Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that a high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms involved in estrogen-deficient diabetic female mice, relevant cell lines, and female T2D patients. Initially, female mice fed a HFHSD exhibited a delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment with miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protects against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management.

Immunomodulation by radiotherapy (RT) is an emerging strategy for improving cancer immunotherapy. Nanomaterials have been employed as innovative tools for cancer therapy. This study aimed to investigate whether mesoporous silica nanoparticles (MSNs) enhance RT-mediated local tumor control and the abscopal effect by stimulating anti-cancer immunity. Hepa1-6 murine hepatocellular carcinoma syngeneic models and immunophenotyping with flow cytometry were used to evaluate the immune responses. When mice harboring bilateral tumors received 8 Gy of X-rays on a single tumor, the direct injection of MSNs into irradiated tumors enhanced the growth inhibition of irradiated and unirradiated contralateral tumors. MSNs enhanced RT-induced tumor infiltration of cytotoxic T cells on both sides and suppressed RT-enhanced infiltration of regulatory T cells. The administration of MSNs pre-incubated with irradiated cell-conditioned medium enhanced the anti-tumor effect of anti-PD1 compared to the as-synthesized MSNs. Intracellular uptake of MSNs activated JAWS II dendritic cells (DCs), which were consistently observed in DCs in tumor-draining lymph nodes (TDLNs). Our findings suggest that MSNs may capture tumor antigens released after RT, which is followed by DC maturation in TDLNs and infiltration of cytotoxic T cells in tumors, thereby leading to systemic tumor regression. Our results suggest that MSNs can be applied as an adjuvant for in situ cancer vaccines with RT.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the progressive destruction of pancreatic β-cells, leading to insulin deficiency. The primary drivers of β-cell destruction in T1D involve autoimmune-mediated processes that trigger chronic inflammation and ultimately β-cell loss. Regulatory microRNAs (miRNAs) play a crucial role in modulating these processes by regulating gene expression through post-transcriptional suppression of target mRNAs. Dysregulated miRNAs have been implicated in T1D pathogenesis, serving as both potential diagnostic biomarkers and therapeutic targets. This review explores the role of miRNAs in T1D, highlighting their involvement in disease mechanisms across both rodent models and human patients. While current antidiabetic therapies manage T1D symptoms, they do not prevent β-cell destruction, leaving patients reliant on lifelong insulin therapy. By summarizing key miRNA expression profiles in diabetic animal models and patients, this review explores the potential of miRNA-based therapies to restore β-cell function and halt or slow the progression of the disease.

MicroRNAs (miRNAs) are key regulators of both physiological and pathophysiological mechanisms in diabetes and gastrointestinal (GI) dysmotility. Our previous studies have demonstrated the therapeutic potential of miR-10a-5p mimic and miR-10b-5p mimic (miR-10a/b mimics) in rescuing diabetes and GI dysmotility in murine models of diabetes. In this study, we elucidated the safety profile of a long-term treatment with miR-10a/b mimics in diabetic mice. Male C57BL/6 mice were fed a high-fat, high-sucrose diet (HFHSD) to induce diabetes and treated by five subcutaneous injections of miR-10a/b mimics for a 5 month period. We examined the long-term effects of the miRNA mimics on diabetes and GI dysmotility, including an assessment of potential risks for cancer and inflammation in the liver and colon using biomarkers. HFHSD-induced diabetic mice subcutaneously injected with miR-10a/b mimics on a monthly basis for 5 consecutive months exhibited a marked reduction in fasting blood glucose levels with restoration of insulin and significant weight loss, improved glucose and insulin intolerance, and restored GI transit time. In addition, the miR-10a/b mimic-treated diabetic mice showed no indication of risk for cancer development or inflammation induction in the liver, colon, and blood for 5 months post-injections. This longitudinal study demonstrates that miR-10a/b mimics, when subcutaneously administered in diabetic mice, effectively alleviate diabetes and GI dysmotility for 5 months with no discernible risk for cancer or inflammation in the liver and colon. The sustained efficacy and favorable safety profiles position miR-10a/b mimics as promising candidates in miRNA-based therapeutics for diabetes and GI dysmotility.

Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms pathway in estrogen-deficient diabetic female mice, cell lines, and patients with T2D in female. Initially, female mice fed a HFHSD exhibited delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment of miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protect against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management.

BACKGROUND We previously identified miR-10b-5p as a key regulator of gastrointestinal (GI) motility through its essential role in the development and function of interstitial cells of Cajal (ICC), the pacemaker cells of the gut. Loss of miR-10b-5p in ICC impairs intestinal motility and contributes to constipation, a common condition in the elderly. Notably, miR-10b-5p is co-expressed with its paralog, miR-10a-5p, in ICC. AIM To investigate the roles of miR-10a-5p and miR-10b-5p in age-associated intestinal dysmotility and assess the therapeutic potential of restoring their expression. METHODS We employed aged mice, mir-10a and mir-10b single and double knockout (KO) models, and human plasma and colon samples across age groups. GI and colonic transit, ICC network integrity, and expression levels of miR-10a/b-5p were evaluated. Additionally, we tested whether treatment with their microRNA mimics could restore GI motility in aged mice. RESULTS Aged mice exhibited delayed GI and colonic transit, reduced fecal output, and diminished expression of miR-10a-5p and miR-10b-5p, which peaked during late embryonic and early postnatal stages and declined with age. This decline paralleled ICC network deterioration in the colon. All KO models exhibited impaired motility and ICC loss, with mir-10a KO mice displaying more severe phenotypes than mir-10b KO mice. Double KO mice demonstrated growth retardation and reduced survival, with homozygous mutants living only up to 3 months. Treatment of aged mice with miR-10a-5p and miR-10b-5p mimics encapsulated in jetPEI significantly improved GI and colonic motility. Successful delivery to the gut, including the colon, was confirmed. In human samples, both miR-10a/b-5p and KIT expression decreased with age. CONCLUSION miR-10a-5p and miR-10b-5p are essential for ICC maintenance and colonic motility, and their age-related decline contributes to GI dysmotility in both mice and humans. Restoring their levels offers a promising therapeutic strategy for treating age-related constipation and other motility disorders.