Transcriptome-wide N6-methyladenosine (m6A) methylation profiling of long non-coding RNAs in ovarian endometriosis.

N6-methyladenosine (m6A) methylation is the most prevalent internal epigenetic posttranscriptional mechanism for regulating mammalian RNA. Despite recent advances in determining the biological functions of m6A methylation, its association with the pathology of ovarian endometriosis remains uncertain. Herein, we performed m6A transcriptome-wide profiling to identify key lncRNAs with m6A modification involved in ovarian endometriosis development by bioinformatics analysis. We found the total m6A level was lower in ovarian endometriosis than in normal endometrium samples, with 9663 m6A peaks associated with 8989 lncRNAs detected in ovarian endometriosis and 9902 m6A peaks associated with 9210 lncRNAs detected in normal endometrium samples. These m6A peaks were primarily enriched within AAACU motifs. Functional enrichment analysis indicated that pathways involving the regulation of adhesion and development were significantly enriched in these differentially methylated lncRNAs. The regulatory relationships among lncRNAs, microRNAs (miRNAs), and mRNAs were identified by competing endogenous RNA (ceRNA) analysis and determination of the network regulating lncRNA-mRNA expression. Several specific lncRNA, including LINC00665, LINC00937, FZD10-AS1, DIO3OS and GATA2-AS1 which were differently expressed and modified by m6A, were validated using qRT-PCR and its interaction with infiltrating immune cells was explored. Furthermore, we found LncRNA DIO3OS promotes the invasion and migration of Human endometrial stromal cells (THESCs) and ALKBH5 regulates the expression of the lncRNA DIO3OS through m6A modification in vitro. Our study firstly revealed the transcriptome-wide map of m6A modification in lncRNAs of ovarian endometriosis. These findings may enable the determination of the underlying mechanism governing the pathogenesis of ovarian endometriosis and provide theoretical basis for further deeper research on the role of m6A in the development of ovarian endometriosis.

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

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

The impacts of pullulan soaking on radish seed germination and seedling growth under salt stress.

Pullulan can not only provide a source of organic carbon but also has excellent properties. However, current research is mostly limited to the physical properties of the high molecular-weight components of pullulan, and little is known of the application of its low molecular-weight components. This study was designed to explore the impact of the pre-soaking of radish seeds in a pullulan solution on seed germination and subsequent seedling growth under salt stress conditions. Pullulan soaking was found to enhance the germination rates of radish seeds subjected to salt stress, while also enhancing the aboveground growth of radish seedlings. Pullulan soaking resulted in increases in chlorophyll, soluble protein, and soluble sugar concentrations in the leaves of these seedlings, together with greater peroxidase activity and root activity as well as decreases in Na+ and malondialdehyde concentrations. This provides an important reference for the application of pullulan in plant protection.

The Influence of Kynurenine Metabolites on Neurodegenerative Pathologies.

As the kynurenine pathway's links to inflammation, the immune system, and neurological disorders became more apparent, it attracted more and more attention. It is the main pathway through which the liver breaks down Tryptophan and the initial step in the creation of nicotinamide adenine dinucleotide (NAD+) in mammals. Immune system activation and the buildup of potentially neurotoxic substances can result from the dysregulation or overactivation of this pathway. Therefore, it is not shocking that kynurenines have been linked to neurological conditions (Depression, Parkinson's, Alzheimer's, Huntington's Disease, Schizophrenia, and cognitive deficits) in relation to inflammation. Nevertheless, preclinical research has demonstrated that kynurenines are essential components of the behavioral analogs of depression and schizophrenia-like cognitive deficits in addition to mediators associated with neurological pathologies due to their neuromodulatory qualities. Neurodegenerative diseases have been extensively associated with neuroactive metabolites of the kynurenine pathway (KP) of tryptophan breakdown. In addition to being a necessary amino acid for protein synthesis, Tryptophan is also transformed into the important neurotransmitters tryptamine and serotonin in higher eukaryotes. In this article, a summary of the KP, its function in neurodegeneration, and the approaches being used currently to target the route therapeutically are discussed.

Light Intensity Regulates Low-Temperature Adaptability of Tea Plant through ROS Stress and Developmental Programs.

Low-temperature stress limits global tea planting areas and production efficiency. Light is another essential ecological factor that acts in conjunction with temperature in the plant life cycle. However, it is unclear whether the differential light environment affects the low temperature adaptability of tea plant (Camellia sect. Thea). In this study, tea plant materials in three groups of light intensity treatments showed differentiated characteristics for low-temperature adaptability. Strong light (ST, 240 µmol·m-2·s-1) caused the degradation of chlorophyll and a decrease in peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and polyphenol oxidase (PPO) activities, as well as an increase in soluble sugar, soluble protein, malondialdehyde (MDA), and relative conductivity in tea leaves. In contrast, antioxidant enzyme activities, chlorophyll content, and relative conductivity were highest in weak light (WT, 15 µmol·m-2·s-1). Damage was observed in both ST and WT materials relative to moderate light intensity (MT, 160 µmol·m-2·s-1) in a frost resistance test. Chlorophyll degradation in strong light was a behavior that prevented photodamage, and the maximum photosynthetic quantum yield of PS II (Fv/Fm) decreased with increasing light intensity. This suggests that the browning that occurs on the leaf surface of ST materials through frost may have been stressed by the previous increase in reactive oxygen species (ROS). Frost intolerance of WT materials is mainly related to delayed tissue development and tenderness holding. Interestingly, transcriptome sequencing revealed that stronger light favors starch biosynthesis, while cellulose biosynthesis is enhanced in weaker light. It showed that light intensity mediated the form of carbon fixation in tea plant, and this was associated with low-temperature adaptability.

A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis.

IL-10 is a potent anti-inflammatory cytokine capable of suppressing a number of proinflammatory signals associated with intestinal inflammatory diseases, such as ulcerative colitis and Crohn's disease. Clinical use of human IL-10 (hIL-10) has been limited by anemia and thrombocytopenia following systemic injection, side effects that might be eliminated by a gut-restricted distribution. We have identified a transcytosis pathway used by cholix, an exotoxin secreted by nonpandemic forms of the intestinal pathogen Vibrio cholerae A nontoxic fragment of the first 386 aa of cholix was genetically fused to hIL-10 to produce recombinant AMT-101. In vitro and in vivo characterization of AMT-101 showed it to efficiently cross healthy human intestinal epithelium (SMI-100) by a vesicular transcytosis process, activate hIL-10 receptors in an engineered U2OS osteosarcoma cell line, and increase cellular phospho-STAT3 levels in J774.2 mouse macrophage cells. AMT-101 was taken up by inflamed intestinal mucosa and activated pSTAT3 in the lamina propria with limited systemic distribution. AMT-101 administered to healthy mice by oral gavage or to cynomolgus monkeys (nonhuman primates) by colonic spray increased circulating levels of IL-1R antagonist (IL-1Ra). Oral gavage of AMT-101 in two mouse models of induced colitis prevented associated pathological events and plasma cytokine changes. Overall, these studies suggest that AMT-101 can efficiently overcome the epithelial barrier to focus biologically active IL-10 to the intestinal lamina propria.

[Research progress in synthetic biology of active compounds in Chinese medicinal plants].

Mecicinal plants boast abundant natural compounds with significant pharmacological activity, and such compounds, featuring diversified and complex structures, can be used for research and development of drugs. At present, these natural compounds are directly extracted from herbs which, however, suffer from damaged wild resources and shortage of planting resources attributing to the increasing demand. Moreover, the low content in medicinal plants and complex structures are another challenge to the research and development of drugs. Heterologous synthesis with synthetic biology methods is a solution that has attracted wide attention. Synthetic bio-logy for the production of natural active compounds in Chinese medicinal plants involves the exploration of key enzymes in compound bio-synthetic pathways from plants, analysis of enzyme functions and mechanisms, and reconstruction and optimization of biosynthetic pathways in microorganisms for efficient synthesis of compounds. This study briefed the development process of synthetic biology and the biosynthetic pathways of terpenoids, alkaloids, and flavonoids, and summarized the related strategies of synthetic biology such as the reconstruction and optimization of metabolic pathways, regulation of fermentation process, and strain improvement, and the latest applications of heterogeneous synthetic biology in the production of natural compounds from Chinese medicinals. This study is expected to serve as a reference for the efficient production of terpenoids, alkaloids, flavonoids, and other active compounds from Chinese medicinal plants with strategies of synthetic biology.

Caveolin enhances hepatocellular carcinoma cell metabolism, migration, and invasion in vitro via a hexokinase 2-dependent mechanism.

The development and progression of hepatocellular carcinoma (HCC) have been associated with abnormal cellular metabolism. Gene Expression Profiling Interactive Analysis RNA sequencing data revealed caveolin-1 (CAV-1) and hexokinase 2 (HK2) messenger RNA (mRNA) were significantly upregulated in human HCC compared with normal tissues, and high HK2 expression was associated with significantly poorer overall survival in HCC ( p < 0.05). CAV-1 and HK2 mRNA and protein expression were upregulated and positively correlated in 42 fresh human HCC tissues compared with tumor-adjacent normal tissues. Overexpression of CAV-1 or HK2 in SMMC-7721 and HepG2 HCC cells enhanced glucose and lactate metabolism and increased cell migration and invasion in transwell assays; knocking down CAV-1 or HK2 had the opposite effects. Overexpression of CAV-1 increased HK2 expression; overexpression of HK2 did not affect CAV-1 expression. Knocking down HK2 partially reversed the ability of CAV-1 to promote cellular metabolism, invasion, and migration in HCC, indicating CAV-1 enhances glycolysis, invasion, and metastasis in HCC cells via HK2-dependent mechanism. Further studies of the function and relationship between CAV-1 or HK2 expression are warranted to explore the potential of these proteins as metabolic targets for the treatment of HCC.

Global and Targeted Metabolomics Evidence of the Protective Effect of Chinese Patent Medicine Jinkui Shenqi Pill on Adrenal Insufficiency after Acute Glucocorticoid Withdrawal in Rats.

Glucocorticoids are commonly used in anti-inflammatory and immunomodulatory therapies, but glucocorticoid withdrawal can result in life-threatening risk of adrenal insufficiency. Chinese patented pharmaceutical product Jinkui Shenqi pill (JKSQ) has potent efficacy on clinical adrenal insufficiency resulting from glucocorticoid withdrawal. However, the underlying molecular mechanism remains unclear. We used an animal model to study JKSQ-induced metabolic changes under adrenal insufficiency and healthy conditions. Sprague-Dawley rats were treated with hydrocortisone for 7 days with or without 15 days of JKSQ pretreatment. Sera were collected after 72 h hydrocortisone withdrawal and used for global and free fatty acids (FFAs)-targeted metabolomics analyses using gas chromatography/time-of-flight mass spectrometry and ultraperformance liquid chromatography/quadruple time-of-flight mass spectrometry. Rats without hydrocortisone treatment were used as controls. JKSQ pretreatment normalized the significant changes of 13 serum metabolites in hydrocortisone-withdrawal rats, involving carbohydrates, lipids, and amino acids. The most prominent effect of JKSQ was on the changes of FFAs and some [product FFA]/[precursor FFA] ratios, which represent estimated desaturase and elongase activities. The opposite metabolic responses of JKSQ in adrenal insufficiency rats and normal rats highlighted the "Bian Zheng Lun Zhi" (treatment based on ZHENG differentiation) guideline of TCM and suggested that altered fatty acid metabolism was associated with adrenal insufficiency after glucocorticoid withdrawal and the protective effects of JKSQ.

A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model.

Many serious bacterial infections are difficult to treat due to biofilm formation, which provides physical protection and induces a sessile phenotype refractory to antibiotic treatment compared to the planktonic state. A key structural component of biofilm is extracellular DNA, which is held in place by secreted bacterial proteins from the DNABII family: integration host factor (IHF) and histone-like (HU) proteins. A native human monoclonal antibody, TRL1068, has been discovered using single B-lymphocyte screening technology. It has low-picomolar affinity against DNABII homologs from important Gram-positive and Gram-negative bacterial pathogens. The disruption of established biofilm was observedin vitroat an antibody concentration of 1.2 µg/ml over 12 h. The effect of TRL1068in vivowas evaluated in a murine tissue cage infection model in which a biofilm is formed by infection with methicillin-resistantStaphylococcus aureus(MRSA; ATCC 43300). Treatment of the established biofilm by combination therapy of TRL1068 (15 mg/kg of body weight, intraperitoneal [i.p.] administration) with daptomycin (50 mg/kg, i.p.) significantly reduced adherent bacterial count compared to that after daptomycin treatment alone, accompanied by significant reduction in planktonic bacterial numbers. The quantification of TRL1068 in sample matrices showed substantial penetration of TRL1068 from serum into the cage interior. TRL1068 is a clinical candidate for combination treatment with standard-of-care antibiotics to overcome the drug-refractory state associated with biofilm formation, with potential utility for a broad spectrum of difficult-to-treat bacterial infections.

A high-affinity native human antibody neutralizes human cytomegalovirus infection of diverse cell types.

Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an ex vivo infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation.

Transcriptome signature in young children with acute otitis media due to non-typeable Haemophilus influenzae.

Non-typeable Haemophilus influenzae (NTHi) causes acute otitis media (AOM) in young children. In our recent paper in Microbes and Infection we described the transcriptome signature elicited from PBMCs at onset of AOM caused by Streptococcus pneumoniae. In the current study we found very different results with NTHi AOM infections; 5.1% of 29 187 genes were differentially regulated by more than 2-fold at the onset of AOM compared with the pre-infection healthy state in the same children. Among the 1487 transcripts, 100 genes associated with the immune defense response were specifically analyzed. About half of the differentially regulated genes associated with antibacterial activity and the cell-mediated immune response were activated and half were suppressed. The important signatures for NTHi in children suggested that the balance of the immune response was toward suppression. Moreover, 90% of the genes associated with a pro-inflammatory cytokine response were down-regulated. The genes associated with the classic complement pathway were down-regulated, although the alternative complement pathway genes were up-regulated. These results provide the first human transcriptome data identifying gene expression in the immune response to be predominantly down-regulated at the onset of AOM due to NTHi.

CsNYC1a Mediates Chlorophyll Degradation and Albino Trait Formation in the Arbor-Type Tea Plant Camellia nanchuanica.

Albino germplasms are prized tea plant mutants with yellow/white leaves. However, understanding of the albino mechanisms in non-Camellia sinensis tea species remains limited. This study elucidated the albino trait formation in Nanchuan Dachashu (C. nanchuanica), an arbor-type tea species, and its association with tea quality. The yellow-leaved albino individual NH1 exhibited abnormal chloroplast ultrastructure and reduced chlorophyll/carotenoid levels compared to green-leaved NL1. Integrating transcriptomics, metabolomics, yeast one-hybrid, and transgenic approaches identified the chlorophyll b reductase gene CsNYC1a as a key regulator, which was significantly up-regulated in NH1, and its overexpression in Arabidopsis recapitulated the albino phenotype. In yeast, histone CsH1.2 binds to the CsNYC1a promoter. These findings suggest that CsH1.2-CsNYC1a-mediated chlorophyll degradation may be a key mechanism underlying albino formation in Nanchuan Dachashu. In addition, as a germplasm with higher polyphenol-to-amino acid ratio than NL1, NH1 offers more possibilities for breeding and application.

Health assessment of an electro-hydraulic servo pump control system for servomotor based on LGA deep neural network.

Due to its advantages of having a high power-to-weight ratio and being energy-efficient, the electro-hydraulic servo pump control system (abbreviated as EHSPCS) is frequently employed in the industrial field, such as the electro-hydraulic servo pump control (EHSPC) servomotor for steam turbine valve regulation control. However, the EHSPCS has strong nonlinearity and time-varying features, and the factors that cause system performance degradation are complex. Once a system failure occurs, it may lead to serious accidents, causing serious casualties and economic losses. To address the above issues, a system health assessment method based on LSTM-GRNN-ANN (LGA) deep neural network is proposed in this paper. Firstly, with oil volume gas content, servo motor air-gap flux density, and system leakage coefficient as the health assessment performance indicators, a health assessment performance index system for the EHSPCS is built, Furthermore, the system performance index threshold is set. Secondly, an LGA deep neural network is constructed by combining LSTM, GRNN and ANN, and a deep neural network based on the LGA is used to create an EHSPCS health assessment model. Subsequently, system feature parameter extraction, algorithm design, and parameter debugging are carried out. Finally, an EHSPCS experimental platform is established, typical system failure simulation experiments are designed, and comparative experimental analysis is conducted. The experimental findings demonstrate that the average accuracy of the system health assessment model based on the LGA deep neural network suggested in this paper is 96.37%, compared to 89.84%, 87.99% for LSTM and GRNN, which validates the accuracy of the system health assessment model based on the LGA deep neural network.

Evaluate the in vitro effect of anthracycline and alkylating cytophosphane chemotherapeutics on dopaminergic neurons.

BACKGROUND: Iatrogenesis is an inevitable global threat to healthcare that drastically increases morbidity and mortality. Cancer is a fatal pathological condition that affects people of different ages, sexes, and races around the world. In addition to the detrimental cancer pathology, one of the most common contraindications and challenges observed in cancer patients is severe adverse drug effects and hypersensitivity reactions induced by chemotherapy. Chemotherapy-induced cognitive neurotoxicity is clinically referred to as Chemotherapy-induced cognitive impairment (CICI), chemobrain, or chemofog. In addition to CICI, chemotherapy also causes neuropsychiatric issues, mental disorders, hyperarousal states, and movement disorders. A synergistic chemotherapy regimen of Doxorubicin (Anthracycline-DOX) and Cyclophosphamide (Alkylating Cytophosphane-CPS) is indicated for the management of various cancers (breast cancer, lymphoma, and leukemia). Nevertheless, there are limited research studies on Doxorubicin and Cyclophosphamide's pharmacodynamic and toxicological effects on dopaminergic neuronal function. AIM: This study evaluated the dopaminergic neurotoxic effects of Doxorubicin and Cyclophosphamide. METHODS AND RESULTS: Doxorubicin and Cyclophosphamide were incubated with dopaminergic (N27) neurons. Neuronal viability was assessed using an MTT assay. The effect of Doxorubicin and Cyclophosphamide on various prooxidants, antioxidants, mitochondrial Complex-I & IV activities, and BAX expression were evaluated by Spectroscopic, Fluorometric, and RT-PCR methods, respectively. Prism-V software (La Jolla, CA, USA) was used for statistical analysis. Chemotherapeutics dose-dependently inhibited the proliferation of the dopaminergic neurons. The dopaminergic neurotoxic mechanism of Doxorubicin and Cyclophosphamide was attributed to a significant increase in prooxidants, a decrease in antioxidants, and augmented apoptosis without affecting mitochondrial function. CONCLUSION: This is one of the first reports that reveal Doxorubicin and Cyclophosphamide induce significant dopaminergic neurotoxicity. Thus, Chemotherapy-induced adverse drug reaction issues substantially persist during and after treatment and sometimes never be completely resolved clinically. Consequently, failure to adopt adequate patient care measures for cancer patients treated with certain chemotherapeutics might substantially raise the incidence of numerous movement disorders.

Reverse remodeling of mitral leaflets after medical treatment in recent-onset dilated cardiomyopathy.

BACKGROUND: The growth of mitral leaflets (MLs) adaptive to left ventricluar (LV) remodeling has been observed. However, the elasticity of MLs upon mechanical stimuli would be supposed if it shrinks with LV reverse remodeling (LVRR). MATERIAL AND METHODS: Patients with idiopathic recent-onset dilated cardiomyopathy (RODCM) (n = 82) and 50 matched normal controls (NC) were prospectively enrolled. Echocardiography was performed at baseline and 6 months of follow-up for the anterior and posterior mitral leaflet (AML and PML) length, mitral annular dimension (MAD), and tenting height (TH). LVRR was measured as a ≥ 15% reduction in LV end-diastolic volume (LVEDV). RESULTS: After 6 months, LVRR was achieved in 69.5% of patients. The AML (28 ± 3 vs. 26 ± 3 mm, p = 0.004) and PML (19 ± 4 vs. 17 ± 3 mm, p < 0.001) decreased in length, as well as the MAD (31 ± 5 vs. 28 ± 5 mm, p = 0.001) and TH (10 ± 3 vs. 8 ± 2 mm, p < 0.001). Compared with the NC group, the AML and PML of the RODCM group were 16.7% and 35.7% longer at baseline and remained 8.3% and 21.2% longer at follow-up, respectively. The change in AML or PML correlated moderately with that in LVEDV (r = 0.487, p < 0.001; r = 0.516, p < 0.001, respectively). The AML and PML length decreased in the LVRR (+) subgroup (AML, 28 ± 3 vs. 26 ± 3 mm, p = 0.001; PML, 20 ± 4 vs. 16 ± 3 mm, p < 0.001), but remained the same in the LVRR (-) subgroup (27 ± 4 vs. 28 ± 4 mm, p = 0.318; 17 ± 3 vs. 17 ± 3 mm, p = 0.790). CONCLUSIONS: Enlarged MLs could reverse accompanied by LV reverse remodeling. This study provided the other facet of ML plasticity adaptive to mechanical stretching.

Assessing effects of Cannabis on various neuropathologies: A systematic review.

Natural bioactives possess a wide range of chemical structures that can exert a plethora of pharmacological and toxicological actions, resulting in neuroprotection or neurotoxicity. These pharmacodynamic properties can positively or negatively impact human and animal global healthcare. Remarkably, Ayurvedic botanical Cannabis has been used worldwide by different ethnicities and religions for spiritual, commercial, recreational, nutraceutical, cosmeceutical, and medicinal purposes for centuries. Cannabis-based congeners have been approved by the United States of America's (USA) Food & Drug Administration (FDA) and other global law agencies for various therapeutic purposes. Surprisingly, the strict laws associated with possessing cannabis products have been mitigated in multiple states in the USA and across the globe for recreational use. This has consequently led to a radical escalation of exposure to cannabis-related substances of abuse. However, there is a lacuna in the literature on the acute and chronic effects of Cannabis and its congeners on various neuropathologies. Moreover, in the post-COVID era, there has been a drastic increase in the incidence and prevalence of numerous neuropathologies, leading to increased morbidity and mortality. There is an impending necessity for a safe, economically viable, multipotent, natural bioactive to prevent and treat various neuropathologies. The ayurvedic herb, Cannabis is one of the oldest botanicals known to humans and has been widely used. However, the comprehensive effect of Cannabis on various neuropathologies is not well established. Hence, this review presents effects of Cannabis on various neuropathologies.

CsXDH1 gene promotes caffeine catabolism induced by continuous strong light in tea plant.

Tea plant (Camellia sinensis) is an important cash crop with extensive adaptability in the world. However, complex environmental factors force a large variation of tea quality-related components. Caffeine is essential for the formation of bitter and fresh flavors in tea, and is the main compound of tea that improves human alertness. Continuous strong light stimulation was observed to cause caffeine reduction in tea leaves, but the mechanism is not clear. In this study, the response of tea plant to light intensity was analysed mainly by multi-omics association, antisense oligodeoxynucleotide (asODN) silencing technique, and in vitro enzyme activity assay. The results revealed multiple strategies for light intensity adaptation in tea plant, among which the regulation of chloroplasts, photosynthesis, porphyrin metabolism, and resistance to oxidative stress were prominent. Caffeine catabolism was enhanced in continuous strong light, which may be a light-adapted strategy due to strict regulation by xanthine dehydrogenase (XDH). asODN silencing and enzymatic activity assays confirmed that CsXDH1 is a protein induced by light intensity to catalyze the substrate xanthine. CsXDH1 asODN silencing resulted in significant up-regulation of both caffeine and theobromine in in vitro enzyme activity assay, but not in vivo. CsXDH1 may act as a coordinator in light intensity adaptation, thus disrupting this balance of caffeine catabolism.

A novel defined risk signature of endoplasmic reticulum stress-related genes for predicting the prognosis and immune infiltration status of ovarian cancer.

Endoplasmic reticulum (ER) stress, as an emerging hallmark feature of cancer, has a considerable impact on cell proliferation, metastasis, invasion, and chemotherapy resistance. Ovarian cancer (OvCa) is one of the leading causes of cancer-related mortality across the world due to the late stage of disease at diagnosis. Studies have explored the influence of ER stress on OvCa in recent years, while the predictive role of ER stress-related genes in OvCa prognosis remains unexplored. Here, we enrolled 552 cases of ER stress-related genes involved in OvCa from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts for the screening of prognosis-related genes. The least absolute shrinkage and selection operator (LASSO) regression was applied to establish an ER stress-related risk signature based on the TCGA cohort. A seven-gene signature revealed a favorable predictive efficacy for the TCGA, International Cancer Genome Consortium (ICGC), and another GEO cohort (P<0.001, P<0.001, and P=0.04, respectively). Moreover, functional annotation indicated that this signature was enriched in cellular response and senescence, cytokines interaction, as well as multiple immune-associated terms. The immune infiltration profiles further delineated an immunologic unresponsive status in the high-risk group. In conclusion, ER stress-related genes are vital factors predicting the prognosis of OvCa, and possess great application potential in the clinic.

GRP75 as a functional element of cholix transcytosis.

Cholix (Chx) is secreted by non-pandemic strains of Vibrio cholerae in the intestinal lumen. For this exotoxin to induce cell death in non-polarized cells in the intestinal lamina propria, it must traverse the epithelium in the fully intact form. We identified host cell elements in polarized enterocytes associated with Chx endocytosis and apical to basal (A→B) vesicular transcytosis. This pathway overcomes endogenous mechanisms of apical vesicle recycling and lysosomal targeting by interacting with several host cell proteins that include the 75 kDa glucose-regulated protein (GRP75). Apical endocytosis of Chx appears to involve the single membrane spanning protein TMEM132A, and interaction with furin before it engages GRP75 in apical vesicular structures. Sorting within these apical vesicles results in Chx being trafficked to the basal region of cells in association with the Lectin, Mannose Binding 1 protein LMAN1. In this location, Chx interacts with the basement membrane-specific heparan sulfate proteoglycan perlecan in recycling endosomes prior to its release from this basal vesicular compartment to enter the underlying lamina propria. While the furin and LMAN1 elements of this Chx transcytosis pathway undergo cellular redistribution that are reflective of the polarity shifts noted for coatamer complexes COPI and COPII, GRP75 and perlecan fail to show these dramatic rearrangements. Together, these data define essential steps in the A→B transcytosis pathway accessed by Chx to reach the intestinal lamina propria where it can engage and intoxicate certain non-polarized cells.

The Vibrio cholerae exotoxin protein cholix interacts with a number of host cell proteins, including GRP75, to facilitate its vesicular transcytosis across polarized intestinal epithelial cells following apical endocytosis.