-
American Journal of Physiology. Renal... Jun 2024Acid sphingomyelinase (ASM) has been reported to increase tissue ceramide and thereby mediate hyperhomocysteinemia (hHcy)-induced glomerular nucleotide-binding...
Acid sphingomyelinase (ASM) has been reported to increase tissue ceramide and thereby mediate hyperhomocysteinemia (hHcy)-induced glomerular nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of gene (mouse ASM gene code) attenuates hHcy-induced NLRP3 inflammasome activation and associated extracellular vesicle (EV) release in podocytes and thereby suppresses glomerular inflammatory response and injury. In vivo, somatic podocyte-specific Smpd1 gene silencing almost blocked hHcy-induced glomerular NLRP3 inflammasome activation in Podo (podocyte-specific expression of cre recombinase) mice compared with control littermates. By nanoparticle tracking analysis (NTA), floxed shRNA transfection was found to abrogate hHcy-induced elevation of urinary EV excretion in Podo mice. In addition, gene silencing in podocytes prevented hHcy-induced immune cell infiltration into glomeruli, proteinuria, and glomerular sclerosis in Podo mice. Such protective effects of podocyte-specific gene silencing were mimicked by global knockout of gene in mice. On the contrary, podocyte-specific gene overexpression exaggerated hHcy-induced glomerular pathological changes in /Podo (podocyte-specific gene overexpression) mice, which were significantly attenuated by transfection of floxed shRNA. In cell studies, we also confirmed that gene knockout or silencing prevented homocysteine (Hcy)-induced elevation of EV release in the primary cultures of podocyte isolated from mice or podocytes of Podo mice transfected with floxed shRNA compared with WT/WT podocytes. gene overexpression amplified Hcy-induced EV secretion from podocytes of Smpd1/Podo mice, which was remarkably attenuated by transfection of floxed shRNA. Mechanistically, Hcy-induced elevation of EV release from podocytes was blocked by ASM inhibitor (amitriptyline, AMI), but not by NLRP3 inflammasome inhibitors (MCC950 and glycyrrhizin, GLY). Super-resolution microscopy also showed that ASM inhibitor, but not NLRP3 inflammasome inhibitors, prevented the inhibition of lysosome-multivesicular body interaction by Hcy in podocytes. Moreover, we found that podocyte-derived inflammatory EVs (released from podocytes treated with Hcy) induced podocyte injury, which was exaggerated by T cell coculture. Interstitial infusion of inflammatory EVs into renal cortex induced glomerular injury and immune cell infiltration. In conclusion, our findings suggest that ASM in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and inflammatory EV release during hHcy and that the development of podocyte-specific ASM inhibition or gene silencing may be a novel therapeutic strategy for treatment of hHcy-induced glomerular disease with minimized side effect. In the present study, we tested whether podocyte-specific silencing of gene attenuates hyperhomocysteinemia (hHcy)-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and associated inflammatory extracellular vesicle (EV) release in podocytes and thereby suppresses glomerular inflammatory response and injury. Our findings suggest that acid sphingomyelinase (ASM) in podocytes plays a crucial role in the control of NLRP3 inflammasome activation and inflammatory EV release during hHcy. Based on our findings, it is anticipated that the development of podocyte-specific ASM inhibition or gene silencing may be a novel therapeutic strategy for treatment of hHcy-induced glomerular disease with minimized side effects.
Topics: Animals; Sphingomyelin Phosphodiesterase; Podocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Hyperhomocysteinemia; Inflammasomes; Mice, Knockout; Kidney Glomerulus; Glomerulonephritis; Gene Silencing; Mice; Mice, Inbred C57BL; Extracellular Vesicles; Male; Disease Models, Animal
PubMed: 38634138
DOI: 10.1152/ajprenal.00195.2023 -
Frontiers in Pharmacology 2024Amidst rising global burden of depression and the associated challenges with conventional antidepressant therapies, there is a growing interest in exploring the...
Amidst rising global burden of depression and the associated challenges with conventional antidepressant therapies, there is a growing interest in exploring the efficacy and safety of alternative treatments. This study uses a Bayesian network meta-analysis to rigorously evaluate the therapeutic potential of Chinese herbal medicines in the treatment of depression, focusing on their comparative efficacy and safety against standard pharmacological interventions. Five databases (PubMed, Wanfang Data, EMBASE, CNKI, and the Cochrane Library) and grey literature were searched from inception to end of July 2023 to identify studies that assessed the efficacy and safety of Chinese herbal medicines in treating depression. The response rate, Hamilton Depression Scale (HAMD) scores, and rates of adverse events were assessed through both direct and indirect comparisons. Data extraction and risk of bias assessment were meticulously performed. Statistical analysis used Markov chain Monte Carlo methods, with effect size estimates provided as odd ratios and their 95% confidence intervals. A total of 198 RCTs involving 8,923 patients were analyzed, assessing 17 Chinese herbal medicines. Surface Under the Cumulative Ranking results indicated that the top three treatments with the best response rate were possibly , , and ; the top three treatments on the reduction of HAMD scores were , , and ; and the top three treatments with the lowest adverse effects rates were , , and . Interestingly, commonly used synthetic drugs such as , , , , , and , not only appeared to be less effective than specific Chinese herbal medicines (, , , , and ), but they were also related to substantially higher risk of adverse events. Our findings elucidate the promising therapeutic potential of Chinese herbal medicines as viable alternatives in the treatment of depression, with certain herbs demonstrating enhanced efficacy and safety profiles. The outcomes of this study advocate for the integration of these alternative modalities into contemporary depression management paradigms. However, it underscores the necessity for larger, methodologically robust trials to further validate and refine these preliminary findings. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023452109.
PubMed: 38633609
DOI: 10.3389/fphar.2024.1295564 -
BMJ Case Reports Apr 2024Serotonin syndrome (SS) is a drug-induced clinical syndrome characterised by a combination of cognitive, neuromuscular and autonomic dysfunctions. The symptoms may...
Serotonin syndrome (SS) is a drug-induced clinical syndrome characterised by a combination of cognitive, neuromuscular and autonomic dysfunctions. The symptoms may include mild non-specific symptoms such as tremors and diarrhoea to coma and sudden death. Herein, we describe a case of SS in which acute dizziness was associated with supine hypertension and orthostatic hypotension. A man in his mid-30s had a 10-month history of anxiety, depression and chronic tension-type headache. He had been on amitriptyline (25 mg daily) and sertraline (50 mg daily). Increment of sertraline (75 mg daily) and amitriptyline (75 mg daily) and the addition of tramadol led to the development of acute severe dizziness. Physical examinations demonstrate supine hypertension and orthostatic hypotension. He also met the diagnostic criteria of SS. The administration of cyproheptadine provided a complete response to dizziness, supine hypertension, orthostatic hypotension and other clinical features of SS.
Topics: Male; Humans; Hypotension, Orthostatic; Dizziness; Serotonin Syndrome; Amitriptyline; Sertraline; Hypertension; Vertigo
PubMed: 38627042
DOI: 10.1136/bcr-2024-260229 -
Canadian Family Physician Medecin de... Apr 2024To provide a summary of the noteworthy medical articles published in 2023 that are relevant to family physicians. (Review)
Review
OBJECTIVE
To provide a summary of the noteworthy medical articles published in 2023 that are relevant to family physicians.
SELECTING THE EVIDENCE
Articles were chosen and ranked by the PEER (Patients, Experience, Evidence, Research) team, a group of primary care health professionals focused on evidence-based medicine. The selection process involved routine surveillance of tables of contents in high-impact medical journals and continuous monitoring of EvidenceAlerts. Articles were prioritized based on their direct applicability to and potential to influence primary care practice.
MAIN MESSAGE
Selected articles addressed various clinical areas of primary care. The topics included a comparison of a treat-to-target approach versus a high-intensity statins prescription for lipid management; semaglutide and its impact on cardiovascular outcomes; respiratory syncytial virus vaccine for older adults; chlorthalidone versus hydrochlorothiazide in preventing cardiovascular events; amitriptyline for irritable bowel syndrome; the role of opioids in acute back pain; safety of oral penicillin challenges in patients allergic to penicillin; spironolactone for facial acne; strategies to reverse frailty in older adults; and identifying the provider of chronic disease management. Two "up and coming" medications are also mentioned: retatrutide for weight loss and fezolinetant for vasomotor symptoms of menopause.
CONCLUSION
Research published in 2023 yielded several high-quality articles with topics relevant to primary care, including cardiovascular care, irritable bowel syndrome, care of the elderly, and acne management.
Topics: Female; Humans; Aged; Irritable Bowel Syndrome; Analgesics, Opioid; Primary Health Care; Penicillins; Acne Vulgaris
PubMed: 38626998
DOI: 10.46747/cfp.7004245 -
Oral Diseases Apr 2024
PubMed: 38622839
DOI: 10.1111/odi.14966 -
Annals of Internal Medicine May 2024This article summarizes clinically important gastroenterology developments from 2023 for internal medicine specialists. In colorectal cancer screening, a new RNA fecal... (Review)
Review
This article summarizes clinically important gastroenterology developments from 2023 for internal medicine specialists. In colorectal cancer screening, a new RNA fecal screening test is on the horizon, as well as a new analysis on the benefits of using artificial intelligence in screening colonoscopy to detect more polyps. There is new evidence for management of gastrointestinal bleeding, a new drug for treatment of recurrent small-intestinal angiodysplasia, and a new endoscopic treatment method in patients with gastrointestinal tumor bleeding. The authors feature a randomized trial about amitriptyline as treatment for patients with irritable bowel syndrome by primary care providers and bring you news about new biologic agents for inflammatory bowel disease and eosinophilic esophagitis. Finally, they review 2 important articles on new terminology and management of metabolic dysfunction-associated fatty liver disease.
Topics: Humans; Early Detection of Cancer; Gastrointestinal Hemorrhage; Gastroenterology; Colorectal Neoplasms; Colonoscopy; Gastrointestinal Diseases
PubMed: 38621241
DOI: 10.7326/M24-0505 -
Physiology & Behavior Jul 2024Recent research has highlighted the potential role of Helicobacter pylori in the pathogenesis of psychiatric disorders. This study aimed to evaluate the potential...
BACKGROUND
Recent research has highlighted the potential role of Helicobacter pylori in the pathogenesis of psychiatric disorders. This study aimed to evaluate the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in a mouse model.
METHODS
Male C57BL/6 mice were divided into four groups: control, H. pylori infection, antidepressant treatment, and combined treatment. H. pylori infection was induced by oral gavage with a clinically relevant strain, and the antidepressant drug was administered via intraperitoneal injections. Behavioral tests including the forced swim test, sucrose preference test, and open field test were conducted to assess depressive-like behaviors and locomotor activity.
RESULTS
The study demonstrated that H. pylori infection induced depressive-like behaviors in mice, as evidenced by increased immobility time in the forced swim test and reduced sucrose preference. Antidepressant treatment alone partially ameliorated these behavioral changes. Strikingly, the combined treatment of the antidepressant drug and H. pylori eradication therapy led to a significantly greater reduction in depressive-like behaviors compared to either treatment alone. Furthermore, the combined treatment group exhibited increased locomotor activity in the open field test, suggesting a potential improvement in overall psychomotor functioning. ELISA assays revealed alterations in inflammatory cytokines in the H. pylori-infected mice, which were partially attenuated by the combined treatment.
CONCLUSION
The study provides novel evidence for the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in alleviating depressive-like behaviors in a mouse model.
Topics: Animals; Male; Mice, Inbred C57BL; Helicobacter Infections; Amitriptyline; Cytokines; Helicobacter pylori; Disease Models, Animal; Depression; Mice; Antidepressive Agents; Anti-Bacterial Agents; Drug Synergism; Motor Activity; Swimming
PubMed: 38614419
DOI: 10.1016/j.physbeh.2024.114552 -
International Journal of Molecular... Mar 2024Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent... (Review)
Review
Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact.
Topics: Humans; Amitriptyline; Antidepressive Agents, Tricyclic; Drug Packaging; Environmental Pollutants; Environmental Restoration and Remediation
PubMed: 38612638
DOI: 10.3390/ijms25073822 -
Journal of Family Medicine and Primary... Feb 2024Approximately 15% of migraine sufferers need preventative medicine because they have more than two episodes each month. Migraine is a regular, persistent condition that...
BACKGROUND
Approximately 15% of migraine sufferers need preventative medicine because they have more than two episodes each month. Migraine is a regular, persistent condition that frequently makes victims helpless. Numerous drugs from various classes have so far been used in migraine prophylaxis. Their effectiveness is recurrently overshadowed by their side effects because they must be used for a long time, which occasionally necessitates stopping the drug.
MATERIALS AND METHODS
In the tertiary care teaching hospital's department of medicine, a prospective, comparative, open-label study was initiated. Two groups of 80 patients were randomly chosen. For 3 months, the 40 patients in Group A were given a tablet of amitriptyline 10 mg once daily, whereas the 40 patients in Group B were given a tablet of propranolol 20 mg once a day. At the conclusion of the fourth, eighth, and twelfth weeks, the patients' own self-assessment migraine diary and a 4-point pain scale were used to grade the intensity of the headaches.
RESULTS
As a result, in Group A, the mean migraine attack severity in periods 1 and 2 was 5.88 2.69 and 5.41 2.48, respectively. In Group B, the mean was 5.15 2.75 in period 1 and 5.66 2.78 in period 2, respectively. The average length of a migraine attack in Group A was 20.30 5.61 h in period 1 and 16.75 5.23 h in period 2. In Group B, the mean was 16.59 3.21 in period 1 and 18.78 5.14 in period 2. Between groups A and B, there was a statistically significant difference.
CONCLUSION
The average number of migraine attacks reduced in the amitriptyline and propranolol groups as the treatment duration increased. Amitriptyline is a popular medication with established effectiveness and manageable levels of negative side effects. It is the tricyclic antidepressant that is most frequently used to prevent headaches. When administered for migraine prevention, it generates a quick response within 3 months. Propranolol is less effective than amitriptyline at reducing the frequency, length, and severity of episodes.
PubMed: 38605779
DOI: 10.4103/jfmpc.jfmpc_927_23 -
The International Journal of... Apr 2024This study aims to analyze the clinical effects of combining carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot.
OBJECTIVE
This study aims to analyze the clinical effects of combining carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot.
METHODS
A total of 120 diabetic neuropathy patients treated at our hospital from June 2022 to November 2023 were included in the study. Patients meeting the inclusion criteria were registered, and their basic data were collected. The patients were randomly divided into two groups: the control group treated with amitriptyline and the study group treated with a combination of carbamazepine and amitriptyline.
RESULTS
The study group demonstrated significantly better clinical efficacy compared to the control group ( < 0.05). There were no significant differences in psychological status and pain perception before treatment between the two groups ( > 0.05). However, post-treatment, the study group showed improved psychological status, reduced pain perception, and overall better quality of life in both physiological and psychological dimensions compared to the control group ( < 0.05).
CONCLUSION
The combined use of carbamazepine and amitriptyline in the treatment of diabetic neuropathy with concurrent diabetic foot yields positive clinical outcomes. It effectively alleviates symptoms, improves psychological well-being, reduces pain sensation, and enhances overall quality of life. These findings can guide physicians in adopting a more evidence-based treatment approach and provide patients with more effective individualized treatment strategies.
PubMed: 38597593
DOI: 10.1080/00207454.2024.2341915