Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 10, 2023

Background: Osteoporosis is widespread and has become an emerging problem in the elderly. MicroRNAs could affect osteoblast differentiation and further regulate the occurrence of osteoporosis by targeting osteogenic differentiation signaling pathways. Our screening study found that miR-12200-5p simultaneously targeted six important factors within the Wnt signaling pathway (Apc, Tcf4, Tcf7, Wnt3a, Wnt5a, and Lrp6), indicating that miR-12200-5p might function as a strong regulator of this pathway. Since the Wnt pathway exists as one of the most essential pathways for osteogenic differentiation, miR-12200-5p may have an important role in the development of osteoporosis. Objective: This study intended to explore the regulatory role and corresponding mechanism of miR-12200-5p in osteoblast differentiation. Methods: We investigated the differentiation of osteoblast after the treatments of miR-12200-5p mimic and inhibitor. The interactions between miR-12200-5p and its target genes were also detected. Furthermore, the rescue effect of miR-12200-5p inhibitor on osteoporosis was evaluated using an ovariectomized osteoporosis mouse model. Results: MiR-12200-5p significantly inhibited osteoblast differentiation, and bound with the 3’-UTR sequences of its target genes (Apc, Tcf4, Tcf7, Wnt3a, Wnt5a, and Lrp6) to reduce the expressions of these genes. The inhibition of miR-12200-5p would almost fully alleviate postmenopausal osteoporosis. Conclusion: MiR-12200-5p could strongly repress osteoblast differentiation and bone formation by targeting multiple members of the Wnt signaling pathway simultaneously. The study supplemented the theoretical and experimental basis for researching the mechanism of osteogenic differentiation and inspired the development of novel therapeutic strategies for osteoporosis.

Background: Growing pieces of evidence demonstrate a close relationship between bone regeneration disorders of diabetic patients and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Drugs targeting NLRP3 in the treatment of diabetic bone disorders have been heatedly discussed in recent years, and new R ideas should be explored. Objective: This review analyzes molecular mechanisms of how hyperglycemia activates NLRP3 and leads to bone disorders in diabetic patients. Also, this review focuses on the research of drugs targeting NLRP3 inflammasome in the treatment of diabetic bone disorders, and eventually points out the ideas for new drug development. Results: In diabetic patients, hyperglycemia ultimately increases the expression of NLRP3 inflammasome which cleaves pro-IL-1β into mature IL-1β by caspase-1, leading to impaired bone formation. Drugs targeting NLRP3 inflammasome are divided into two categories. Indirect-acting drugs for NLRP3 inflammasomes include dipeptidyl peptidase-4 inhibitors, lipoxygen A4, epigallocatechin gallate, and vitamin D3. Direct-acting drugs include Glyburide, Dioscin, and Pristimerin. Conclusion: The presented studies indicate that hyperglycemia is the initiating factor for NLRP3-induced bone disorders in diabetic patients. The main drug targets are the molecules relevant to the assembly and activation of NLRP3 inflammasome. These data may provide a theoretical basis for the further development of drugs targeting NLRP3 inflammasome in the treatment of diabetic bone disorders.

Background: Bone health relies on the equilibrium between resorption and new bone generation. Postmenopausal osteoporosis depends on estrogen deficiency which favorite bone resorption and elevated risk of fractures. Moreover, osteoporosis is characterized by a high release of proinflammatory cytokines suggesting the role of the immune system in the pathogenesis of this complex disease (immunoporosis). Aims: To review the pathophysiology of osteoporosis from an endocrinological and immunological viewpoint and treatments with a specific focus on nutraceuticals. Methods: PubMed/MEDLINE, Scopus, Google Scholar, and institutional web site were searched. Original articles and reviews were screened and selected by September 2022. Results: The activation of the Gut Microbiota-Bone Axis contributes to bone health by releasing several metabolites, including short-chain fatty acids (SCFAs), that facilitate bone mineralization directly and indirectly by the induction of T regulatory cells, triggering anti-inflammatory pathways. Conclusion: Treatments of postmenopausal osteoporosis are based on lifestyle changes, calcium and vitamin D supplementation, and anti-resorptive and anabolic agents, such as bisphosphonates, Denosumab, Teriparatide, Romosozumab. However, phytoestrogens, polyphenols, probiotics, and polyunsaturated fatty acids may improve bone health by several mechanisms, including anti-inflammatory properties. Specific clinical trials are needed to assess the efficacy/effectiveness of the possible anti-osteoporotic activity of natural products as add on to background treatment.

Breast cancer is avertible yet one of the most widespread carcinomas globally. Though periodic screening and monitoring have resulted in reduced incidences, the malignancy claims increased death rates across the globe. Due to the non-specific and aggressive nature of available conventional cancer therapeutics, there is a crucial need for better treatment paradigms. Recent advancements in nanotechnology have aided in this by utilizing nanocarriers in targeted drug delivery approaches. Optimized nanoparticles have been used to enhance the circulation time and target the efficacy of conventional therapeutic drugs. Passive targeting comprises surface modulation to avoid drug elimination via a standard body defense system. Active targeting includes chemical interaction with various genes, receptors, and antigens overexpressed during cancer progression. Therefore, the present review recapitulates drug delivery approaches and nanoparticle-based targeting that can potentially overcome the limitations of conventional drug therapies.

Aims: Develop a novel murine models of malignant pancreatitis. Background: Although patients with chronic pancreatitis are at a greater risk of developing pancreatic cancer, there is no definitive mouse model that currently develops chronic pancreatitis-induced pancreatic cancer. Objective: Characterization of eosinophilic inflammation-mediated malignant pancreatitis in novel murine model. Methods: We developed a murine model of chronic eosinophilic inflammation associated with pancreatitis that also shows characteristic features of pancreatic malignancy. The mouse received cerulein and azoxymethane via intraperitoneal administration developed pathological malignant phenotype, as well as concomitant lung inflammation. Results: We discovered pathological alterations in the pancreas that were associated with chronic pancreatitis, including a buildup of eosinophilic inflammation. Eosinophil degranulation was reported nearby in the pancreas tissue sections that show acinar-to-ductal metaplasia and acinar cell atrophy, both of which are characteristic of pancreatic malignancies. Additionally, we also observed the formation of PanIN lesions after three initial doses of AOM and eight weeks of cerulein with the AOM treatment regimen. We discovered that persistent pancreatic eosinophilic inflammation linked with a pancreatic malignant phenotype contributes to pulmonary damage. The RNA seq analysis also confirmed the induction of fibro-inflammatory and oncogenic proteins in pancreas and lung tissues. Further, in the current manuscript, we now report the stepwise kinetically time-dependent cellular inflammation, genes and proteins involved in the development of pancreatitis malignancy and associated acute lung injury by analyzing the mice of 3 AOM with 3, 8, and 12 weeks of the cerulein challenged protocol regime. Conclusion: We first show that sustained long-term eosinophilic inflammation induces time-dependent proinflammatory, profibrotic and malignancy-associated genes that promote pancreatic malignancy and acute lung injury in mice.

Patients with insulin resistance (IR) have a higher thyroid volume therefore the aim of our study is to examine the correlation between IR and thyroid volume in the residents of Georgia. Methods: 413 patients with a mean age of 37.3 ± and 11.4 years were included in this study. Out of those, 120 were males, and 293 were females who were studied retrospectively. They had hyperinsulinemia and were referred to the clinic from 2017 to 2019. The factors studied were age, sex, body mass index (BMI), clinical signs, thyroid ultrasound, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids, fasting insulin, fasting glucose, thyroid stimulating hormone (TSH), Free thyroxine (FT4), and Zinc (Zn). Results: IR was detected in 252 individuals. The frequency of men with insulin resistance was significantly higher than in the control group - 72.50%, and 56.31%, respectively (F = 9.55, p= 0.0021). Mean thyroid volume in the patients with IR was significantly higher compared to the controls 20.52 + 6.39 cm³ and 15.25 + 6.55 cm³, respectively (p < 0.001). Hyperinsulinemia had a significant positive correlation with Goiter r = 0.445, p < 0.0001. The associated factors for hyperinsulinemia are: Goiter (1) – OR = 5.12 (95% CI:3.02-8.69); Cholesterol – OR = OR = 3.31 (95% CI: 1.54-7.14); Triglycerides – OR = 3.23 (95% CI:1.02-10.28); Obesity (1)- OR = 3.94 (95% CI: 2.23-6.98); Thyroid structural changes (1) – OR = 2.01 (95% CI: 1.12-3.60); ALT/AST-OR = 4.53 (95% CI: 2.33-8.80); Zn decreased Odds Ratio hyperinsulinemia – OR = 0.95 (95% CI: 0.94-0.97). Conclusion: Hyperinsulinemia is the most common cause of diffuse goiter and the heterogeneous structure of the thyroid. The volume of the thyroid gland shows a significant positive association with the characteristics of metabolic syndrome and increased thyroid volume predictors of metabolic syndrome.

Introduction: Diabetes mellitus is associated with the development of carbonyl-oxidative stress (COS) and an increased risk of a cerebral hemorrhage. Vitamin D3 is considered an additional drug to have an impact on COS and proteolysis in the extracellular matrix. Objective: The study aimed to evaluate the impact of D3 on the COS-markers and matrix metalloproteinases MMP2/MMP9 activity after acute intracerebral hemorrhage (ICH) in rats with experimental type 2 diabetes mellitus (Т2DM) compared to metformin (Met). Methods: T2DM was induced in rats via the intraperitoneal injection of streptozotocin (STZ) and nicotinamide (NA), ICH – by microinjection of bacterial collagenase into the striatum. Rats were randomized into five groups: 1 – intact animals (n = 8), 2 – T2DM (n = 9); 3 – T2DM+ICH (n = 7); 4 – T2DM+ICH+Met (n = 7); 5 – T2DM+ICH+D3 (n = 7). Blood glucose, glycated hemoglobin, and oral glucose tolerance test (OGTT) were assessed using commercial kits. Advanced oxidation protein products (AOPP), protein carbonyls (PC370/430), and ischemia-modified albumin (IMA) were measured by spectrophotometry, advanced glycation end products (AGEs) by quantitative fluorescence, and matrix metalloproteinases MMP2/9 by gelatin zymography. Results: D3 does not significantly affect the glucose level and OGTT in rats with T2DM+ICH. However, it reduces AOPP, PC, and AGEs, thus reducing the COS index. In contrast, the activity of proMMP9 increases after D3 administration. These effects of D3 have been reported to be stronger and sometimes opposite to those of metformin. Conclusion: D3 supplementation may decrease the negative consequences of a cerebral hemorrhage in T2DM by reducing COS and preventing the accumulation of COS-modified proteins in the brain by regulating the expression and activity of MMP9.

Introduction: NPC2 is well known as a player for cholesterol transport. However, the biological role of NPC2 in cancer development and therapy is far from clear. Methods: Here, we explore the potential role of NPC2 in prognosis and immunotherapy across multiple cancer types by integrating RNA-seq data from TCGA and GTEx, protein data from CPTAC, and multiple web analysis databases. Results: Expression depiction between tumour and normal tissues indicated that NPC2 is overexpressed in the majority of the most common cancer types, including glioblastoma and pancreatic cancer, two cancers mostly difficult to diagnose and treat. Conclusion: Cancer stemness in glioblastoma is negatively associated with NPC2 level. NPC2 expression is positively correlated with immune cell infiltration and the expression of several immune checkpoints. IDH1 mutation in GBM is negatively correlated with NPC2 level, while a positive correlation has been found between TP53 mutation and NPC2 expression in pancreatic cancer. NPC2 is also correlated with levels of serum biomarkers used for diagnosis of pancreatic cancer.