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Review of the therapeutic potential of Forsythiae Fructus on the central nervous system: Active ingredients and mechanisms of action.
Zhang, L, Lang, F, Feng, J, Wang, J
Journal of ethnopharmacology. 2024;(Pt 2):117275
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine has gained significant attention in recent years owing to its multi-component, multi-target, and multi-pathway advantages in treating various diseases. Forsythiae Fructus, derived from the dried fruit of Forsythia suspensa (Thunb.) Vahl, is one such traditional Chinese medicine with numerous in vivo and ex vivo therapeutic effects, including anti-inflammatory, antibacterial, and antiviral properties. Forsythiae Fructus contains more than 200 chemical constituents, with forsythiaside, forsythiaside A, forsythiaside B, isoforsythiaside, forsythin, and phillyrin being the most active ingredients. Forsythiae Fructus exerts neuroprotective effects by modulating various pathways, including oxidative stress, anti-inflammation, NF-κB signaling, 2-AG, Nrf2 signaling, acetylcholinesterase, PI3K-Akt signaling, ferroptosis, gut-brain axis, TLR4 signaling, endoplasmic reticulum stress, PI3K/Akt/mTOR signaling, and PPARγ signaling pathway. AIM OF THE STUDY This review aims to highlight the potential therapeutic effects of Forsythiae Fructus on the central nervous system and summarize the current knowledge on the active ingredients of Forsythiae Fructus and their effects on different pathways involved in neuroprotection. MATERIALS AND METHODS In this review, we conducted a comprehensive search of databases (PubMed, Google Scholar, Web of Science, China Knowledge Resource Integrated, local dissertations and books) up until June 2023 using key terms such as Forsythia suspensa, Forsythiae Fructus, forsythiaside, isoforsythiaside, forsythin, phillyrin, Alzheimer's disease, Parkinson's disease, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, aging, and herpes simplex virus encephalitis. RESULTS Our findings indicate that Forsythiae Fructus and its active ingredients own therapeutic effects on the central nervous system by modulating various pathways, including oxidative stress, anti-inflammation, NF-κB signaling, 2-AG, Nrf2 signaling, acetylcholinesterase, PI3K-Akt signaling, ferroptosis, the gut-brain axis, TLR4 signaling, endoplasmic reticulum stress, PI3K/Akt/mTOR signaling, and PPARγ signaling pathway. CONCLUSION Forsythiae Fructus and its active ingredients have demonstrated promising neuroprotective properties. Future in vivo and clinical studies of Forsythiae Fructus and its active ingredients should be conducted to establish precise dosage and standard guidelines for a more effective application in the treatment of neurological disorders.
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Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
Amare, A, Thalamuthu, A, Schubert, KO, Fullerton, J, Ahmed, M, Hartmann, S, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, et al
Research square. 2023
Abstract
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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Requirement of Na+/H+ Exchanger NHE1 for Vasopressin-Induced Osteogenic Signaling and Calcification in Human Aortic Smooth Muscle Cells.
Zhu, X, Ma, K, Zhou, K, Pan, X, Liu, J, Nürnberg, B, Alesutan, I, Völkl, J, Lang, F
Kidney & blood pressure research. 2022;(6):399-409
Abstract
BACKGROUND/AIMS: Vasopressin is a powerful stimulator of vascular calcification, augmenting osteogenic signaling in vascular smooth muscle cells (VSMCs) including upregulation of transcription factors such as core-binding factor α-1 (CBFA1), msh homeobox 2 (MSX2), and SRY-Box 9 (SOX9), as well as of tissue-nonspecific alkaline phosphatase (ALPL). Vasopressin-induced osteogenic signaling and calcification require the serum- and glucocorticoid-inducible kinase 1 (SGK1). Known effects of SGK1 include upregulation of Na+/H+ exchanger 1 (NHE1). NHE1 further participates in the regulation of reactive oxygen species (ROS). NHE1 has been shown to participate in the orchestration of bone mineralization. The present study, thus, explored whether vasopressin modifies NHE1 expression and ROS generation, as well as whether pharmacological inhibition of NHE1 disrupts vasopressin-induced osteogenic signaling and calcification in VSMCs. METHODS Human aortic smooth muscle cells (HAoSMCs) were treated with vasopressin in the absence or presence of SGK1 silencing, SGK1 inhibitor GSK-650394, and NHE1 blocker cariporide. Transcript levels were determined by using quantitative real-time polymerase chain reaction, protein abundance by Western blotting, ROS generation with 2',7'-dichlorofluorescein diacetate fluorescence, and ALP activity and calcium content by using colorimetric assays. RESULTS Vasopressin significantly enhanced the NHE1 transcript and protein levels in HAoSMCs, effects significantly blunted by SGK1 inhibition with GSK-650394 or SGK1 silencing. Vasopressin increased ROS accumulation, an effect significantly blocked by the NHE1 inhibitor cariporide. Vasopressin further significantly increased osteogenic markers CBFA1, MSX2, SOX9, and ALPL transcript levels, as well as ALP activity and calcium content in HAoSMCs, all effects significantly blunted by SGK1 silencing or in the presence of GSK-650394 or cariporide. CONCLUSION Vasopressin stimulates NHE1 expression and ROS generation, an effect dependent on SGK1 and required for vasopressin-induced stimulation of osteogenic signaling and calcification of VSMCs.
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Hydration for health hypothesis: a narrative review of supporting evidence.
Perrier, ET, Armstrong, LE, Bottin, JH, Clark, WF, Dolci, A, Guelinckx, I, Iroz, A, Kavouras, SA, Lang, F, Lieberman, HR, et al
European journal of nutrition. 2021;(3):1167-1180
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Abstract
PURPOSE An increasing body of evidence suggests that excreting a generous volume of diluted urine is associated with short- and long-term beneficial health effects, especially for kidney and metabolic function. However, water intake and hydration remain under-investigated and optimal hydration is poorly and inconsistently defined. This review tests the hypothesis that optimal chronic water intake positively impacts various aspects of health and proposes an evidence-based definition of optimal hydration. METHODS Search strategy included PubMed and Google Scholar using relevant keywords for each health outcome, complemented by manual search of article reference lists and the expertise of relevant practitioners for each area studied. RESULTS The available literature suggest the effects of increased water intake on health may be direct, due to increased urine flow or urine dilution, or indirect, mediated by a reduction in osmotically -stimulated vasopressin (AVP). Urine flow affects the formation of kidney stones and recurrence of urinary tract infection, while increased circulating AVP is implicated in metabolic disease, chronic kidney disease, and autosomal dominant polycystic kidney disease. CONCLUSION In order to ensure optimal hydration, it is proposed that optimal total water intake should approach 2.5 to 3.5 L day-1 to allow for the daily excretion of 2 to 3 L of dilute (< 500 mOsm kg-1) urine. Simple urinary markers of hydration such as urine color or void frequency may be used to monitor and adjust intake.
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Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease.
Peikert, K, Glaß, H, Federti, E, Matte, A, Pelzl, L, Akgün, K, Ziemssen, T, Ordemann, R, Lang, F, Patients, TNFTRFN, et al
Journal of personalized medicine. 2021;(5)
Abstract
Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8-50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for "clinical trial readiness". We suggest a panel of outcome parameters for future clinical trials in ChAc.
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D-2-Hydroxyglutarate in Glioma Biology.
Chou, FJ, Liu, Y, Lang, F, Yang, C
Cells. 2021;(9)
Abstract
Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in glioma, which result in the accumulation of an "oncometabolite", D-2-hydroxyglutarate (D-2-HG). Abnormally elevated D-2-HG levels result in a distinctive pattern in cancer biology, through competitively inhibiting α-ketoglutarate (α-KG)/Fe(II)-dependent dioxgenases (α-KGDDs). Recent studies have revealed that D-2-HG affects DNA/histone methylation, hypoxia signaling, DNA repair, and redox homeostasis, which impacts the oncogenesis of IDH-mutated cancers. In this review, we will discuss the current understanding of D-2-HG in cancer biology, as well as the emerging opportunities in therapeutics in IDH-mutated glioma.
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The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium.
Lang, F, Rajaxavier, J, Singh, Y, Brucker, SY, Salker, MS
Frontiers in cell and developmental biology. 2020;:556543
Abstract
The serum- and glucocorticoid-inducible kinase 1 (SGK1) is subject to genetic up-regulation by diverse stimulators including glucocorticoids, mineralocorticoids, dehydration, ischemia, radiation and hyperosmotic shock. To become active, the expressed kinase requires phosphorylation, which is accomplished by PI3K/PDK1 and mTOR dependent signaling. SGK1 enhances the expression/activity of various transport proteins including Na+/K+-ATPase as well as ion-, glucose-, and amino acid- carriers in the plasma membrane. SGK1 can further up-regulate diverse ion channels, such as Na+-, Ca2+-, K+- and Cl- channels. SGK1 regulates expression/activity of a wide variety of transcription factors (such as FKHRL1/Foxo3a, β-catenin, NFκB and p53). SGK1 thus contributes to the regulation of transport, glycolysis, angiogenesis, cell survival, immune regulation, cell migration, tissue fibrosis and tissue calcification. In this review we summarized the current findings that SGK1 plays a crucial function in the regulation of endometrial function. Specifically, it plays a dual role in the regulation of endometrial receptivity necessary for implantation and, subsequently in pregnancy maintenance. Furthermore, fetal programming of blood pressure regulation requires maternal SGK1. Underlying mechanisms are, however, still ill-defined and there is a substantial need for additional information to fully understand the role of SGK1 in the orchestration of embryo implantation, embryo survival and fetal programming.
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Stimulation of ORAI1 expression, store-operated Ca2+ entry, and osteogenic signaling by high glucose exposure of human aortic smooth muscle cells.
Ma, K, Sukkar, B, Zhu, X, Zhou, K, Cao, H, Voelkl, J, Alesutan, I, Nürnberg, B, Lang, F
Pflugers Archiv : European journal of physiology. 2020;(8):1093-1102
Abstract
Diabetes and chronic kidney disease (CKD) both trigger vascular osteogenic signaling and calcification leading to early death by cardiovascular events. Osteogenic signaling involves upregulation of the transcription factors CBFA1, MSX2, and SOX9, as well as alkaline phosphatase (ALP), an enzyme fostering calcification by degrading the calcification inhibitor pyrophosphate. In CKD, osteogenic signaling is triggered by hyperphosphatemia, which upregulates the serum and glucocorticoid-inducible kinase SGK1, a strong stimulator of the Ca2+-channel ORAI1. The channel is activated by STIM1 and accomplishes store-operated Ca2+-entry (SOCE). The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to high extracellular glucose concentrations similarly upregulates ORAI1 and/or STIM1 expression, SOCE, and osteogenic signaling. To this end, HAoSMCs were exposed to high extracellular glucose concentrations (15 mM, 24 h) without or with additional exposure to the phosphate donor ß-glycerophosphate. Transcript levels were estimated using qRT-PCR, protein abundance using Western blotting, ALP activity using a colorimetric assay kit, calcium deposits utilizing Alizarin red staining, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 μM). As a result, glucose enhanced the transcript levels of SGK1 and ORAI1, ORAI2, and STIM2, protein abundance of ORAI1, SOCE, the transcript levels of CBFA1, MSX2, SOX9, and ALPL, as well as calcium deposits. Moreover, glucose significantly augmented the stimulating effect of ß-glycerophosphate on transcript levels of SGK1 and ORAI1, SOCE, the transcript levels of osteogenic markers, as well as calcium deposits. ORAI1 inhibitor MRS1845 (10 μM) significantly blunted the glucose-induced upregulation of the CBFA1 and MSX2 transcript levels. In conclusion, the hyperglycemia of diabetes stimulates expression of SGK1 and ORAI1, thus, augmenting store-operated Ca2+-entry and osteogenic signaling in HAoSMCs.
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Green Tea Polyphenol-Sensitive Calcium Signaling in Immune T Cell Function.
Singh, Y, Salker, MS, Lang, F
Frontiers in nutrition. 2020;:616934
Abstract
Polyphenol compounds found in green tea have a great therapeutic potential to influence multiple human diseases including malignancy and inflammation. In this mini review, we describe effects of green tea and the most important component EGCG in malignancy and inflammation. We focus on cellular mechanisms involved in the modification of T cell function by green tea polyphenol EGCG. The case is made that EGCG downregulates calcium channel activity by influencing miRNAs regulating expression of the channel at the post-transcriptional level.
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Isocitrate Dehydrogenase Mutations in Glioma: Genetics, Biochemistry, and Clinical Indications.
Liu, Y, Lang, F, Chou, FJ, Zaghloul, KA, Yang, C
Biomedicines. 2020;(9)
Abstract
Mutations in isocitrate dehydrogenase (IDH) are commonly observed in lower-grade glioma and secondary glioblastomas. IDH mutants confer a neomorphic enzyme activity that converts α-ketoglutarate to an oncometabolite D-2-hydroxyglutarate, which impacts cellular epigenetics and metabolism. IDH mutation establishes distinctive patterns in metabolism, cancer biology, and the therapeutic sensitivity of glioma. Thus, a deeper understanding of the roles of IDH mutations is of great value to improve the therapeutic efficacy of glioma and other malignancies that share similar genetic characteristics. In this review, we focused on the genetics, biochemistry, and clinical impacts of IDH mutations in glioma.