Endocrine, metabolic & immune disorders drug targets最新文献

Toll-Like Receptors (TLRs) is a pattern recognition receptor that connects innate and adaptive immunity and participates in inflammatory responses play a key role in common autoimmune diseases such as Rheumatoid Arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, and Sjögren's syndrome (SS) by participating in antigen recognition, immune cell activation, and inflammatory factor release. Due to the multi-component and multi-target characteristics of traditional Chinese medicine (TCM), the role of TCM active ingredients acting on TLRs has been widely studied. This article describes the relationship between TLR and four autoimmune diseases, as well as a review of the efficacy of TLR intervention by active ingredients of traditional Chinese medicine. To provide some basis for the future clarification of the mechanism of action of drugs for autoimmune diseases and to assist in the development of new medicines.

Background: Combination therapy with levothyroxine (L-T4) and slow-release T3 (SRT3) in the treatment of hypothyroidism results in a normal triiodothyronine/thyroxine (T3/T4) ratio above that of L-T4 monotherapy. No clinical study has been reported with SRT3 monotherapy for hypothyroidism.

Methods: This study was conducted in two parts. In part one, 20 patients with primary hypothyroidism and serum thyrotropin (TSH) >30 mU/L were randomized into 3 groups receiving 1.6 μg/kg L-T4, equivalent doses of SRT3 or L-T3 of 0.55 μg/kg for 4 weeks and fasting serum free T4 (fT4), T3 and TSH were measured weekly, before taking medication, up to 4 weeks. In part two, in 9 hypothyroid patients on L-T4 therapy and normal serum TSH, L-T4 therapy was discontinued and a once daily dose of SRT3 0.55 μg/kg was replaced. Serum fT4, T3 and TSH were measured weekly.

Results: Part One; in patients treated with L-T3 and L-T4 serum TSH decreased to normal values after 4 weeks of intervention. In 7 patients on SRT3, serum T3 increased from 47±12 at baseline to 110±16 ng/dL and serum TSH decreased from 60±11 at baseline to 24±10 and 26±7 mU/L, respectively, at 14 and 21 days after intervention. At the end of 28 days, mean serum T3 was 110±16, 168±74 and 96±18 ng/dL in SRT3, L-T3 and L-T4 groups, respectively, p<0.001. Part Two: serum fT4 decreased from 1.43±0.7 to 0.41±0.14 ng/dLand serum T3 increased from 86±21 to 113±27 ng/dL by 21 days. Mean serum TSH remained in the normal range until 14 days but increased to 15.1±7.6 mU/L at 21 days. At the end, mean serum fT4, T3 and TSH were 0.35±0.17 ng/dl, 77.4±8.9 ng/dL and 35±11 mU/L.

Conclusion: In patients with primary hypothyroidism SRT3 monotherapy with an equivalent dose to L-T4 maintains normal serum T3, but is unable to sustain normal serum TSH concentration.

Background: Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF.

Methods: We established a rat model of HFpEF using Dahl salt-sensitive rats and evaluated three experimental groups: control (A), HFpEF (B), and canagliflozin-treated HFpEF (C). This study carried out comprehensive analyses of cardiac structure and function, metabolomic profiling, and detailed assessment of myocardial energy metabolism, including mitochondrial respiratory capacity and ATP synthesis. Additionally, we validated our findings using H9C2 cardiomyocytes under controlled conditions.

Results: Canagliflozin treatment significantly improved cardiac remodeling markers, including reduced myocardial volume and fibrosis area, while enhancing diastolic function (E/A ratio). Metabolomic analysis revealed normalization of hypermetabolic states, with significant reductions in key metabolites, including L-lysine, D-glucose, and uridine. The treatment restored balance in multiple metabolic pathways, particularly affecting β-alanine metabolism, pyrimidine metabolism, and the citrate cycle. Notably, canagliflozin enhanced mitochondrial respiratory function, increased ATP synthesis, and optimized fatty acid utilization, as evidenced by reduced free fatty acid content.

Conclusion: Our findings demonstrated that canagliflozin exerts cardioprotective effects through multiple metabolic pathways, suggesting its potential as a therapeutic option for HFpEF. The ability of the drug to optimize energy metabolism and improve mitochondrial function represents a novel mechanism for treating this challenging condition.

Background and aim: In the context of gastrointestinal diseases, the role of monoacylglycerol lipase (MAGL) is significant. Therefore, the objective of this study was to examine the protective effects of MAGL inhibition using JZL184 in rat models of severe acute pancreatitis (SAP) and to explore its mechanism.

Methods: In this study, a rat model of SAP was established, and the rats were divided into three groups for treatment: the Control group (CON), the SAP group (SAP), and the SAP group treated with JZL184 (JZL184). The serum levels of amylase (AMS), alanine aminotransferase (ALT), creatinine (Cr), nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and phosphodiesterase (PDE) were measured using enzyme-linked immunosorbent detection kits. The ascites volume was determined using the cotton ball weighing method. The levels of reactive oxygen species (ROS) were detected using the ROS Kit. Additionally, histological tissue changes were assessed through hematoxylin and eosin staining.

Results: The SAP group showed increased levels of AMS, ALT, Cr, ROS, and ascites volume compared to the CON group. Additionally, the SAP group exhibited congested and edematous lung and pancreatic tissues with inflammation. However, the JZL184 group, when compared to the SAP group, showed decreased levels of AMS, ALT, Cr, and ROS, reduced ascites volume, and significantly reduced lung tissue and pancreatic histopathology scores. In the NO/cGMP/PDE system, compared with the CON group, the levels of NO and PDE in the SAP group were higher and the levels of cGMP were lower. Compared with the SAP group, the JZL184 group decreased NO and PDE levels and increased cGMP levels.

Conclusions: Indeed, the inhibition of MAGL with JZL184 has been found to have a protective effect on rats with SAP. Specifically, it has shown significant improvement in the pathological damage of lung and pancreatic tissues. Furthermore, JZL184 has also exhibited protective effects on the liver and kidney. The mechanism may be related to the effect of JZL184 on the NO/cGMP/ PDE signaling pathway.

Sjögren's syndrome (SS) is an autoimmune disease and its management is palliative. There is no specific dietary protocol for SS patients. A gluten-free diet has been tested in SS patients with celiac disease (CD) and indicated modest improvements. Whether gluten-free diets per sè could alleviate autoimmune inflammatory processes in the salivary glands of SS patients with associated CD or even in SS patients without CD is an interesting hypothesis and warrants clinical studies. Hypokalemia in SS patients is among the most frequent sequelae of renal tubular acidosis. Supplementation with potassium (K)-rich diets can reduce inflammation and oxidative stress. K level in CD patients is highly abnormal at diagnosis and gluten-free diets help to normalize its serum level in CD patients. Furthermore, treatment of severe cases of SS requires concomitant glucocorticoid therapy and K supplementation. Results of two separate clinical trials in (i) patients with rheumatoid arthritis (RA) -a disease with similar pathology to SS- indicated that the enhanced serum cortisol followed K supplementation, and in (ii) celiac patients, serum K levels were normalized after the administration of a gluten-free diet. We reviewed the literature extensively on this topic to propose a hypothesis to address this problem and suggest a novel potential for K-rich, gluten-free diets in SS patients. Based on causal associations, we propose that higher K absorption and cortisol secretion following gluten-free diets accompanied by K-rich diets in SS patients with low serum potassium levels, may confer a higher therapeutic potential. Clinical trials are needed to test this hypothesis.

Background: Low adherence to Oral Antidiabetic Drugs (OADs) in adults with Type 2 Diabetes Mellitus (T2DM) leads to complications, death, and increased healthcare costs.

Objective: This study aimed to evaluate the effectiveness of medication adherence education interventions for the clinical outcomes of adults with T2DM.

Materials and methods: Seventy adults with T2DM from an outpatient clinic in the City of Ardabil, Iran, participated in this study. The participants were randomized into an intervention group (n=35) or a non-interventional group (n=35). The intervention group underwent four educational sessions focused on adherence to OADs. Content within classes was influenced by a participant's Stage of Change (SOC) result, which was related to behavior change modeling. Participants in the non-interventional group were placed on a waiting list to receive educational content after the follow- up. Assessments were conducted at baseline, four weeks, and six months.

Results: Significant improvements in Fasting Plasma Glucose (FPG) (P = 0.018) and 2-hour Plasma Glucose (2-hPG) (P < 0.001) levels were found in the intervention group compared to the noninterventional group post-intervention. Additionally, HbA1C was significantly lower at follow-up in the intervention group than in the non-intervention group (P < 0.001). The Homeostasis Model of Insulin Resistance Assessment (HOMA-IR) revealed a significant increase in target cell sensitivity to insulin in the intervention group compared to that in the non-interventional during the follow- up period (P = 0.009). The SOC for adherence to OADs was significantly improved in the intervention group compared to that in the non-intervention group at the follow-up timepoint (P< 0.001).

Conclusion: Medication adherence education interventions may improve the clinical outcomes of adults with T2DM.

Sedentary lifestyles and prolonged physical inactivity are often linked to poor mental and physical health as well as an increased risk of a number of chronic illnesses, including cancer, obesity, type 2 diabetes, and cardiovascular problems. Metabolic Syndrome (MetS), as the new disease, has emerged as the world's leading cause of illness. Despite having its roots in the West, this issue has now completely globalized due to the development of the Western way of life throughout the world. It currently affects almost one-fifth of the American and European populations, and its incidence has increased in Southeast Asian nations as well. Comparing patients with metabolic syndrome to the general population, it is estimated that they have a 5-fold greater risk of diabetes mellitus and a 2-fold increased risk of atherosclerotic cardiovascular illnesses. MetS is a chronic or prevalent condition associated with various lifestyle conditions characterized by abdominal obesity, low HDL-c cholesterol, insulin resistance, high blood pressure, and dyslipidemia. It has been suggested that insulin resistance, chronic inflammation, and neurohormonal activation are the factors behind the development of metabolic syndrome. In lieu of an upsurge in the complications associated with MetS in modern society, many alternative approaches apart from medicine are being constantly explored. Effects of vivid dietary patterns and nutritional interventions have been thoroughly researched, although the most effective dietary approach remains undetermined. This review discussed different etiological aspects of MetS and brought forth the role of nutritional approaches, micro- and macronutrient intake, lifestyle changes, and herbal intervention in its management.

Background: Diabetes and osteoporosis, as chronic diseases with high incidence, have caused deep concern in the field of global public health due to their high morbidity and mortality. More importantly, the complex and close relationship between diabetes and osteoporosis has gradually become the focus of scientific research. It is very meaningful to carry out bibliometric analysis in the research field of diabetes and osteoporosis to describe the current international trend and present a visual representation of the past and emerging trends of diabetes and osteoporosis in the past decade.

Methods: In this study, the characteristics of the articles on "diabetes and osteoporosis" retrieved and downloaded from the Web of Science Core Collection [WoSCC] database from January 1, 2011 to December 1, 2022 were analyzed by bibliometrics to clarify the evolution and theme trends between the two diseases. Citespace software was used for data analysis and visualization, including countries, academic institutions, journals, authors, subject categories, keywords, references, and citations. In addition, some important subtopics identified by bibliometric characterization were further discussed and reviewed.

Results: Finally, 3372 articles were included in the analysis, including a total of 96 countries, 407 organizations, 1161 journals, and 617 keywords. Articles related to diabetes and osteoporosis were first published in 2011 and then showed an increasing trend year by year. The United States, China, Italy, England, and Japan were the top 5 countries associated with the largest number of publications. University of California-San Francisco, China Medical University, University of Toronto, Shanghai Jiao Tong University, and Mayo Clinic were the top 5 academic institutions in terms of the number of published papers. The top 5 authors with the highest number of publications were William D, Ann V, Nicola, Peter, and Toshitsugu. Osteoporosis International has published 130 articles in this field, ranking first among highly productive journals. In addition to diabetes and osteoporosis, the most frequently used keywords were bone mineral density, obesity, and fracture.

Conclusions: More and more studies have been conducted on diabetes and osteoporosis, and the current research mainly focuses on the pathogenesis of various chronic diseases. In the future, more attention may be paid to the prevention and management of these two chronic diseases and the production and application of new drugs.

Background: Crohn's Disease (CD) is a chronic inflammatory gastrointestinal disease. Ustekinumab (UST) has been utilized as a therapeutic option for CD patients. However, approximately 40-60% of patients exhibit an inadequate response to UST. Accumulating evidence has confirmed the involvement of oral bacteria in the development of CD. Nevertheless, the relationship between oral microbiota and the efficacy of UST therapy in CD patients has remained unexplored.

Materials and methods: We recruited 28 healthy individuals and 53 CD patients, 47 of whom completed the entire UST therapy. Oral samples and clinical data were collected. The clinical response and clinical remission were defined based on the CDAI score. Oral samples were analyzed by 16S rRNA gene sequencing. The analysis of sequence data was performed by QIIME and R.

Results: We revealed the oral microbial difference between the Healthy Control (HC) group and the CD group. The enrichment of Fusobacteria, Leptotrichia, Capnocytophaga, and Campylobacter, and the diminution of Haemophilus and Rothia were observed in the CD group. Differences in oral microbiota were also identified among patients with different efficacy of UST. Compared to the response and remission groups, both the non-response and non-remission groups showed significantly higher levels of Fusobacteria and Leptotrichia. Predictive models for clinical response and clinical remission in UST were developed based on oral microbiota, with the Area Under the Curve (AUC) value of 0.944 and 0.930, respectively.

Conclusion: Oral microbiota was relevant to the UST efficacy in patients with CD based on the predictive model. These findings suggest that oral microbiota could serve as a non-invasive prognostic biomarker for UST treatment in CD patients.