MGF

BACKGROUND AND HYPOTHESIS: Retatrutide is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors that reduced weight and HbA1c in individuals with obesity and type 2 diabetes (T2D). Retatrutide may also address key chronic kidney disease (CKD)-related pathophysiological pathways. Mechanism-of-action studies are needed to understand its effects on kidney function. METHODS: TRANSCEND-CKD is a double-blind, placebo-controlled, Phase 2b mechanistic study evaluating the efficacy of retatrutide in adults with overweight/obesity and CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2, with and without T2D. Participants were randomized 1:1 to once-weekly retatrutide maximum tolerated dose up to 12 mg or matched placebo. The primary objective is to evaluate the effect of retatrutide versus placebo on change in measured glomerular filtration rate (mGFR) by iohexol clearance from baseline to Week 24. Additional objectives include changes in MRI-assessed kidney hemodynamic and volumetric measurements, including perirenal and renal sinus fat. RESULTS: Of 367 participants screened, 146 were randomized to study interventions. The mean age was 65.1 years [SD 10.6], 45.2% were female, and 69.9% were White. The mean weight was 101.1 kg (SD 20.6) and BMI 35.7 kg/m2 (SD 6.1). Participants with T2D (37.7%) had a mean HbA1c of 7.1% (SD 1.1%), while HbA1c was 5.7% (SD 0.3%) in participants without T2D. The mean mGFR was 49.3 mL/min/1.73 m2 (SD 19.0), cystatin C-based eGFR was 49.6 mL/min/1.73 m2 (SD 13.2), and creatinine-based eGFR was 64.2 mL/min/1.73 m2 (SD 17.8). The median baseline urine albumin-to-creatinine ratio was 14.0 mg/g (IQR 6.0-69.0). A total of 21.8% of participants were treated with sodium-glucose co-transporter-2 inhibitors at baseline. CONCLUSIONS: TRANSCEND-CKD is designed to provide mechanistic insights on the effects of retatrutide on kidney function and structure, and to inform clinical findings in the ongoing cardio-kidney outcome trial TRIUMPH-Outcomes (NCT06383390).

Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent.

Nerve injuries and lesions often lead to the loss of neural control, reducing the patients' quality of lives. Nerve self-repair is difficult due to the low regeneration capacity, insufficient secretion of neurotrophic factors, secondary complications, and adverse microenvironmental conditions such as severe hypoxia-ischemia, inflammation, and oxidative stress. Effective therapies that can accelerate nerve regeneration have been explored. Cytokine therapy can significantly improve neural survival and myelin regeneration during nerve repair. Insulin-like growth factor-1 (IGF-1) and its isoforms (IGF- 1Ea and IGF-1Eb/Ec [also known as MGF]) represent a promising therapeutic approach regarding nerve repair, given their well-described proliferative and anti-apoptotic capacities on neurons withstanding the adverse environmental conditions. This review summarizes the research progress regarding the effects of IGF-1 and its isoforms on nerve repair after nerve injury, hypoxic-ischemic insult, inflammation, and oxidative stress. We provide a theoretical basis for the clinical treatment of nerve injuries.

KEY POINTS: Treatment with semaglutide compared with placebo for 24 weeks reduced lean body mass and fat mass in adults with CKD and overweight or obesity. Changes in lean body mass or fat mass during semaglutide treatment did not correlate with changes in creatinine or cystatin C‑eGFR or measured GFR. Semaglutide significantly reduced extracellular water and BP, and changes in BP correlated with extracellular water. BACKGROUND: The glucagon-like peptide-1 receptor agonist semaglutide reduces hemoglobin A1c, body weight, BP, and GFR decline. Semaglutide may influence serum creatinine and cystatin C levels by nonkidney-related mechanisms and thereby affect eGFR. We studied the relationship between changes in body composition, eGFR and measured GFR (mGFR), and BP during semaglutide treatment. METHODS: We performed a prespecified analysis of a randomized placebo-controlled double-blind clinical trial in 101 adults with CKD with overweight status or obesity and without type 2 diabetes. Participants were randomized to 24 weeks of semaglutide 2.4 mg/wk subcutaneously or matched placebo treatment. We measured GFR with iohexol clearance, estimated GFR with creatinine and cystatin C, and used bioimpedance spectroscopy to determine lean body mass, fat mass, and extracellular water. RESULTS: After 24 weeks of treatment, semaglutide compared with placebo changed total body weight, lean body mass, and fat mass by -9.1 (95% confidence interval [CI], -11.0 to -7.2), -2.5 (95% CI, -6.6 to 1.6), and -3.9 (95% CI, -7.8 to 0.0) kg, respectively. No correlations were present between changes in total body weight, lean body mass, and fat mass with changes in eGFR (creatinine or cystatin C) or mGFR during semaglutide treatment (all Spearman correlation coefficients <0.23). Similar results were observed in multivariable adjusted analyses. Semaglutide compared with placebo changed extracellular water and systolic BP by -0.9 (95% CI, -1.6 to -0.1) L and -6.3 (95% CI, -10.9 to -1.7) mm Hg, respectively. Systolic BP changes during semaglutide treatment correlated with extracellular water changes (Spearman correlation 0.40; P = 0.005). CONCLUSIONS: Semaglutide reduced lean body mass and fat mass in patients with CKD with overweight status or obesity. These changes did not correlate with changes in creatinine or cystatin C eGFR or mGFR, suggesting that body weight reductions of 10% with semaglutide do not influence GFR estimates. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT04889183.

BACKGROUND AND HYPOTHESIS: Semaglutide is a glucagon-like peptide-1 receptor agonist widely used for its glucose-lowering effects in people with type 2 diabetes (T2D), as well as its cardiovascular and kidney-protective properties. However, it remains unclear whether semaglutide influences blood concentrations of endogenous filtration markers like creatinine, cystatin C, beta-trace protein (BTP), and beta-2 microglobulin (B2M). We investigated the effect of semaglutide on these filtration markers and the performance of estimated glomerular filtration rate (eGFR) equations compared with measured glomerular filtration rate (mGFR). METHODS: Post hoc analysis of a randomized, double-blind, placebo-controlled clinical trial. Individuals with T2D and albuminuria were randomized in a 1:1 ratio to receive semaglutide 1 mg weekly or matching placebo for 26 weeks on top of empagliflozin. mGFR was determined by 99m-Tc-DTPA plasma clearance and eGFR was calculated using CKD-EPI equations based on plasma creatinine (eGFRcre), cystatin C (eGFRcys), their combination (eGFRcomb), or a panel of creatinine, cystatin C, BTP, and B2M (eGFRpanel). Outcomes included change in filtration marker concentration, mGFR, and eGFR from baseline to end-of-treatment, as well as eGFR performance compared to mGFR at each timepoint. RESULTS: Among 48 participants (median age 70 years; 16.7% female), semaglutide treatment was associated with a small but significant increase in plasma creatinine and BTP compared with placebo, whereas there was no significant change in cystatin C or B2M. Semaglutide treatment was not associated with a significant change in mGFR (median [IQR] change of 0 [-7.5 to 10.3] mL/min/1.73 m2) compared with placebo (median [IQR] change of -2 [-11.3 to 3.0] mL/min/1.73 m2). Both eGFRcre and eGFRcys were consistently outperformed by eGFRcomb and eGFRpanel at baseline and end-of-treatment. CONCLUSION: Semaglutide treatment was associated with a small increase in plasma creatinine and BTP but not cystatin C or B2M, and eGFRcomb yielded the most reliable estimates of mGFR.

Clinical evidence shows that the mechanical stimulation obtained from occlusion could enhance periodontal ligament (PDL) remodeling. Mechano-growth factor (MGF) is a growth factor produced specifically following mechanical stimulus Here, we aim to investigate the mechanical enhancement potential and mechanism of the MGF in PDL regeneration. In vivo study found that MGF produced from the PDL under occlusion force could strongly enhance PDL remodeling. In vitro experiments and mathematical modeling further confirmed the mechanical enhancement effect of MGF for PDLSC differentiation toward fibroblasts. A mechanochemical coupling effect of MGF mediated the enhancement of mechanical effect, which was modulated by Fyn-FAK kinases signaling and subsequent MAPK pathway. Finally, enhanced PDL regeneration under the mechanochemical coupling of MGF and occlusal force was verified in vivo. There exists an additive mechanical effect of MGF mediated by Fyn-FAK crosstalk and subsequent ERK1/2 and p38 phosphorylation, which could be developed as an MGF-centered adjuvant treatment to optimize PDL remodeling, especially for patients with weakened bite force or destroyed periodontium.