TRPM7 in neurodevelopment and therapeutic prospects for neurodegenerative disease.

Neurodevelopment, a complex and highly regulated process, plays a foundational role in shaping the structure and function of the nervous system. The transient receptor potential melastatin 7 (TRPM7), a divalent cation channel with an α-kinase domain, mediates a wide range of cellular functions, including proliferation, migration, cell adhesion, and survival, all of which are essential processes in neurodevelopment. The global knockout of either TRPM7 or TRPM7-kinase is embryonically lethal, highlighting the crucial role of TRPM7 in development in vivo. Subsequent research further revealed that TRPM7 is indeed involved in various key processes throughout neurodevelopment, from maintaining pluripotency during embryogenesis to regulating gastrulation, neural tube closure, axonal outgrowth, synaptic density, and learning and memory. Moreover, a discrepancy in TRPM7 expression and/or function has been associated with neuropathological conditions, including ischemic stroke, Alzheimer's disease, and Parkinson's disease. Understanding the mechanisms of proper neurodevelopment may provide us with the knowledge required to develop therapeutic interventions that can overcome the challenges of regeneration in CNS injuries and neurodegenerative diseases. Considering that ion channels are the third-largest class targeted for drug development, TRPM7's dual roles in development and degeneration emphasize its therapeutic potential. This review provides a comprehensive overview of the current literature on TRPM7 in various aspects of neurodevelopment. It also discusses the links between neurodevelopment and neurodegeneration, and highlights TRPM7 as a potential therapeutic target for neurodegenerative disorders, with a focus on repair and regeneration.

In vitro anti-Helicobacter pylori activity and antivirulence activity of cetylpyridinium chloride.

The primary treatment method for eradicating Helicobacter pylori (H. pylori) infection involves the use of antibiotic-based therapies. Due to the growing antibiotic resistance of H. pylori, there has been a surge of interest in exploring alternative therapies. Cetylpyridinium chloride (CPC) is a water-soluble and nonvolatile quaternary ammonium compound with exceptional broad-spectrum antibacterial properties. To date, there is no documented or described specific antibacterial action of CPC against H. pylori. Therefore, this study aimed to explore the in vitro activity of CPC against H. pylori and its potential antibacterial mechanism. CPC exhibited significant in vitro activity against H. pylori, with MICs ranging from 0.16 to 0.62 µg/mL and MBCs ranging from 0.31 to 1.24 µg/mL. CPC could result in morphological and physiological modifications in H. pylori, leading to the suppression of virulence and adherence genes expression, including flaA, flaB, babB, alpA, alpB, ureE, and ureF, and inhibition of urease activity. CPC has demonstrated in vitro activity against H. pylori by inhibiting its growth, inducing damage to the bacterial structure, reducing virulence and adherence factors expression, and inhibiting urease activity.

Development and Validation of Analytical Procedure for Elemental Impurities in Rosuvastatin Calcium Tablets by ICP-MS and Microwave Digestion.

Rosuvastatin calcium is a widely used 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. To establish a control strategy for the elemental impurities, a new digestion method combined with an inductively coupled plasma-mass spectrometer (ICP-MS) was developed and validated by our team to determine elements Cd, Pb, As, Hg, Co, V, and Ni in rosuvastatin calcium tablets, which digest the sample perfectly even in the presence of a large number of excipients, especially titanium dioxide. The measurement mode was collision cell mode with kinetic energy discrimination (KED). 209Bi+, 115In+, and 89Y+ were chosen as internal standard elements. The recoveries of the limit of quantitation (LOQ) ranged from 90.5% to 106.4%, concentrations of the abovementioned elements in LOQ were 0.25 µg·L-1, 0.25 µg·L-1, 0.75 µg·L-1, 1.5 µg·L-1, 2.5 µg·L-1, 5 µg·L-1, and 8 µg·L-1 , respectively, linear correlation coefficients were above 0.9997, the recoveries in accuracy item ranged from 91.8% to 103.6%, and relative standard deviations (RSDs) of recovery in precision were not more than 1.8%, reflecting a reliable method of high sensitivity, strong anti-interference capacity, and good precision, and that it was suitable for the determination of elemental impurities in drugs.

Neurodegeneration and glial morphological changes are both prevented by TRPM2 inhibition during the progression of a Parkinson's disease mouse model.

Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuron death and neuroinflammation. Emerging evidence points to the involvement of the transient receptor potential melastatin 2 (TRPM2) channel in neuron death and glial activation in several neurodegenerative diseases. However, the involvement of TRPM2 in PD and specifically its relation to the neuroinflammation aspect of the disease remains poorly understood. Here, we hypothesized that AG490, a TRPM2 inhibitor, can be used as a treatment in a mouse model of PD. Mice underwent stereotaxic surgery for 6-hydroxydopamine (6-OHDA) administration in the right striatum. Motor behavioral tests (apomorphine, cylinder, and rotarod) were performed on day 3 post-injection to confirm the PD model induction. AG490 was then daily injected i.p. between days 3 to 6 after surgery. On day 6, motor behavior was assessed again. Substantia nigra (SNc) and striatum (CPu) were collected for immunohistochemistry, immunoblotting, and RT-qPCR analysis on day 7. Our results revealed that AG490 post-treatment reduced motor behavior impairment and nigrostriatal neurodegeneration. In addition, the compound prevented TRPM2 upregulation and changes of the Akt/GSK-3ß/caspase-3 signaling pathway. The TRPM2 inhibition also avoids the glial morphology changes observed in the PD group. Remarkably, the morphometrical analysis revealed that the ameboid-shaped microglia, found in 6-OHDA-injected animals, were no longer present in the AG490-treated group. These results indicate that AG490 treatment can reduce dopaminergic neuronal death and suppress neuroinflammation in a PD mouse model. Inhibition of TRPM2 by AG490 could then represent a potential therapeutical strategy to be evaluated for PD treatment.

Transient Receptor Potential Melastatin 7 (TRPM7) Ion Channel Inhibitors: Preliminary SAR and Conformational Studies of Xenicane Diterpenoids from the Hawaiian Soft Coral Sarcothelia edmondsoni.

Waixenicin A, a xenicane diterpene from the octocoral Sarcothelia edmondsoni, is a selective, potent inhibitor of the TRPM7 ion channel. To study the structure-activity relationship (SAR) of waixenicin A, we isolated and assayed related diterpenes from S. edmondsoni. In addition to known waixenicins A (1) and B (2), we purified six xenicane diterpenes, 7S,8S-epoxywaixenicins A (3) and B (4), 12-deacetylwaixenicin A (5), waixenicin E (6), waixenicin F (7), and 20-acetoxyxeniafaraunol B (8). We elucidated the structures of 3-8 by NMR and MS analyses. Compounds 1, 2, 3, 4, and 6 inhibited TRPM7 activity in a cell-based assay, while 5, 7, and 8 were inactive. A preliminary SAR emerged showing that alterations to the nine-membered ring of 1 did not reduce activity, while the 12-acetoxy group, in combination with the dihydropyran, appears to be necessary for TRPM7 inhibition. The bioactive compounds are proposed to be latent electrophiles by formation of a conjugated oxocarbenium ion intermediate. Whole-cell patch-clamp experiments demonstrated that waixenicin A inhibition is irreversible, consistent with a covalent inhibitor, and showed nanomolar potency for waixenicin B (2). Conformational analysis (DFT) of 1, 3, 7, and 8 revealed insights into the conformation of waixenicin A and congeners and provided information regarding the stabilization of the proposed pharmacophore.

Neuroprotective effects of dendrobium endophytes metabolites in SH-SY5Y cells via the Nrf2/Keap1 pathway.

Recent studies have revealed that endophytes in plants can produce metabolites with activity that is comparable to or identical to the host. Dendrobine has attracted much attention in the field of neurodegenerative diseases by exhibiting anti-oxidative stress and neuroprotective effects. This study aimed to investigate the protective effects and mechanisms of metabolites of dendrobium endophytes Pseudomonas protegens CM-YJ44 and Priestia megaterium D-HT207 against H2O2-induced oxidative stress injury in SH-SY5Y cells. Results showed that there were 50 neuroprotective compounds in CM-YJ44 and 72 neuroprotective compounds in D-HT207. Those both increased significantly cell viability, decreased contents of ROS in H2O2-induced SH-SY5Y cells. It was confirmed that metabolites of CM-YJ44 and D-HT207 inhibited the H2O2-induced oxidative stress injury in SH-SY5Y cells, which mechanism is related to inhibition of ROS production, alteration of MMP, and inhibition of apoptosis and inflammatory factors expression via the Nrf2/Keap1 pathway.

In vitro anti-Helicobacter pylori activity and the underlining mechanism of an empirical herbal formula - Hezi Qingyou.

Background: Helicobacter pylori (H. pylori) is thought to primarily colonize the human stomach and lead to various gastrointestinal disorders, such as gastritis and gastric cancer. Currently, main eradication treatment is triple or quadruple therapy centered on antibiotics. Due to antibiotic resistance, the eradication rate of H. pylori is decreasing gradually. Therefore, searching for anti-H. pylori drugs from herbal sources has become a strategy for the treatment. Our team proposed a Hezi Qingyou Formula (HZQYF), composed of Chebulae Fructus, Ficus hirta Vahl and Cloves, and studied its anti-H. pylori activity and mechanism. Methods: Chemical components of HZQYF were studied using UHPLC-MS/MS and HPLC. Broth microdilution method and agar dilution method were used to evaluate HZQYF's antibacterial activity. The effects of HZQYF on expression of adhesion genes (alpA, alpB, babA), urease genes (ureE, ureF), and flagellar genes (flaA, flaB) were explored using Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) technology. Effects on morphology and permeability of the extracellular membrane were studied using scanning electron microscopy (SEM) and N-phenylnaphthalen-1-amine (NPN) uptake. Effect on urease activity was studied using a urease kinetics analysis in vitro. Immunofluorescence staining method was used to examine the effect on adhesion. Western blot was used to examine the effect on cagA protein. Results: Minimum inhibitory concentration (MIC) values of the formula against H. pylori clinical strains and standard strains were 80-160 µg/mL, and minimum bactericidal concentration (MBC) values were 160-320 µg/mL. The formula could down-regulate the expression of adhesion genes (alpA, alpB, babA), urease genes (ureE, ureF) and flagellar genes (flaA, flaB), change the morphology of H. pylori, increase its extracellular membrane permeability, and decrease its urease activity. Conclusion: Present studies confirmed that HZQYF had promising in vitro anti-H. pylori activities and demonstrated its possible mechanism of action by down-regulating the bacterial adhesion, urease, and flagellar gene expression, which provided scientific bases for further clinical investigations.

1,3,6-Trigalloylglucose: A Novel Potent Anti-Helicobacter pylori Adhesion Agent Derived from Aqueous Extracts of Terminalia chebula Retz.

1,3,6-Trigalloylglucose is a natural compound that can be extracted from the aqueous extracts of ripe fruit of Terminalia chebula Retz, commonly known as "Haritaki". The potential anti-Helicobacter pylori (HP) activity of this compound has not been extensively studied or confirmed in scientific research. This compound was isolated using a semi-preparative liquid chromatography (LC) system and identified through Ultra-high-performance liquid chromatography-MS/MS (UPLC-MS/MS) and Nuclear Magnetic Resonance (NMR). Its role was evaluated using Minimum inhibitory concentration (MIC) assay and minimum bactericidal concentration (MBC) assay, scanning electron microscope (SEM), inhibiting kinetics curves, urea fast test, Cell Counting Kit-8 (CCK-8) assay, Western blot, and Griess Reagent System. Results showed that this compound effectively inhibits the growth of HP strain ATCC 700392, damages the HP structure, and suppresses the Cytotoxin-associated gene A (Cag A) protein, a crucial factor in HP infection. Importantly, it exhibits selective antimicrobial activity without impacting normal epithelial cells GES-1. In vitro studies have revealed that 1,3,6-Trigalloylglucose acts as an anti-adhesive agent, disrupting the adhesion of HP to host cells, a critical step in HP infection. These findings underscore the potential of 1,3,6-Trigalloylglucose as a targeted therapeutic agent against HP infections.

SNAP-25, but not SNAP-23, is essential for photoreceptor development, survival, and function in mice.

SNARE-mediated vesicular transport is thought to play roles in photoreceptor glutamate exocytosis and photopigment delivery. However, the functions of Synaptosomal-associated protein (SNAP) isoforms in photoreceptors are unknown. Here, we revisit the expression of SNAP-23 and SNAP-25 and generate photoreceptor-specific knockout mice to investigate their roles. Although we find that SNAP-23 shows weak mRNA expression in photoreceptors, SNAP-23 removal does not affect retinal morphology or vision. SNAP-25 mRNA is developmentally regulated and undergoes mRNA trafficking to photoreceptor inner segments at postnatal day 9 (P9). SNAP-25 knockout photoreceptors develop normally until P9 but degenerate by P14 resulting in severe retinal thinning. Photoreceptor loss in SNAP-25 knockout mice is associated with abolished electroretinograms and vision loss. We find mistrafficked photopigments, enlarged synaptic vesicles, and abnormal synaptic ribbons which potentially underlie photoreceptor degeneration. Our results conclude that SNAP-25, but not SNAP-23, mediates photopigment delivery and synaptic functioning required for photoreceptor development, survival, and function.

UHPLC-MS/MS Method Development and Validation for the Genotoxic Impurities Trimethyl Phosphate and Triisopropyl Phosphate of Elagolix Sodium.

Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary gland to treat moderate to severe pain associated with endometriosis. To keep the safety and quality of the drug, a fast quantitative method by reversed-phase ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry has been developed and validated for the identification, assay and estimation of potential genotoxic impurities trimethyl phosphate and triisopropyl phosphate in commercial batches of this active pharmaceutical ingredient in accordance with International Conference on Harmonization guidelines Q2 and M7. The method was validated by assessing specificity, sensitivity, linearity, the limit of quantification and detection, accuracy, precision and robustness for above analytes at a very low concentration, whose quantification and detection limits reached to 24 and 4.8 pg/ml, respectively, and the total run time for a single injection was 6 min.

The accelerated organ senescence and proteotoxicity in thyrotoxicosis mice.

The mechanism of aging has always been the focus of research, because aging is related to disease susceptibility and seriously affects people's quality of life. The diseases also accelerate the aging process, especially the pathological changes of substantive organs, such as cardiac hypertrophy, severely shortened lifespan. So, lesions in organs are both a consequence and a cause of aging. However, the disease in a given organ is not in isolation but is a systemic problem. Our previous study found that thyrotoxicosis mice model has aging characteristics including immunosenescence, lipotoxicity, malnutrition. But all these characteristics will lead to organ senescence, therefore, this study continued to study the aging changes of important organs such as heart, liver, and kidney in thyrotoxicosis mice using tandem mass tags (TMT) proteomics method. The results showed that the excess thyroxine led to cardiac hypertrophy. In the liver, the ability to synthesize functional proteins, detoxify, and metabolism were declined. The effect on the kidney was the decreased ability of detoxify and metabolism. The main finding of the present study was that the acceleration of organ senescence by excess thyroxine was due to proteotoxicity. The shared cause of proteotoxicity in the three organs included the intensify of oxidative phosphorylation, the redundancy production of ribosomes, and the lack of splicing and ubiquitin proteasome system function. Totally, proteotoxicity was another parallel between thyrotoxicosis and aging in addition to lipotoxicity. Our research provided a convenient and appropriate animal model for exploring aging mechanism and antiaging drugs.

A small molecule 20C from Gastrodia elata inhibits α-synuclein aggregation and prevents progression of Parkinson's disease.

Parkinson's disease (PD) is pathologically manifested by the aggregation of α-synuclein, which has been envisioned as a promising disease-modifying target for PD. Here, we identified 20C, a bibenzyl compound derived from Gastrodia elata, able to inhibit the aggregation of A53T variants of α-synuclein directly in vitro. Computational analysis revealed that 20C binds to cavities in mature α-synuclein fibrils, and it indeed displays a strong interaction with α-synuclein and reduced their ß-sheet structure by microscale thermophoresis and circular dichroism, respectively. Moreover, incubating neural cells with 20C reduced the amounts of α-synuclein inclusions significantly. The treatment of A53T α-Syn transgenic mice with 20C significantly reduces the toxic α-synuclein levels, improves behavioral performance, rescues dopaminergic neuron, and enhances functional connections between SNc and PD associated brain areas. The transcriptome analysis of SNc demonstrated that 20C improves mitochondrial dynamics, which protects mitochondrial morphology and function against α-synuclein induced degeneration. Overall, 20C appears to be a promising candidate for the treatment of PD.

Sanguisorba officinalis L. enhances the 5-fluorouracil sensitivity and overcomes chemoresistance in 5-fluorouracil-resistant colorectal cancer cells via Ras/MEK/ERK and PI3K/Akt pathways.

Sanguisorba officinalis L., a traditional Chinese medicine (TCM) called DiYu (DY) in China, has a strong tradition of utilization as a scorching, blood-cooling, and hemostatic medication, and was used for cancer prevention and treatment due to its potential immune-enhancing and hematological toxicity-reducing effects. Previous studies have reported significant effects of DY on cancers including colorectal cancer (CRC), which is one of the most common malignancies worldwide. The first-line cure 5-fluorouracil (5-FU) plays decisive commerce in the sedative of CRC as a clinically available chemotherapeutic agent. One of the primary causes of cancer treatment failure is the acquisition of chemotherapy drug resistance. In order to successfully combat the emergence of chemoresistance, it is essential to identify herbs or traditional Chinese medicine that have adjuvant therapeutic effects on CRC. Therefore, this study aimed to determine whether DY could improve the sensitivity, conquer the chemoresistance of 5-FU-resistant CRC cells, and investigate its intrinsic mechanism. Materials and methods: MTT, Hoechst 33258 staining, and flow cytometry assays were used to determine the anticancer activity of DY alone or in combination with 5-FU against 5-FU-resistant CRC cells (RKO-R and HCT15-R) and wound healing assays were conducted to detect cell migration. Transcriptomic techniques were carried out to explore the effect and mechanism of DY on drug-resistant CRC cells. Western Blot and RT q-PCR assays were performed to validate the mechanism by which DY overcomes drug-resistant CRC cells. Results: These results indicated that DY alone or in combination with 5-FU significantly inhibited the proliferation and the migration of resistant CRC cells, and potentiated the susceptibility of 5-FU to drug-resistant CRC cells. GO and KEGG enrichment analysis showed that the mechanisms of drug resistance in CRC cells and DY against drug-resistant CRC cells highly overlapped, involved in the modulation of biological processes such as cell migration, positive regulation of protein binding and cytoskeleton, and MAPK (Ras-ERK-MEK), PI3K/Akt, and other signaling pathways. Moreover, DY can mediate the expression of p-R-Ras, p-ERK1/2, p-MEK1/2, p-PI3K, p-AKT, HIF-1A and VEGFA proteins. In addition, DY significantly suppressed the expression of AKT3, NEDD9, BMI-1, and CXCL1 genes in resistant CRC cells. Conclusion: In conclusion, DY could inhibit the proliferation and migration of 5-FU-resistant cells and strengthen the sensitivity of 5-FU to CRC-resistant cells. Furthermore, DY may prevail over chemoresistance through the Ras/MEK/ERK and PI3K/Akt pathways. These findings imply that DY may be a potential drug for clinical treatment or adjuvant treatment of drug-resistant CRC.

Pathological findings in congenital diaphragmatic hernia on necropsy studies: A single-center case series.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is associated with high mortality rates and significant pulmonary morbidities. The objective of this study was to delineate the histopathological features observed in necropsies of CDH patients and correlate these with their clinical manifestations. METHODS: We retrospectively reviewed the postmortem findings and corresponding clinical characteristics in eight CDH cases from 2017 to July 2022. RESULTS: The median survival time was 46 (8-624) hours. Autopsy reports showed that diffuse alveolar damage (congestion and hemorrhage) and hyaline membrane formation were the primary pathological lung changes observed. Notably, despite significant reduction in lung volume, the lung development appeared normal in 50% of the cases, while lobulated deformities were present in three (37.5%) cases. All patients displayed a large patent ductus arteriosus (PDA) and a patent foramen ovale, resulting in increased right ventricle (RV) volume, and myocardial fibers appeared slightly congested and swollen. The pulmonary vessels indicated thickening of the arterial media and adventitia. Lung hypoplasia and diffuse lung damage resulted in impaired gas exchange, while PDA and pulmonary hypertension led to RV failure, subsequent organ dysfunction and ultimately death. CONCLUSIONS: Patients with CDH typically succumb to cardiopulmonary failure, a condition driven by a complex interplay of pathophysiological factors. This complexity accounts for the unpredictable response to currently available vasodilators and ventilation therapies.

Neuronal SNAP-23 is critical for synaptic plasticity and spatial memory independently of NMDA receptor regulation.

SNARE-mediated membrane fusion plays a crucial role in presynaptic vesicle exocytosis and also in postsynaptic receptor delivery. The latter is considered particularly important for synaptic plasticity and learning and memory, yet the identity of the key SNARE proteins remains elusive. Here, we investigate the role of neuronal synaptosomal-associated protein-23 (SNAP-23) by analyzing pyramidal-neuron specific SNAP-23 conditional knockout (cKO) mice. Electrophysiological analysis of SNAP-23 deficient neurons using acute hippocampal slices showed normal basal neurotransmission in CA3-CA1 synapses with unchanged AMPA and NMDA currents. Nevertheless, we found theta-burst stimulation-induced long-term potentiation (LTP) was vastly diminished in SNAP-23 cKO slices. Moreover, unlike syntaxin-4 cKO mice where both basal neurotransmission and LTP decrease manifested changes in a broad set of behavioral tasks, deficits of SNAP-23 cKO are more limited to spatial memory. Our data reveal that neuronal SNAP-23 is selectively crucial for synaptic plasticity and spatial memory without affecting basal glutamate receptor function.

A novel small-molecular CCR5 antagonist promotes neural repair after stroke.

Chemokine receptor 5 (CCR5) is one of the main co-receptors of HIV-1, and has been found to be a potential therapeutic target for stroke. Maraviroc is a classic CCR5 antagonist, which is undergoing clinical trials against stroke. As maraviroc shows poor blood-brain barrier (BBB) permeability, it is of interest to find novel CCR5 antagonists suitable for neurological medication. In this study we characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 was discovered in screening millions compounds in the Chemdiv library based on the molecular docking diagram of CCR5 and maraviroc. We found that A14 dose-dependently inhibited the CCR5 activity with an IC50 value of 4.29 µM. Pharmacodynamic studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and vivo. In a SH-SY5Y cell line overexpressing CCR5, A14 (0.1, 1 µM) significantly alleviated OGD/R-induced cell injury. We found that the expression of CCR5 and its ligand CKLF1 was significantly upregulated during both acute and recovery period in focal cortical stroke mice; oral administration of A14 (20 mg·kg-1·d-1, for 1 week) produced sustained protective effect against motor impairment. A14 treatment had earlier onset time, lower onset dosage and much better BBB permeability compared to maraviroc. MRI analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of treatment. We further revealed that A14 treatment blocked the protein-protein interaction between CCR5 and CKLF1, increasing the activity of CREB signaling pathway in neurons, thereby improving axonal sprouting and synaptic density after stroke. In addition, A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune cells. These results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke. A14 blocked the protein-protein interaction between CKLF1 and CCR5 after stroke by binding with CCR5 stably, improved the infarct area and promoted motor recovery through reversing the CREB/pCREB signaling which was inhibited by activated CCR5 Gαi pathway, and benefited to the dendritic spines and axons sprouting.

Interleukin-6 as a marker of Huntington's disease progression: Systematic review and meta-analysis.

Huntington's disease (HD) is a rare, inherited disorder with a broad spectrum of manifestations that vary with disease severity and progression. Although genetic testing can readily confirm the initial diagnosis of HD, markers sensitive to HD progression are needed to aid the development of individual treatment plans. The current analysis aims to identify plasma Interleukin-6 (IL-6) as a marker of disease progression in HD patients. A systematic search of PubMed and Medline from conception through October 2021 was conducted. Studies reporting plasma IL-6 levels of mutation-positive HD patients and healthy controls that met inclusion criteria were selected. The search strategy collected 303 studies, 9 of which met analysis inclusion criteria. From included studies, plasma IL-6 levels of 469 individuals with the HD mutation and 206 healthy controls were collected. Plasma IL-6 levels were meta-analytically compared between healthy controls and individuals with the confirmed HD mutation at all stages of disease and correlated to performance on standardized measures of total cognitive and motor function. Plasma IL-6 was significantly increased in HD groups compared to controls (g = 0.73, 95% CI = 0.31,1.16, P < 0.01) and increased significantly throughout most stages of disease progression, notably between pre-manifest and manifest (g = 0.31, 95% CI = 0.04,0.59, P < 0.05) and early and moderate HD stages (g = 0.52, 95% CI = 0.18,0.86, P < 0.01). Significant correlations between plasma IL-6 levels and HD symptomatic progression were identified, with increased cytokine levels associated with more severe motor impairments (r = 0.179, 95% CI = 0.0479,0.304, P = 0.008) and more extreme disabilities in activities of daily living and/or work tasks (r = -0.229, 95% CI = -0.334, -0.119, P < 0.001). Conclusively, plasma IL-6 levels correlate with disease and motor symptom progression and may act as a viable marker for clinical use. Analysis is limited by small study numbers and highlights the need for future work to identify definitive ranges or rates of change of plasma IL-6 levels that correlate to progressive HD disease states.

A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke.

Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-hypoxia inducible factor 1α (HIF-1α) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke.

Antimicrobial activity and comparative metabolomic analysis of Priestia megaterium strains derived from potato and dendrobium.

The growth of endophytic bacteria is influenced by the host plants and their secondary metabolites and activities. In this study, P. megaterium P-NA14 and P. megaterium D-HT207 were isolated from potato tuber and dendrobium stem respectively. They were both identified as Priestia megaterium. The antimicrobial activities and metabolites of both strains were explored. For antimicrobial activities, results showed that P. megaterium P-NA14 exhibited a stronger inhibition effect on the pathogen of dendrobium, while P. megaterium D-HT207 exhibited a stronger inhibition effect on the pathogen of potato. The supernatant of P. megaterium P-NA14 showed an inhibition effect only on Staphylococcus aureus, while the sediment of P. megaterium D-HT207 showed an inhibition effect only on Escherichia coli. For metabolomic analysis, the content of L-phenylalanine in P. megaterium P-NA14 was higher than that of P. megaterium D-HT207, and several key downstream metabolites of L-phenylalanine were associated with inhibition of S. aureus including tyrosine, capsaicin, etc. Therefore, we speculated that the different antimicrobial activities between P. megaterium P-NA14 and P. megaterium D-HT207 were possibly related to the content of L-phenylalanine and its metabolites. This study preliminarily explored why the same strains isolated from different hosts exhibit different activities from the perspective of metabolomics.