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1.
CNS Neurosci Ther ; 30(7): e14855, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38992889

ABSTRACT

BACKGROUND: G1 is a specific agonist of G protein-coupled estrogen receptor 1 (GPER1), which binds and activates GPER1 to exert various neurological functions. However, the preventive effect of G1 on post-traumatic stress disorder (PTSD) and its mechanisms are unclear. OBJECTIVE: To evaluate the protective effect of G1 against synaptic and mitochondrial impairments and to investigate the mechanism of G1 to improve PTSD from brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling. METHODS: This study initially detected GPER1 expression in the hippocampus of single prolonged stress (SPS) mice, utilizing both Western blot and immunofluorescence staining. Subsequently, the effects of G1 on PTSD-like behaviors, synaptic, and mitochondrial functions in SPS mice were investigated. Additionally, the involvement of BDNF/TrkB signaling involved in the protection was further confirmed using GPER1 antagonist and TrkB inhibitor, respectively. RESULTS: The expression of GPER1 was reduced in the hippocampus of SPS mice, and G1 treatment given for 14 consecutive days significantly improved PTSD-like behaviors in SPS mice compared with model group. Electrophysiological local field potential (LFP) results showed that G1 administration for 14 consecutive days could reverse the abnormal changes in the gamma oscillation in the CA1 region of SPS mice. Meanwhile, G1 administration for 14 consecutive days could significantly improve the abnormal expression of synaptic proteins, increase the expression of mitochondria-related proteins, increase the number of synapses in the hippocampus, and ameliorate the damage of hippocampal mitochondrial structure in SPS mice. In addition, G15 (GPER1 inhibitor) and ANA-12 (TrkB inhibitor) blocked the ameliorative effects of G1 on PTSD-like behaviors and aberrant expression of hippocampal synaptic and mitochondrial proteins in SPS mice and inhibited the reparative effects of G1 on structural damage to hippocampal mitochondria, respectively. CONCLUSION: G1 improved PTSD-like behaviors in SPS mice, possibly by increasing hippocampal GPER1 expression and promoting BDNF/TrkB signaling to repair synaptic and mitochondrial functional impairments. This study would provide critical mechanism for the prevention and treatment of PTSD.


Subject(s)
Brain-Derived Neurotrophic Factor , Hippocampus , Mitochondria , Receptors, Estrogen , Receptors, G-Protein-Coupled , Stress Disorders, Post-Traumatic , Synapses , Animals , Stress Disorders, Post-Traumatic/metabolism , Stress Disorders, Post-Traumatic/prevention & control , Stress Disorders, Post-Traumatic/drug therapy , Brain-Derived Neurotrophic Factor/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/antagonists & inhibitors , Mice , Male , Mitochondria/drug effects , Mitochondria/metabolism , Receptors, Estrogen/metabolism , Synapses/drug effects , Synapses/metabolism , Hippocampus/metabolism , Hippocampus/drug effects , Receptor, trkB/metabolism , Receptor, trkB/antagonists & inhibitors , Mice, Inbred C57BL
2.
Phytomedicine ; 129: 155639, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38669966

ABSTRACT

BACKGROUND: Cerebral microcirculation disturbance manifested by decrease of cerebral blood flow (CBF) is one of early features of Alzheimer's disease (AD). Shenqi Yizhi prescription (SQYZ) is widely used in the treatment of AD. However, the effect of SQYZ on the early feature of AD is not clarified. PURPOSE: To explore the effect and mechanism of SQYZ on AD-like behavior from the perspective of early pathological features of AD. METHODS: The fingerprint of SQYZ was established by ultra-high-performance liquid chromatograph. The improvement effect of SQYZ on Aß1-42 Oligomer (AßO)-induced AD-like behavior of mice was evaluated by behavioral test. The changes of CBF were detected by laser doppler meter and laser speckle imaging. The pathological changes of the hippocampus were observed by HE staining and transmission electron microscope. The expressions of intercellular communication molecules were detected by western blotting or immunofluorescence staining. The content of platelet-derived growth factor-BB (PDGF-BB) was detected by ELISA. Finally, the core components of SQYZ were docked with platelet-derived growth factor receptor beta (PDGFRß) using AutoDock Vina software. RESULTS: The similarity of the components in SQYZ extracted from different batches of medicinal materials was higher than 0.9. SQYZ administration could improve AßO-induced memory impairment and CBF reduction. Compared with the sham group, the number of neurons in the hippocampi of AßO group was significantly reduced, and the microvessels were shrunken and deformed. By contrary, SQYZ administration mitigated those pathological changes. Compared with the sham mice, the expressions of CD31, N-cadherin, PDGFRß, glial fibrillary acidic protein, phosphorylation of focal adhesion kinase, integrin ß1, and integrin α5 in the hippocampi of AßO mice were significantly increased. However, SQYZ administration significantly reduced AßO-induced expression of those proteins. Interestingly, the effect of PDGFRß inhibitor, sunitinib demonstrated a consistent modulating effect as SQYZ. Finally, the brain-entering components of SQYZ, including ginsenoside Rg5, coptisine, cryptotanshinone, dihydrotanshinone IIA, stigmasterol, and tanshinone IIA had high binding force with PDGFRß, implicating PDGFRß as a potential target for SQYZ. CONCLUSIONS: Our data indicate that SQYZ improves CBF in AßO-triggered AD-like mice through inhibiting brain pericyte contractility, indicating the treatment potential of SQYZ for AD at the early stage.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Drugs, Chinese Herbal , Hippocampus , Memory Disorders , Pericytes , Animals , Drugs, Chinese Herbal/pharmacology , Amyloid beta-Peptides/metabolism , Male , Mice , Memory Disorders/drug therapy , Memory Disorders/chemically induced , Alzheimer Disease/drug therapy , Pericytes/drug effects , Hippocampus/drug effects , Peptide Fragments , Becaplermin/pharmacology , Cerebrovascular Circulation/drug effects , Brain/drug effects , Disease Models, Animal , Ginsenosides/pharmacology
3.
CNS Neurosci Ther ; 30(3): e14688, 2024 03.
Article in English | MEDLINE | ID: mdl-38516808

ABSTRACT

BACKGROUND: Accumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors of Alzheimer's disease (AD). However, oligodendrocytes (OLs) were also widely investigated in the pathogenesis and treatment for AD. AIMS: We aimed to update the regulatory targets of the differentiation and maturation of OLs, and emphasized the key role of OLs in the occurrence and treatment of AD. METHODS: This review first concluded the targets of OL differentiation and maturation with AD pathogenesis, and then advanced the key role of OLs in the pathogenesis of AD based on both clinic and basic experiments. Later, we extensively discussed the possible application of the current progress in the diagnosis and treatment of this complex disease. RESULTS: Molecules involving in OLs' differentiation or maturation, including various transcriptional factors, cholesterol homeostasis regulators, and microRNAs could also participate in the pathogenesis of AD. Clinical data point towards the impairment of OLs in AD patients. Basic research further supports the central role of OLs in the regulation of AD pathologies. Additionally, classic drugs, including donepezil, edaravone, fluoxetine, and clemastine demonstrate their potential in remedying OL impairment in AD models, and new therapeutics from the perspective of OLs is constantly being developed. CONCLUSIONS: We believe that OL dysfunction is one important pathogenesis of AD. Factors regulating OLs might be biomarkers for early diagnosis and agents stimulating OLs warrant the development of anti-AD drugs.


Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/pathology , Amyloid beta-Peptides , Oligodendroglia/pathology
4.
J Ethnopharmacol ; 323: 117713, 2024 Apr 06.
Article in English | MEDLINE | ID: mdl-38181935

ABSTRACT

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Anshen Dingzhi prescription (ADP), which was first published in the masterpiece of traditional Chinese Medicine in the Qing Dynasty, "Yi Xue Xin Wu" (1732 CE), is documented to interrupt panic-related disorders. However, the mechanism of its action is still not clear. AIM OF THE STUDY: This study aims to investigate the effects of ADP on post-traumatic stress disorder (PTSD)-like behaviors and explore the mechanism from perspective of sirtuin1 (SIRT1)-peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α)-dependent mitochondrial function. MATERIALS AND METHODS: The changes of SIRT1-PGC-1α signal and mitochondrial function were evaluated in the hippocampus of mice receiving single prolonged stress (SPS). Later, the roles of this signaling pathway played in fear memory generalization and anxiety-like behavior in SPS mice was investigated using two agonists of this signaling pathway. On this basis, the effects of ADP (36.8 mg/kg) with definite therapeutic effects, on mitochondrial function were investigated and further confirmed by a SIRT1 inhibitor. Finally, the possible components of ADP targeting PGC-1α were monitored through bioinformatics. RESULTS: Compared with control mice, SIRT1-PGC-1α signal in the hippocampus was impaired in SPS mice, accompanied with dysfunction of mitochondria and abnormal expression of synaptic proteins. The agonists of SIRT1-PGC-1α signal, ZLN005, as well as resveratrol improved the behavioral changes of mice caused by SPS, reversed the decline of proteins in SIRT1-PGC-1α signal, mitochondrial dysfunction, and the abnormal expression of synaptic proteins. The fingerprint was established for the quality control of ADP. At a dose of 36.8 mg/kg, ADP could prevent fear memory generalization and anxiety-like behavior in SPS mice. Mechanically, ADP promoted SIRT1-PGC-1α signal and repaired mitochondrial function. Importantly, SIRT1 inhibitor, selisistat eliminated the ameliorative effects of ADP on behavioral and mitochondrial function. Through molecular docking simulation, the brain-entering components of ADP, including malkangunin, Rg5, fumarine, frutinone A, celabenzine, and inermin had high binding energy with PGC-1α. CONCLUSION: Dysfunction of SIRT1-PGC-1α-dependent mitochondrial function is attributed to SPS-triggered fear generalization and anxiety-like behavior, and ADP could improve PTSD-like behaviors likely through activating this signaling pathway.


Subject(s)
Mitochondria , Sirtuin 1 , Mice , Animals , Sirtuin 1/metabolism , Molecular Docking Simulation , Disease Models, Animal , Hippocampus/metabolism , Prescriptions
5.
Zhen Ci Yan Jiu ; 48(11): 1079-1087, 2023 Nov 25.
Article in English, Chinese | MEDLINE | ID: mdl-37984904

ABSTRACT

OBJECTIVES: To explore the effect of electroacupuncture (EA) at "Baihui" (GV20) and "Shenting" (GV24) on the microvascular structure and related protein expression in the hippocampus of vascular dementia (VD) rat model, and to investigate the mechanism of EA in the treatment of VD. METHODS: A total of 24 SD rats were randomly divided into sham operation, model, EA, and oxiracetam groups, with 6 rats in each group. Multiple cerebral infarction method was used to establish VD model. In the EA group, EA was applied to GV20 and GV24 for 30 min, once daily for 14 days. Rats in the oxiracetam group were treated with oxiracetam (50 mg/kg) by intraperitoneal injection, and the course of treatment was the same as that in the EA group. Learning and memory ability were evaluated by using Morris water maze test and new object recognition experiment. The cerebral blood flow was detected by laser doppler. The microvascular structure in the hippocampus was observed by transmission electron microscopy. The expression of vascular structure related proteins of platelet-derived growth factor receptor (PDGFR)-ß, platelet endothelial cell adhesion molecule-1(CD31), neural cadherin N-Cadherin, Zonula occludens protein-1(ZO-1) in the hippocampus were measured by Western blot. RESULTS: Compared with the sham operation group, the rats in the model group had a significant increase in time of first crossing the platform, a significant decrease in the number of crossing platform and the new object preference index (P<0.05), a significant decrease in cerebral blood flow (P<0.05), and a significant increase in the brain weight (P<0.05). The structure boundary of pericyte and endothelial cells in the microvessels of the hippocampal CA1 area of model group was blurred, accompanied by obvious edema around the vessels and the reduction of tight junctions. The protein expression levels of PDGFR-ß, CD31, N-Cadherin, ZO-1 were significantly decreased in the model group compared with those in the sham operation group (P<0.05). Compared with the model group, the time of first crossing the platform of rats in the EA and oxiracetam group was shortened, the number of crossing platform were increased (P<0.05), the cerebral blood flow was increased (P<0.05), the brain weight was decreased (P<0.05), the morphology and structure of pericyte and endothelial cells in the microvessels of hippocampal CA1 area were intact, accompanied by the increase of tight junctions. Additionally, Compared with the model group, the EA group had a significant increase in the new object preference index (P<0.05), the protein expression levels of PDGFR-ß, CD31, ZO-1 in the EA group were increased (P<0.05), and the expression of PDGFR-ß, N-Cadherin, ZO-1 in the oxiracetam group were increased (P<0.05). CONCLUSIONS: EA at GV20 and GV24 can improve the learning and memory ability of VD rats, and the mechanism may be related to the repair of microvascular structures and improvement of cerebral blood flow.


Subject(s)
Dementia, Vascular , Electroacupuncture , Rats , Animals , Dementia, Vascular/genetics , Dementia, Vascular/therapy , Dementia, Vascular/metabolism , Rats, Sprague-Dawley , Endothelial Cells/metabolism , Hippocampus/metabolism , Cadherins/metabolism
6.
Phytomedicine ; 119: 155009, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37573807

ABSTRACT

BACKGROUND: Neurovascular glial unit (NVGU) dysfunction has been reported to be an early and critical event in the pathophysiology of Alzheimer's disease (AD) and vascular dementia (VD). Although herbal medicines, with their favorable safety profiles and low adverse effects, have been suggested to be useful for the treatment of cognitive impairment, the potential role of the NVGU as the target of the effects of herbal medicines is still unclear. PURPOSE: This review aimed to retrieve evidence from experimental studies of phytopharmaceuticals targeting the NVGU for the treatment of cognitive impairment in AD and VD, and discussed the potential of phytopharmaceuticals to improve cognitive impairment from the perspective of the NVGU. STUDY DESIGN AND METHODS: We systematically searched PubMed, Google Scholar, Web of Science, and CNKI. The keywords used for searching information on the NVGU in the treatment of cognitive impairments included "Alzheimer's disease," "Vascular dementia," "Herbal medicines," "Natural products," "Neurovascular," "Adverse reaction," and "Toxicity, etc." We selected studies on the basis of predefined eligibility criteria. RESULTS: NVGU mainly consists of endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons, and damage to these cells can induce cognitive impairment by impairing the blood-brain barrier (BBB) and cerebral blood flow (CBF) as well as neuronal function. The active components of herbal medicines, including Ginkgo biloba L., Ginseng Radix et Rhizoma, Epimedium Folium, Chuanxiong Rhizoma, Carthami flos, and Acorus tatarinowii Schott, as well as traditional Chinese medicine prescriptions have shown the potential to improve BBB function and increase CBF to prevent cognitive impairment by inhibiting astrocyte and microglia activation, protecting oligodendrocyte myelin function, reducing neuronal apoptosis, and promoting angiogenesis. CONCLUSIONS: Herbal medicines demonstrate great potential to prevent cognitive impairment. Multiple components from herbal medicines may function through different signaling pathways to target the NVGU. Future studies using novel drug-carrier or delivery systems targeting the NVGU will certainly facilitate the development of phytopharmaceuticals for AD and VD.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Dementia, Vascular , Drugs, Chinese Herbal , Plants, Medicinal , Alzheimer Disease/drug therapy , Cognitive Dysfunction/drug therapy , Dementia, Vascular/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Endothelial Cells , Phytotherapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Humans
7.
Zhen Ci Yan Jiu ; 48(3): 226-32, 2023 Mar 25.
Article in Chinese | MEDLINE | ID: mdl-36951073

ABSTRACT

OBJECTIVE: To observe the effect of moxibustion on the expression of miR-345-3p, miR-216a-5p and nuclear factor-κB p65(NF-κB p65) in colonic tissue of rats with diarrhea-predominant irritable bowel syndrome (IBS-D), so as to explore its anti-inflammatory mechanism in relieving IBS-D. METHODS: SD rats were randomly divided into normal control (n=12), model (n=12), moxibustion (n=12) and ammonium pyrrolidine dithiocarbamate (PDTC,n=12) groups. The IBS-D model was established by neonatal mother-child separation combined with acetic acid enema stimulation and chronic binding methods. The rats in the moxibustion group received moxibustion stimulation of "Tianshu"(ST25) and "Shangjuxu"(ST37) for 20 min, once a day, for 7 days, and those of the PDTC group received intraperitoneal injection of PDTC (50 mg·kg-1·d-1) once daily for 7 days. After the intervention, the body weight, loose stool rate and the minimum volume threshold of abdominal withdrawal reflex (AWR) were observed, and histopathological changes of colonic mucosa were observed by HE staining. The contents of interleukin-1ß (IL-1ß), interleukin-4 (IL-4), interleukin-6 (IL-6) and tumor necrosis factor α (TNF- α) in serum were measured by ELISA. The expression of miR-345-3p, miR-216a-5p and NF-κB p65 mRNA in the colon tissue were detected by quantitative real-time PCR, and the immunoactivities of IL-1ß, IL-6, TNF-α and NF-κB p65 in the colon tissue were determined by immunofluorescence histochemistry. RESULTS: Compared with the normal control group, the loose stool rate, contents of IL-1ß, IL-6 and TNF-α, experssion of NF-κB p65 mRNA and the immunoactivities of IL-1ß, IL-6, TNF-α and NF-κB p65 were significantly increased (P<0.01), whereas the body weight, minimum volume threshold of AWR, content of IL-4, and the relative expression of miR-345-3p and miR-216a-5p were remarkably decreased in the model group (P<0.01). In comparison with the model group, the loose stool rate, contents of IL-1ß, IL-6, TNF-α, expression of NF-κB p65 mRNA and the immunoactivities of IL-1ß, IL-6, TNF-α and NF-κB p65 were considerably down-regulated (P<0.01), while the content of IL-4 and the relative expressions of miR-345-3p and miR-216a-5p were obviously up-regulated in both moxibustion and PDTC groups (P<0.01, P<0.05). The content of IL-6 in serum was significantly lower in the PDTC group than in the moxibustion group (P<0.01). CONCLUSION: Moxibustion can reduce the level of intestinal inflammation and visceral hypersensitivity in IBS-D rats, which may be related to its functions in increasing the expression levels of miR-345-3p and miR-216a-5p and in inhibiting the expression of NF-κB p65, thus reducing the levels of inflammatory factors.


Subject(s)
Irritable Bowel Syndrome , MicroRNAs , Moxibustion , Rats , Animals , Irritable Bowel Syndrome/genetics , Irritable Bowel Syndrome/therapy , NF-kappa B/metabolism , Interleukin-4 , Rats, Sprague-Dawley , Interleukin-6 , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Inflammation/genetics , Inflammation/therapy , Diarrhea/genetics , Diarrhea/therapy , MicroRNAs/genetics
8.
Acta Pharmacol Sin ; 44(5): 913-930, 2023 May.
Article in English | MEDLINE | ID: mdl-36380226

ABSTRACT

Ginseng has been used in China as a superior medicinal material for thousands of years that can nourish the five internal organs, calm the mind and benefit wisdom. Due to its anti-inflammatory, antioxidant and neuroprotective activities, one of the active components of ginseng, ginsenoside Rg1, has been extensively investigated in the remedy of brain disorders, especially dementia and depression. In this review, we summarized the research progress on the action mechanisms of Rg1 ameliorating depression-like behaviors, including inhibition of hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis, regulation of synaptic plasticity and gut flora. Rg1 may alleviate Alzheimer's disease in the early phase, as well as in the middle-late phases through repairing dendrite, axon and microglia- and astrocyte-related inflammations. We also proposed that Rg1 could regulate memory state (the imbalance of working and aversive memory) caused by distinct stimuli. These laboratory studies would further the clinical trials on Rg1. From the prospective of drug development, we discussed the limitations of the present investigations and proposed our ideas to increase permeability and bioavailability of Rg1. Taken together, Rg1 has the potential to treat neuropsychiatric disorders, but a future in-depth investigation of the mechanisms is still required. In addition, drug development will benefit from the clinical trials in one specific neuropsychiatric disorder.


Subject(s)
Alzheimer Disease , Ginsenosides , Humans , Alzheimer Disease/drug therapy , Ginsenosides/pharmacology , Ginsenosides/therapeutic use , Inflammation/drug therapy , Neuronal Plasticity/drug effects , Depression/drug therapy , Brain Diseases/drug therapy
9.
Oxid Med Cell Longev ; 2022: 6080282, 2022.
Article in English | MEDLINE | ID: mdl-36211826

ABSTRACT

Cognitive impairment (CI) related to Alzheimer's disease (AD) and vascular cognitive disorders (VCDs) has become a key problem worldwide. Importantly, CI is a neuropsychiatric abnormality mainly characterized by learning and memory impairments. The hippocampus is an important brain region controlling learning and memory. Recent studies have highlighted the effects of acupuncture on memory deficits in AD and VCDs. By reviewing the literature published on this topic in the past five years, the present study intends to summarize the effects of acupuncture on memory impairment in AD and VCDs. Focusing on hippocampal synaptic plasticity, we reviewed the mechanisms underlying the effects of acupuncture on memory impairments through regulation of synaptic proteins, AD characteristic proteins, intestinal microbiota, neuroinflammation, microRNA expression, orexin system, energy metabolism, etc., suggesting that hippocampal synaptic plasticity may be the common as well as the core link underlying the above mechanisms. We also discussed the potential strategies to improve the effect of acupuncture. Additionally, the effects of acupuncture on synaptic plasticity through the regulation of vascular-glia-neuron unit were further discussed.


Subject(s)
Acupuncture Therapy , Alzheimer Disease , MicroRNAs , Alzheimer Disease/metabolism , Animals , Cognition , Disease Models, Animal , Hippocampus/metabolism , Humans , Memory Disorders/metabolism , MicroRNAs/metabolism , Neuronal Plasticity , Orexins/metabolism , Orexins/pharmacology
10.
Front Oncol ; 12: 906372, 2022.
Article in English | MEDLINE | ID: mdl-35734592

ABSTRACT

According to authoritative surveys, the overall morbidity and mortality of malignant tumors show an upward trend, and it is predicted that this trend will not be well contained in the upcoming new period. Since the influencing factors, pathogenesis, and progression characteristics of malignant tumors have not been fully elucidated, the existing treatment strategies, mainly including surgical resection, ablation therapy and chemotherapy, cannot achieve satisfactory results. Therefore, exploring potential therapeutic targets and clarifying their functions and mechanisms in continuous research and practice will provide new ideas and possibilities for the treatment of malignant tumors. Recently, a double-transmembrane protein named transmembrane protein 88 (TMEM88) was reported to regulate changes in downstream effectors by mediating different signaling pathways and was confirmed to be widely involved in cell proliferation, differentiation, apoptosis and tumor progression. At present, abnormal changes in TMEM88 have been found in breast cancer, ovarian cancer, lung cancer, thyroid cancer and other malignant tumors, which has also attracted the attention of tumor research and attempted to clarify its function and mechanism. However, due to the lack of systematic generalization, comprehensive and detailed research results have not been comprehensively summarized. In view of this, this article will describe in detail the changes in TMEM88 in the occurrence and development of malignant tumors, comprehensively summarize the corresponding molecular mechanisms, and explore the potential of targeting TMEM88 in the treatment of malignant tumors to provide valuable candidate targets and promising intervention strategies for the diagnosis and cure of malignant tumors.

11.
J Fungi (Basel) ; 8(2)2022 Feb 18.
Article in English | MEDLINE | ID: mdl-35205952

ABSTRACT

Multidrug resistance, defined as the resistance to multiple drugs in different categories, has been an increasing serious problem. Limited antifungal drugs and the rapid emergence of antifungal resistance prompt a thorough understanding of how the occurrence of multidrug resistance develops and which mechanisms are involved. In this study, experimental evolution was performed under single-azole-drug stress with the model filamentous fungus Neurospora crassa. By about 30 weeks of continuous growth on agar plates containing ketoconazole or voriconazole with weekly transfer, four evolved multidrug-resistant strains 30thK1, 30thK2, 26thV1, and 24thV2 were obtained. Compared to the ancestral strain, all four strains increased resistance not only to commonly used azoles, including ketoconazole, voriconazole, itraconazole, fluconazole, and triadimefon, but also to antifungal drugs in other categories, including terbinafine (allylamine), amorolfine (morpholine), amphotericin B (polyene), polyoxin B (chitin synthesis inhibitor), and carbendazim (ß-tubulin inhibitor). After 8 weeks of growth on agar plates without antifungal drugs with weekly transfer, these evolved strains still displayed multidrug-resistant phenotype, suggesting the multidrug resistance could be stably inherited. Transcriptional measurement of drug target genes and drug transporter genes and deletion analysis of the efflux pump gene cdr4 in the evolved strains suggest that overexpression of cdr4 played a major role in the resistance mechanisms for azoles and terbinafine in the evolved strains, particularly for 30thK2 and 26thV1, and evolved drug-resistant strains had less intracellular ketoconazole accumulation and less disruption of ergosterol accumulations under ketoconazole stress compared to wild type. Mutations specifically present in evolved drug-resistant strains were identified by genome re-sequencing, and drug susceptibility test of knockout mutants for most of mutated genes suggests that mutations in 16 genes, functionally novel in drug resistance, potentially contribute to multidrug resistance in evolved strains.

12.
Neural Plast ; 2021: 2412220, 2021.
Article in English | MEDLINE | ID: mdl-34899899

ABSTRACT

This study is aimed at investigating the potential roles of G protein-coupled estrogen receptor 1 (GPER, also known as GPR30) in the preventive effect of ginsenoside Rg1 against cognitive impairment and hippocampal cell apoptosis in experimental vascular dementia (VD) in mice. The effects of bilateral common carotid artery stenosis (BCAS) on GPR30 expression at mRNA level were evaluated. Thereafter, the BCAS mouse model was utilized to evaluate the protection of Rg1 (0.1, 1, 10 mg/kg, 14 days, ip). Spatial memory was evaluated by water Morris Maze 7 days post BCAS. After behavioral tests, neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and potential mechanisms were determined using western blotting and quantitative real-time PCR. Our results showed that GPR30 expression in the hippocampal region at mRNA level was promoted 30 min, 3 h, 6 h, and 24 h following BCAS. Ginsenoside Rg1 (1 or 10 mg/kg, 14 days, ip) promoted GPR30 expression in the hippocampus of model mice (after behavioral tests) but did not alter GPR30 expression in the hippocampus of control mice. Moreover, treatment of ginsenoside Rg1 (10 mg/kg) or G1 (5 µg/kg), a GPR30 agonist, prevented BCAS-induced memory impairment and hippocampal neuronal loss and apoptosis and promoted the ratio of Bcl-2 to Bax expression in the hippocampus (after behavioral tests). On the contrary, G15 (185 µg/kg), an antagonist of GPR30, aggravated BCAS-induced hippocampal neuronal loss and apoptosis. Finally, drug-target molecular docking pointed that Rg1 had a lower binding energy with GPR30 compared with Bax and Bcl-2. Together, our data implicate that ginsenoside Rg1 prevents cognitive impairment and hippocampal neuronal apoptosis in VD mice, likely through promoting GPR30 expression. These results would provide important implications for the application of Rg1 in the treatment of VD.


Subject(s)
Apoptosis/drug effects , Cognitive Dysfunction/prevention & control , Dementia, Vascular/metabolism , Ginsenosides/therapeutic use , Hippocampus/drug effects , Neurons/drug effects , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Cognitive Dysfunction/etiology , Cognitive Dysfunction/metabolism , Dementia, Vascular/complications , Disease Models, Animal , Ginsenosides/pharmacology , Hippocampus/metabolism , Maze Learning/drug effects , Mice , Neurons/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Quinolines/pharmacology
13.
Vaccine ; 39(5): 780-785, 2021 01 29.
Article in English | MEDLINE | ID: mdl-33414050

ABSTRACT

Although the direct health impact of Coronavirus disease (COVID-19) pandemic on child health is low, there are indirect impacts across many aspects. We compare childhood vaccine uptake in three types of healthcare facilities in Singapore - public primary care clinics, a hospital paediatric unit, and private paediatrician clinics - from January to April 2020, to baseline, and calculate the impact on herd immunity for measles. We find a 25.6% to 73.6% drop in Measles-Mumps-Rubella (MMR) uptake rates, 0.4 - 10.3% drop for Diphtheria-Tetanus-Pertussis-inactivated Polio-Haemophilus influenza (5-in-1), and 8.0-67.8% drop for Pneumococcal conjugate vaccine (PCV) across all 3 sites. Consequent herd immunity reduces to 74-84% among 12-month- to 2-year-olds, well below the 95% coverage that is protective for measles. This puts the whole community at risk for a measles epidemic. Public health efforts are urgently needed to maintain efficacious coverage for routine childhood vaccines during the COVID-19 pandemic.


Subject(s)
COVID-19/epidemiology , Child Health/statistics & numerical data , Public Health/standards , Vaccination Coverage/statistics & numerical data , COVID-19/prevention & control , Child, Preschool , Diphtheria-Tetanus-Pertussis Vaccine/administration & dosage , Haemophilus Vaccines/administration & dosage , Hepatitis B Vaccines/administration & dosage , Humans , Immunity, Herd , Immunization Schedule , Infant , Measles-Mumps-Rubella Vaccine/administration & dosage , Poliovirus Vaccine, Inactivated/administration & dosage , Retrospective Studies , Singapore/epidemiology
14.
J Nurs Res ; 13(1): 11-20, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15977131

ABSTRACT

The beneficial effects of Tai Chi on an elder's well-being have been well documented; however, not many frail elders practice it. The purpose of this descriptive study was to explore the perspectives frail elders have about Tai Chi, including its movements, practice frequency and duration, and practice preferences. Using focus groups, 40 frail elders who lived in long-term care facilities were interviewed. Results indicated that Tai Chi styles with slow and large motions were manageable. Subjects preferred to practice Tai Chi in a group of 10 to 20 people, twice a week with 31 to 60 minutes of practice in the early morning or in the afternoon after napping. The practice locations should be wide, flat, non-disturbed, and well-ventilated. Tai Chi instructors should be experienced, gentle, considerate, and have clarity in expression. Findings can be used to design a simple Tai Chi program that is specifically tailored to the needs of frail elders.


Subject(s)
Attitude to Health , Frail Elderly/psychology , Tai Ji/psychology , Activities of Daily Living , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Focus Groups , Geriatric Assessment , Health Knowledge, Attitudes, Practice , Health Services Needs and Demand , Humans , Male , Nursing Homes , Nursing Methodology Research , Surveys and Questionnaires , Taiwan , Time Factors
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