment strategies, particularly regarding the roles of formal detoxification and preventive treatment. The arrival of the anti-CGRP monoclonal antibodies has also challenged our views of MOH and its treatment. This review outlines the evolution of MOH diagnostic criteria, presents the current understanding of MOH pathogenesis and discusses the debates over its development and treatment. Data on the efficacy of anti-CGRP monoclonal antibodies in the setting of medication overuse is also presented. These results indicate that patients with medication overuse, who are treated with these new medications, may not need to be detoxified in order to treat MOH. In light of these developments, it is likely that in the future MOH will be more readily diagnosed and treatment will result in better outcomes.

Fetal human neural stem cells (fhNSC) are of considerable interest as potential regenerative therapies for neuronal or glial degeneration or destruction resulting from genetic abnormalities, disease, or injury. Realization of this potential requires securing a supply of cells sufficient to meet the needs of transplantation, which are often tens to hundreds of millions of cells per dose. This challenge necessitates the establishment of safe and efficient cell banking protocols. Cryopreservation, involving the slow freezing or vitrification of cells, enables storage of fhNSC for prolonged periods, while maintaining their viability and multipotency required for clinical use. To optimize cryopreservation of fhNSC, attention has become focused on the composition of the medium used to effect cryopreservation by slow freezing/vitrification-i.e., the cryopreservative medium. The cryopreservative medium is typically specified as a dilution of a concentrated cryoprotectant, such as dimethylsulfoxide or glycerol, in cell culture medium that is often combined with serum or another source of necessary growth factors. The present work is devoted to a computational tool for determining the composition of a cryopreservative medium that can be combined with dissociated fhNSC resuspended in a certain volume of culture medium to achieve the criterion of stoichiometric dilution of cryoprotectant favorable to cell viability in the final mixture of cryopreservative medium and cells. © 2021 Wiley Periodicals LLC. Basic Protocol: Culture and passage of fhNSC, counting of enzymatically dissociated fhNSC, and quantitative formulation of cryomedium Alternate Protocol: Procedure when cell medium is not added to the cryomedium., (© 2021 Wiley Periodicals LLC.)

Volatile organic compounds (VOCs) released by plants serve as information and defense chemicals in mutualistic and antagonistic interactions and mitigate effects of abiotic stress. Passive and dynamic sampling techniques combined with gas chromatography-mass spectrometry analysis have become routine tools to measure emissions of VOCs and determine their various functions. More recently, knowledge of the roles of plant VOCs in the aboveground environment has led to the exploration of similar functions in the soil and rhizosphere. Moreover, VOC patterns have been recognized as sensitive and time-dependent markers of biotic and abiotic stress. This focused review addresses these developments by presenting recent progress in VOC sampling and analysis. We show advances in the use of small, inexpensive sampling devices and describe methods to monitor plant VOC emissions in the belowground environment. We further address latest trends in real-time measurements of volatilomes in plant phenotyping and most recent developments of small portable devices and VOC sensors for non-invasive VOC fingerprinting of plant disease. These technologies allow for innovative approaches to study plant VOC biology and application in agriculture., (© 2021 Society for Experimental Biology and John Wiley & Sons Ltd.)

Objective: To investigate the action mechanisms of electroacupuncture (EA) on postoperative immunosuppression., Methods: Male C57BL/6 mice (5`-7 weeks old) were randomly divided into: the sham injury group, the surgical trauma stressed group, the EA group [surgery + 2/100 Hz EA at Neiguan (PC 6)], and the EA+ Nal (surgery + EA + intraperitoneal injection of naloxone). Abdominal surgical trauma stress mice model was established. EA was performed on bilateral PC 6 acupoints by an EA apparatus (2/100 Hz) for 20 min once a day for 3 days. The mRNA expressions of MOR, DOR, and KOR in thymus and L3`-L5 dorsal root ganglions (DRG) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and the protein expressions of MOR, DOR, and KOR in thymus were measured by Western blot. Flow cytometry assay was used to detect the levels of T lymphocyte subtypes in the peripheral blood., Results: Surgical trauma induced decreased the mRNA expression level of MOR in both thymus (P<0.01) and L3`-L5 DRGs (P<0.05). Moreover, EA treatment not only significantly attenuated the MOR protein and mRNA expression in the thymus (both P<0.05), but also markedly increased expression of DOR and KOR opioid receptor in thymus (P<0.01). However, the mRNA expressions of opioid receptors were not regulated by EA in the DRG (all P>0.05). Furthermore, T lymphocyte population of CD3 + and CD4 + was decreased in the peripheral blood after surgical trauma (both P<0.01). EA treatment can significantly elevate the population of CD 3 + (P<0.01), CD 4 + (P<0.05) and CD 8 + T cells (P<0.01). Intraperitoneal injection of the non-selective opioid receptor antagonist naloxone blocked the up-regulation of T lymphocytes by EA., Conclusion: EA may improve postoperative immunosuppression through the peripheral opioid system.

Key Message: Piriformospora indica symbiosis promoted the growth and photosynthesis, and simultaneously enhanced the resistance against insect herbivory by regulating sporamin-dependent defense in sweet potato. Piriformospora indica (P. indica), a versatile endophytic fungus, promotes the growth and confers resistance against multiple stresses by root colonization in plant hosts. In this study, the effects of P. indica colonization on the growth, physiological change, and herbivore resistance of leaf-vegetable sweet potato cultivar were investigated. P. indica symbiosis significantly improved the biomass in both above- and under-ground parts of sweet potato plants. In comparison with the non-colonized plants, the content of photosynthetic pigments and the efficiency of photosynthesis were increased in P. indica-colonized sweet potato plants. Further investigation showed that the activity of catalase was enhanced in both leaves and roots of sweet potato plants after colonization, but ascorbate peroxidase, peroxidase, and superoxide dismutase were not enhanced. Furthermore, the interaction between P. indica and sweet potato plants also showed the biological function in jasmonic acid (JA)-mediated defense. The plants colonized by P. indica had greatly increased JA accumulation and defense gene expressions, including IbNAC1, IbbHLH3, IbpreproHypSys, and sporamin, leading to elevated trypsin inhibitory activity, which was consistent with a reduced Spodoptera litura performance when larvae fed on the leaves of P. indica-colonized sweet potato plants. The root symbiosis of P. indica is helpful for the plant promoting growth and development and has a strong function as resistance inducers against herbivore attack in sweet potato cultivation by regulating sporamin-dependent defense.

Morphine is a key drug for the treatment of pain but its side effects limit its clinical application. MEL-0614, an endomorphin-1 analog, has fewer side effects than morphine in addition to its powerful analgesic effect. In this study, we measured the effect of morphine and MEL-0614 on hyperalgesia (7 days) and neuropathic allodynia (14 days) after thermal, mechanical, and cold stimulation. We found that after four and eight consecutive days of intrathecal administration (1, 3, and 10 nmol), morphine induced severe hyperalgesia and neuropathic allodynia, respectively. MEL-0614 did not induce hyperalgesia at low doses (1 and 3 nmol) and had a mitigating effect on morphine-induced neuropathic exacerbations in spared nerve injury mice. Hyperalgesia was blocked by Dynorphin A (1-17) antibody but not by an opioid receptor antagonist. To explore the reasons for the different results of morphine and MEL-0614, we used quantitative PCR and immunofluorescence to explore the effects of both on N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B), microglia marker iba-1, and inflammatory mediators. After 8 days of consecutive administration, morphine (10 nmol) promoted an increase in the number of NR2B, iba-1, and inflammatory mediators in the spinal cord of mice. MEL-0614 (10 nmol) had no significant effect on these factors, and after co-administration with morphine, the expression of NR2B, iba-1, and inflammatory mediators was lower than that with morphine injection alone. Our research showed the advantage of MEL-0614 in terms of hyperalgesia and neuropathic allodynia, which may provide clinical relief of hyperalgesia and neuropathic allodynia caused by morphine., (© 2020 International Society for Neurochemistry.)

Background: Huntington's disease is a rare, severe, inherited neurodegenerative disease in which we assessed the safety and efficacy of grafting human fetal ganglionic eminence intrastriatally., Methods: Patients at the early stage of the disease were enrolled in the Multicentric Intracerebral Grafting in Huntington's Disease trial, a delayed-start phase II randomized study. After a run-in period of 12 months, patients were randomized at month 12 to either the treatment group (transplanted at month 13-month 14) or the control group and secondarily treated 20 months later (month 33-month 34). The primary outcome was total motor score compared between both groups 20 months postrandomization (month 32). Secondary outcomes included clinical, imaging, and electrophysiological findings and a comparison of pregraft and postgraft total motor score slopes during the entire study period (month 0-month 52) regardless of the time of transplant., Results: Of 54 randomized patients, 45 were transplanted; 26 immediately (treatment) and 19 delayed (control). Mean total motor score at month 32 did not differ between groups (treated controls difference in means adjusted for M12: +2.9 [95% confidence interval, -2.8 to 8.6]; P = 0.31). Its rate of decline after transplantation was similar to that before transplantation. A total of 27 severe adverse events were recorded in the randomized patients, 10 of which were related to the transplant procedure. Improvement of procedures during the trial significantly decreased the frequency of surgical events.We found antihuman leucocytes antigen antibodies in 40% of the patients., Conclusion: No clinical benefit was found in this trial. This may have been related to graft rejection. Ectopia and high track number negatively influence the graft outcome. Procedural adjustments substantially improved surgical safety. (ClinicalTrials.gov NCT00190450.) © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) has demonstrated its efficacy on motor complications in advanced Parkinson's disease (PD) but does not modify disease progression. Genetic forms of PD have been associated with different cognitive progression profiles., Objective: To assess the effect of PD-related genetic mutations on cognitive outcome after STN-DBS., Methods: Patients with STN-DBS were screened for LRRK2, GBA, and PRKN mutations at the Pitié-Salpêtrière Hospital between 1997 and 2009. Patients with known monogenetic forms of PD from six other centers were also included. The Mattis Dementia Rating Scale (MDRS) was used to evaluate cognition at baseline and one-year post-surgery. The standardized Unified PD Rating Scale (UPDRS) evaluation On and Off medication/DBS was also administered. A generalized linear model adjusted for sex, ethnicity, age at onset, and disease duration was used to evaluate the effect of genetic factors on MDRS changes., Results: We analyzed 208 patients (131 males, 77 females, 54.3 ± 8.8 years) including 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations. PRKN patients were younger and had a longer disease duration at baseline. A GBA mutation was the only significant genetic factor associated with MDRS change (β = -2.51, p = 0.009). GBA mutation carriers had a more pronounced post-operative MDRS decline (3.2 ± 5.1) than patients with LRRK2 (0.9 ± 4.8), PRKN (0.5 ± 2.7) or controls (1.4 ± 4.4). The motor response to DBS was similar between groups., Conclusion: GBA mutations are associated with early cognitive decline following STN-DBS. Neuropsychological assessment and discussions on the benefit/risk ratio of DBS are particularly important for this population., (Copyright © 2020 Elsevier Ltd. All rights reserved.)