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Drug Design, Development and Therapy 2024To explored the potential molecular mechanism of Sugemule-4 decoction (MMS-4D) in treating insomnia.
Integration of Gut Microbiota, Serum Metabolomic, and Network Pharmacology to Reveal the Anti Insomnia Mechanism of Mongolian Medicine Sugemule-4 Decoction on Insomnia Model Rats.
OBJECTIVE
To explored the potential molecular mechanism of Sugemule-4 decoction (MMS-4D) in treating insomnia.
METHODS
-4-chlorophenylalanine (PCPA) + chronic unpredictable mild stress stimulation (CUMS) was used to induce an insomnia model in rats. After the model was successfully established, MMS-4D was intervened at low, medium, and high doses for 7 days. The open-field test (OFT) was used to preliminarily evaluate the efficacy. The potential mechanism of MMS-4D in treating insomnia was investigated using gut microbiota, serum metabolomics, and network pharmacology (NP). Experimental validation of the main components of the key pathways was carried out using ELISA and Western blot.
RESULTS
The weights of the insomnia-model rats were significantly raised ( ≤ 0.05), the total exercise distance in the OFT increased ( ≤ 0.05), the rest time shortened, and the number of standing times increased ( ≤ 0.05), after treatment with MMS-4D. Moreover, there was a substantial recovery in the 5-HT, DA, GABA, and Glu levels in the hypothalamus tissue and the 5-HT and GABA levels in the colon tissue of rats. The expression of DAT and DRD1 proteins in the hippocampus of insomnia rats reduced after drug treatment. MMS-4D may treat insomnia by regulating different crucial pathways including 5-HT -, DA -, GABA -, and Glu-mediated neuroactive light receiver interaction, cAMP signaling pathway, serotonergic, glutamatergic, dopaminergic, and GABAergic synapses.
CONCLUSION
This study revealed that MMS-4D can improve the general state and behavioral changes of insomnia model rats. Its mechanism may be related to the reversal of abnormal pathways mediated by 5-HT, DA, GABA, and Glu, such as Serotonergic synapse, Dopaminergic synapse, Glutamatergic synapse, and GABAergic synapse.
Topics: Animals; Rats; Sleep Initiation and Maintenance Disorders; Network Pharmacology; Gastrointestinal Microbiome; Male; Disease Models, Animal; Rats, Sprague-Dawley; Drugs, Chinese Herbal; Metabolomics; Dose-Response Relationship, Drug
PubMed: 38957410
DOI: 10.2147/DDDT.S455600 -
JBMR Plus Aug 2024This retrospective study investigates the prevalence of atypical femoral fractures (AFFs) among patients admitted with hip and shaft fractures at a tertiary referral...
This retrospective study investigates the prevalence of atypical femoral fractures (AFFs) among patients admitted with hip and shaft fractures at a tertiary referral center in Beirut, Lebanon. We analyzed electronic medical records and radiology studies of patients aged above 40 admitted with hip and shaft fractures between January 2006 and December 2019. Fractures were confirmed by ICD9 or ICD10 codes. All cases were reviewed by radiologists, and AFFs were identified according to the 2013 revised ASBMR criteria. We identified 1366 hip and shaft fracture patients, of which 14 female patients had 19 AFFs. This represents a prevalence of 1.0% among all hip and shaft fractures patients and 1.7% among all female hip and shaft fracture patients. Bilateral AFFs were found in 5 of the 14 patients. Patients with AFF tended to be younger, with a mean age of 74.3 (±8.6) yr compared to 78.0 (±10.6) for patients with non-AFF fractures. A total of 36% of AFF patients had a prior history of non-traumatic fracture at first admission. A high percentage of patients with AFFs reported intake of proton pump inhibitors (42.9%) and glucocorticoids (21.4%). Bisphosphonate exposure was noted in 64.3% of AFF patients. None of the AFF patients were active smokers or consumed alcohol regularly. BMD assessments were available for 7 AFF patients, indicating osteoporosis in 4 and osteopenia in 3 cases. Hip axis length measurements showed no significant difference between AFF patients ( = 7) and sex and age-matched controls ( = 21). The study underlines the prevalence and characteristics of AFFs in Lebanon, which is consistent with the numbers reported in the literature (0.32%-5%). A larger prospective study that includes hospitals across the nation is needed to gain a more comprehensive view of the prevalence of AFFs in the Lebanese population.
PubMed: 38957400
DOI: 10.1093/jbmrpl/ziae069 -
Frontiers in Pharmacology 2024Metabolic imbalance is the common basis of many diseases. As natural isoquinoline alkaloid, berberine (BBR) has shown great promise in regulating glucose and lipids... (Review)
Review
Metabolic imbalance is the common basis of many diseases. As natural isoquinoline alkaloid, berberine (BBR) has shown great promise in regulating glucose and lipids metabolism and treating metabolic disorders. However, the related mechanism still lacks systematic research. To discuss the role of BBR in the whole body's systemic metabolic regulation and further explore its therapeutic potential and targets. Based on animal and cell experiments, the mechanism of BBR regulating systemic metabolic processes is reviewed. Potential metabolism-related targets were summarized using Therapeutic Target Database (TTD), DrugBank, GeneCards, and cutting-edge literature. Molecular modeling was applied to explore BBR binding to the potential targets. BBR regulates the whole-body metabolic response including digestive, circulatory, immune, endocrine, and motor systems through adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), sirtuin (SIRT)1/forkhead box O (FOXO)1/sterol regulatory element-binding protein (SREBP)2, nuclear factor erythroid 2-related factor (Nrf) 2/heme oxygenase (HO)-1, and other signaling pathways. Through these reactions, BBR exerts hypoglycemic, lipid-regulating, anti-inflammatory, anti-oxidation, and immune regulation. Molecular docking results showed that BBR could regulate metabolism targeting FOXO3, Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (Gpx) 4 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). Evaluating the target clinical effects, we found that BBR has the therapeutic potential of anti-aging, anti-cancer, relieving kidney disease, regulating the nervous system, and alleviating other chronic diseases. This review elucidates the interaction between potential targets and small molecular metabolites by exploring the mechanism of BBR regulating metabolism. That will help pharmacologists to identify new promising metabolites interacting with these targets.
PubMed: 38957396
DOI: 10.3389/fphar.2024.1368950 -
Frontiers in Pharmacology 2024
PubMed: 38957392
DOI: 10.3389/fphar.2024.1423125 -
Frontiers in Pharmacology 2024Currently 1.3 billion individuals globally engage in smoking, leading to significant morbidity and mortality, particularly among diabetic patients. There is urgent need... (Review)
Review
Currently 1.3 billion individuals globally engage in smoking, leading to significant morbidity and mortality, particularly among diabetic patients. There is urgent need for a better understanding of how smoking influences antidiabetic treatment efficacy. The review underscores the role of cigarette smoke, particularly polycyclic aromatic hydrocarbons (PAHs), in modulating the metabolic pathways of antidiabetic drugs, primarily through the induction of cytochrome P450 (CYP450) enzymes and uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), thus impacting drug pharmacokinetics and therapeutic outcomes. Furthermore, the review addresses the relatively uncharted territory of how smoking cessation influences diabetes treatment, noting that cessation can lead to significant changes in drug metabolism, necessitating dosage adjustments. Special attention is given to the interaction between smoking cessation aids and antidiabetic medications, a critical area for patient safety and effective diabetes management. This scoping review aims to provide healthcare professionals with the knowledge to better support diabetic patients who smoke or are attempting to quit, ensuring tailored and effective treatment strategies. It also identifies gaps in current research, advocating for more studies to fill these voids, thereby enhancing patient care and treatment outcomes for this at-risk population.
PubMed: 38957391
DOI: 10.3389/fphar.2024.1406860 -
Journal of Molecular and Cellular... Jun 2024Type 2 diabetes mellitus (T2DM) is a metabolic disease and comorbidity associated with several conditions, including cardiac dysfunction leading to heart failure with...
Type 2 diabetes mellitus (T2DM) is a metabolic disease and comorbidity associated with several conditions, including cardiac dysfunction leading to heart failure with preserved ejection fraction (HFpEF), in turn resulting in T2DM-induced cardiomyopathy (T2DM-CM). However, the molecular mechanisms underlying the development of T2DM-CM are poorly understood. It is hypothesized that molecular alterations in myopathic genes induced by diabetes promote the development of HFpEF, whereas cardiac myosin inhibitors can rescue the resultant T2DM-mediated cardiomyopathy. To test this hypothesis, a Leptin receptor-deficient homozygous (Lepr ) mouse model was used to define the pathogenesis of T2DM-CM. Echocardiographic studies at 4 and 6 months revealed that Lepr db/db hearts started developing cardiac dysfunction by four months, and left ventricular hypertrophy with diastolic dysfunction was evident at 6 months. RNA-seq data analysis, followed by functional enrichment, revealed the differential regulation of genes related to cardiac dysfunction in Lepr heart tissues. Strikingly, the level of cardiac myosin binding protein-C phosphorylation was significantly increased in Lepr mouse hearts. Finally, using isolated skinned papillary muscles and freshly isolated cardiomyocytes, (mavacamten, MYK-461), a prescription heart medicine used for symptomatic obstructive hypertrophic cardiomyopathy treatment, was tested for its ability to rescue T2DM-CM. Compared with controls, MYK-461 significantly reduced force generation in papillary muscle fibers and cardiomyocyte contractility in the db/db group. This line of evidence shows that 1) T2DM-CM is associated with hyperphosphorylation of cardiac myosin binding protein-C and 2) MYK-461 significantly lessened disease progression , suggesting its promise as a treatment for HFpEF.
PubMed: 38957358
DOI: 10.1016/j.jmccpl.2024.100075 -
Pathology Oncology Research : POR 2024The delivery of neoadjuvant and perioperative therapies for non-small cell lung cancer has been radically altered by significant advances and by the incorporation of... (Review)
Review
The delivery of neoadjuvant and perioperative therapies for non-small cell lung cancer has been radically altered by significant advances and by the incorporation of targeted therapies as well as immune checkpoint inhibitors alone or alongside conventional chemotherapy. This evolution has been particularly notable in the incorporation of immunotherapy and targeted therapy into the treatment of resectable NSCLC, where recent FDA approvals of drugs such as nivolumab and pembrolizumab, in combination with platinum doublet chemotherapy, have led to considerable improvements in pathological complete response rates and the potential for enhanced long-term survival outcomes. This review emphasizes the growing importance of biomarkers in optimizing treatment selection and explores the impact of emerging studies that challenge existing treatment paradigms and investigate novel therapeutic combinations poised to redefine standard of care practices. Furthermore, the discussion extends to the unmet needs within perioperative treatment assessment and prognostication, highlighting the prospective value of biomarkers in evaluating treatment responses and prognosis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neoadjuvant Therapy; Biomarkers, Tumor; Prognosis
PubMed: 38957347
DOI: 10.3389/pore.2024.1611817 -
Ethiopian Journal of Health Sciences Jan 2024Coronaviruses (CoVs) belong to the RNA viruses family. The viruses in this family are known to cause mild respiratory disease in humans. The origin of the novel... (Review)
Review
BACKGROUND
Coronaviruses (CoVs) belong to the RNA viruses family. The viruses in this family are known to cause mild respiratory disease in humans. The origin of the novel SARS-COV2 virus that caused the coronavirus-19 disease (COVID-19) is the Wuhan city in China from where it disseminated to cause a global pandemic. Although lungs are the predominant target organ for Coronavirus Disease-19 (COVID-19), since its outbreak, the disease is known to affect heart, blood vessels, kidney, intestine, liver and brain. This review aimed to summarize the catastrophic impacts of Coronavirus disease-19 on heart and liver along with its mechanisms of pathogenesis.
METHODS
The information used in this review was obtained from relevant articles published on PubMed, Google Scholar, Google, WHO website, CDC and other sources. Key searching statements and phrases related to COVID-19 were used to retrieve information. Original research articles, review papers, research letters and case reports were used as a source of information.
RESULTS
Besides causing severe lung injury, COVID-19 has also been reported to affect and cause dysfunction of many other organs. COVID-19 infection can affect people by downregulating membrane-bound active angiotensin-converting enzyme (ACE). People who have deficient ACE2 expression are more vulnerable to COVID-19 infection. The patients' pre-existing co-morbidities are major risk factors that predispose individuals to severe COVID-19.
CONCLUSION
The disease severity and its broad spectrum phenotype is a result of combined direct and indirect pathogenic factors. Therefore, protocols that harmonize many therapeutic preferences should be the best alternatives to de-escalate the disease and obviate deaths caused as a result of multiple organ damage and dysfunction induced by the disease.
Topics: Humans; COVID-19; SARS-CoV-2; Liver Diseases; Heart Diseases; Angiotensin-Converting Enzyme 2; Liver
PubMed: 38957334
DOI: 10.4314/ejhs.v34i1.10 -
Ghana Medical Journal Mar 2024To assess the performance of the Sex Hormone-Binding Globulin (SHBG) assay as a diagnostic indicator of Gestational Diabetes Mellitus (GDM) in the study population.
OBJECTIVE
To assess the performance of the Sex Hormone-Binding Globulin (SHBG) assay as a diagnostic indicator of Gestational Diabetes Mellitus (GDM) in the study population.
DESIGN
Analytical cross-sectional study.
SETTING
Hospital-based, Benue State University Teaching Hospital (BSUTH), Makurdi, Nigeria.
PARTICIPANTS
Women with singleton pregnancies at 24 to 28 weeks gestational age attending Antenatal care at BSUTH, Makurdi.
INTERVENTION
Serum SHBG levels were assayed by ELISA during a diagnostic 75-gram Oral Glucose Tolerance Test (OGTT) for assessment of GDM in the cohort of consecutively selected participants who met the inclusion criteria.
MAIN OUTCOME MEASURES
Serum levels of SHBG and presence of GDM in the participants.
RESULT
Serum SHBG was significantly negatively correlated (rpb = - 0.534, p-value < 0.001) with the presence of GDM. It had an area under the ROC curve of 0.897 (95% Confidence Interval = 0.858-0.935; p-value < 0.001). A cut-off value of 452.0 nmol/L indicative of GDM had a diagnostic odds ratio of 21.4 in the study population.
CONCLUSION
SHBG is a valuable diagnostic indicator for GDM in the study population.
FUNDING
None declared.
Topics: Humans; Female; Diabetes, Gestational; Pregnancy; Sex Hormone-Binding Globulin; Cross-Sectional Studies; Adult; Glucose Tolerance Test; Nigeria; ROC Curve; Young Adult; Biomarkers; Enzyme-Linked Immunosorbent Assay
PubMed: 38957276
DOI: 10.4314/gmj.v58i1.8 -
Journal of Orthopaedic Translation Jul 2024Over-activated osteoclast (OC) is a major cause of diseases related to bone loss and bone metabolism. Both bone resorption inhibition and apoptosis induction of...
BACKGROUND
Over-activated osteoclast (OC) is a major cause of diseases related to bone loss and bone metabolism. Both bone resorption inhibition and apoptosis induction of osteoclast are crucial in treating these diseases. is an important interferon-stimulated and apoptotic gene. However, how regulates bone formation and remodeling is unknown.
METHODS
We generate global and chimeric knockout mouse models and utilize these models to explore the function and mechanism of in regulating bone formation and remodeling and .
RESULTS
We show that depletion enhances osteoclast generation . knockout increases osteoclast number and bone resorption, thereby exacerbating bone loss in both OVX and osteolysis models. Activation of XAF1 with BV6 (a potent XIAP inhibitor) suppresses osteoclast formation. Mechanistically, deletion decreases osteoclast apoptosis by facilitating the interaction between XIAP and caspase-3/7.
CONCLUSIONS
Our data illustrates an essential role of in controlling osteoclastogenesis in both osteoporosis and osteolysis mouse models and highlights its underlying mechanism, indicating a potential role in clinical treatment.The translational potential of this article: The translation potential of this article is that we first indicated that osteoclast apoptosis induced by XAF1 contribute to the progression of osteoporosis and osteolysis, which provides a novel strategy in the prevention of osteoporosis and osteolysis.
PubMed: 38957269
DOI: 10.1016/j.jot.2024.05.001