Adiponectin mRNA Conjugated with Lipid Nanoparticles Specifically Targets the Pathogenesis of Type 2 Diabetes.

Type 2 diabetes (T2D) is a widespread health condition both in the United States and around the world, with insulin resistance playing a critical role in its development. Effective treatment strategies are essential for managing T2D and mitigating associated risks. Adiponectin (APN), secreted by adipocytes, exhibits an inverse correlation with obesity-related adiposity, and its levels are negatively associated with insulin resistance and body mass index. This study aimed to enhance endogenous APN levels in a diet-induced obese (DIO) mouse model using lipid nanoparticles (LNP) as safe delivery agents for APN mRNA conjugates. The results indicate that APN-mRNA-LNP administration successfully induced APN synthesis in various tissues, including muscle, liver, kidney, pancreas, and adipose cells. This induction was associated with several positive outcomes, such as preventing diet-induced body weight gain, improving hyperglycemia by promoting Glut-4 expression, alleviating diabetic nephropathy symptoms by blocking the EGFR pathway, and reducing pro-inflammatory cytokine production. In addition, the treatment demonstrated enhanced insulin sensitivity by activating DGKd and inhibiting PKCε. This resulted in reactivation of insulin receptors in insulin target tissues and stimulation of insulin secretion from pancreatic beta cells. The findings of the present study highlight the potential of APN-mRNA-LNP-based nucleic acid therapy as a treatment for type 2 diabetes, offering a comprehensive approach to addressing its complexities.

Establishment of a novel cellular model for Alzheimer's disease in vitro studies.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss, cognitive impairment, and behavioral and psychological symptoms of dementia. The limited efficacy of drugs for the treatment of neurodegenerative diseases reflects their complex etiology and pathogenesis. A novel in vitro model may help to bridge the gap between existing preclinical animal models and human clinical trials, thus identifying promising therapeutic targets that can be explored in upcoming clinical trials. By assisting in the identification of the mechanism of action and potential dangers, in vitro testing can also shorten the time and expense of translation. AIM: As a result of these factors, our objective is to develop a powerful and informative cellular model of AD within a short period of time. Through triggering the MAPK and NF-κß signaling pathways with the aid of small chemical compounds (PAF C-16 and BetA), respectively, in mouse microglial (SIM-A9) and neuroblast Neuro-2a (N2a) cell lines. RESULTS: PAF C-16, initiated an activation effect at a concentration of 3.12 nM to 25 nM in the SIM-A9 and N2a cell lines after 72 h. BetA, activated the NF-κß pathway with a concentration of 12.5 nM to 25 nM in the SIM-A9 and N2a cell lines after 72 h. The combination of the activator chemicals provided suitable activation for MEK1/2-ERK and NF-κß in more than three subcultures. Activators significantly initiate APP and MAPT gene expression, as well as the expression of proteins APP, ß. Amyloid, tau, and p-tau. The activation of the targeted pathways leads to significant morphological changes. CONCLUSION: We can infer that the MEK1/2-ERK and NF-κß pathways, respectively, are directly activated by the PAF C-16 and BetA chemicals. The activation of MEK1/2-ERK pathway results in the activation of the APP gene, which in turn activates the ß. Amyloid protein, which in turn results in plaque. Furthermore, NF-κß activation results in the activation of the MAPT gene, which leads to Tau and p-Tau protein activation, which ultimately results in tangles. This can be put into practice in just three days, with a high level of activity and stability that is passed down to the next three generations (subculture), with significant morphological changes. In microglial and neuroblast cell lines, we were successful in creating a novel AD-cell model.

Does Liquid/Injectable Platelet-Rich Fibrin Help in the Arthrocentesis Treatment of Temporomandibular Joint Disorder Compared to Other Infusion Options? A Systematic Review of Randomized Clinical Trials.

Temporomandibular joint disorders (TMDs) are prevalent musculoskeletal conditions involving pain and dysfunction of jaw mobility and function, which have proven difficult to treat satisfactorily. The present study aimed to assess the effectiveness of a liquid platelet-rich fibrin (i-PRF) infusion during arthrocentesis versus other options using coadjuvant materials to reduce TMD symptoms. A literature search was conducted using PubMed, EMBASE, Web of Science, Scopus, and ClinicalTrials.gov for RCTs published before January 2024, comparing i-PRF to any other TMD treatment. This systematic review was registered on PROSPERO (CRD42023495364). The searches generated several recent RCTs that compared i-PRF injection combined with arthrocentesis (AC) to AC-only or AC with platelet-rich plasma (PRP). The outcomes analyzed included measures of pain (visual analog scale, VAS), maximum mouth opening, joint sounds, and MRI-verified changes in joint structure. Across the RCTs, the addition of i-PRF injection to AC resulted in significant improvements in pain relief, joint function, mouth opening, and structural changes compared to AC-only or with PRP over follow-up periods ranging from 6 to 12 months. Current clinical evidence favors using i-PRF as an adjunct to AC rather than AC-only or AC with PRP for the treatment of TMDs. The improvements in subjective and objective outcome measures are clinically meaningful. Still, additional high-quality RCTs with larger sample sizes and longer follow-ups are required to strengthen the evidence base and better define the role of i-PRF in TMD management guidelines.

A novel lncRNA-mediated epigenetic regulatory mechanism in periodontitis.

Periodontitis is a highly prevalent chronic inflammatory disease with an exaggerated host immune response, resulting in periodontal tissue destruction and potential tooth loss. The long non-coding RNA, LncR-ANRIL, located on human chromosome 9p21, is recognized as a genetic risk factor for various conditions, including atherosclerosis, periodontitis, diabetes, and cancer. LncR-APDC is an ortholog of ANRIL located on mouse genome chr4. This study aims to comprehend the regulatory role of lncR-APDC in periodontitis progression. Our experimental findings, obtained from lncR-APDC gene knockout (KO) mice with induced experimental periodontitis (EP), revealed exacerbated bone loss and disrupted pro-inflammatory cytokine regulation. Downregulation of osteogenic differentiation occurred in bone marrow stem cells harvested from lncR-APDC-KO mice. Furthermore, single-cell RNA sequencing of periodontitis gingival tissue revealed alterations in the proportion and function of immune cells, including T and B cells, macrophages, and neutrophils, due to lncR-APDC silencing. Our findings also unveiled a previously unidentified epithelial cell subset that is distinctively presenting in the lncR-APDC-KO group. This epithelial subset, characterized by the positive expression of Krt8 and Krt18, engages in interactions with immune cells through a variety of ligand-receptor pairs. The expression of Tff2, now recognized for its role in chronic inflammatory conditions, exhibited a notable increase across various tissue and cell types in lncR-APDC deficient mice. Additionally, our investigation revealed the potential for a direct binding interaction between lncR-APDC and Tff2. Intra-gingival administration of AAV9-lncR-APDC was shown to have therapeutic effects in the EP model. In conclusion, our results suggest that lncR-APDC plays a critical role in the progression of periodontal disease and holds therapeutic potential for periodontitis. Furthermore, the presence of the distinctive epithelial subpopulation and significantly elevated Tff2 levels in the lncR-APDC-silenced EP model offer new perspectives on the epigenetic regulation of periodontitis pathogenesis.

Long non-coding RNA APDC plays important regulatory roles in metabolism of bone and adipose tissues.

The long noncoding RNA (lncR) ANRIL in the human genome is an established genetic risk factor for atherosclerosis, periodontitis, diabetes, and cancer. However, the regulatory role of lncR-ANRIL in bone and adipose tissue metabolism remains unclear. To elucidate the function of lncRNA ANRIL in a mouse model, we investigated its ortholog, AK148321 (referred to as lncR-APDC), located on chr4 of the mouse genome, which is hypothesized to have similar biological functions to ANRIL. We initially revealed that lncR-APDC in mouse bone marrow cells (BMSCs) and lncR-ANRIL in human osteoblasts (hFOBs) are both increased during early osteogenesis. Subsequently, we examined the osteogenesis, adipogenesis, osteoclastogenesis function with lncR-APDC deletion/overexpression cell models. In vivo, we compared the phenotypic differences in bone and adipose tissue between APDC-KO and wild-type mice. Our findings demonstrated that lncR-APDC deficiency impaired osteogenesis while promoting adipogenesis and osteoclastogenesis. Conversely, the overexpression of lncR-APDC stimulated osteogenesis, but impaired adipogenesis and osteoclastogenesis. Furthermore, KDM6B was downregulated with lncR-APDC deficiency and upregulated with overexpression. Through binding-site analysis, we identified miR-99a as a potential target of lncR-APDC. The results suggest that lncR-APDC exerts its osteogenic function via miR-99a/KDM6B/Hox pathways. Additionally, osteoclasto-osteogenic imbalance was mediated by lncR-APDC through MAPK/p38 and TLR4/MyD88 activation. These findings highlight the pivotal role of lncR-APDC as a key regulator in bone and fat tissue metabolism. It shows potential therapeutic for addressing imbalances in osteogenesis, adipogenesis, and osteoclastogenesis.

Serum Amino Acids Patterns and 4-Year Sarcopenia Risk in Community-Dwelling Chinese Older Adults.

INTRODUCTION: Dietary protein intake and serum amino acids (AAs) are factors controlling the rate of muscle protein synthesis and catabolism. This study examined the association between serum AAs patterns and incident sarcopenia in community-dwelling older adults. METHODS: Chinese older adults in Hong Kong aged ≥65 years attended a health check at baseline and 4-year follow-up. At baseline, fasting blood was collected to measure 17 serum AAs. Serum AAs patterns were identified using principal component analysis. Dietary protein intake was assessed using a validated food frequency questionnaire. A composite score was computed by summing the principal component score and sex-standardized protein intake. Six composite scores representing each AAs pattern were available for each participant. Sarcopenia was defined using the updated version of the Asian Working Group for Sarcopenia. Crude and adjusted multiple logistic regressions were performed to examine the associations between each of the 6 composite scores and sarcopenia over 4 years. Results are presented as odds ratio (OR) and 95% confidence interval (CI). To address multiple testing, a Bonferroni correction was applied using a corrected significance level of p < 0.008 (α 0.05/6 patterns). RESULTS: Data of 2,610 participants (mean age 71.6 years, 45.4% men) were available. In men, serum AAs patterns characterized by high branched-chain AAs (BCAAs) (OR 0.77, 95% CI 0.69-0.87, p < 0.001) and tyrosine, tryptophan, and phenylalanine (OR 0.79, 95% CI 0.71-0.89, p < 0.001) were significantly associated with a lower risk of sarcopenia over 4-year follow-up. After adjusting for confounders, the associations were no longer significant. In women, serum AAs patterns characterized by glutamine, glutamic acid, and methionine (OR 1.28, 95% CI 1.11-1.47, p = 0.001) and arginine, taurine, and serine (OR 1.20, 95% CI 1.06-1.35, p = 0.003) were associated with a higher risk of sarcopenia. After adjusting for confounders, serum AAs pattern characterized by high BCAAs (adjusted OR 1.52, 95% CI 1.25-1.86, p < 0.001) and arginine, taurine, and serine (adjusted OR 1.30, 95% CI 1.09-1.56, p = 0.004) were significantly associated with a higher risk of sarcopenia. No association between other AAs patterns with incident sarcopenia was found. CONCLUSIONS: In community-dwelling Chinese older adults, serum AAs patterns characterized by high BCAAs and nonessential AAs (arginine, taurine, and serine) were associated with a higher risk of sarcopenia in women. Findings may allow identifying new targets for interventions.