Increased skeletal muscle mass index was involved in glycemic efficacy following diabetes treatment, and changes in fat mass index correlated with the changes in the lipid ratio in type 2 diabetes.

AIM: This study aimed to investigate the association between changes in body composition, glycated hemoglobin, and lipid ratio during the treatment of patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective analysis used data from outpatients with T2DM who had confirmed body composition and measured laboratories at administration and after treatment. The baseline characteristics and prescribed treatment were collected. The total cholesterol/high-density lipoprotein cholesterol (HDL) ratio, low-density lipoprotein cholesterol (LDL)/HDL ratio, and triglyceride-glucose (TyG) index were also calculated. RESULTS: A total of 207 patients (mean patient age, 62.0 ± 13.7 years; 68.1 % males) were enrolled. Fat mass index (FMI) changes correlated with the changes in the lipid ratio, whereas skeletal muscle mass index (SMI) changes inversely correlated with glycated hemoglobin (HbA1c) changes. Multiple regression analysis showed that changes in LDL/HDL and TyG correlated with FMI changes (t = 2.388, p = 0.017, t = 2.022, p = 0.044). Conversely, HbA1c changes correlated with SMI changes (t = -2.552, p = 0.011). CONCLUSION: In patients with T2DM, increased SMI was involved in glycemic efficacy, and FMI changes were associated with LDL/HDL and TyG.

[Pharmacological actions of anifrolumab (Saphnelo®) and clinical trial results as a treatment for systemic lupus erythematosus].

Systemic lupus erythematosus (SLE) is an autoimmune disease which causes damaging inflammation in multiple organs via the accumulation of immune complexes. SLE pathogenesis is associated with type I interferons (IFNs), which are central and reflective of disease activity in SLE. Even before clinical development of disease, genetic and environmental contributions to IFN production lead to abnormal innate and adaptive immune activation. Through the Janus kinase-signal transducer and activator of transcription signaling pathway, IFN play a central role in the immunopathogenicity of SLE. Thus, IFN-blocking therapy may be used to regulate inflammation in individuals with SLE. Food and Drug Administration (FDA)-approved anifrolumab (Saphnelo®), which is a human IgG1κ monoclonal antibody that binds to subunit 1 of the type I interferon receptor with high specificity and affinity, was also approved for the treatment of adult patients with moderate to severe SLE who are receiving standard therapy by Pharmaceuticals and Medical Device Agency (PMDA), in Japan in September 2021; anifrolumab is administered as an intravenous infusion, 300 mg over a 30-minute period, every 4 weeks. In this article, we reviewed the actions of type I IFN and anifrolumab as a treatment for SLE.

Sarcopenia is associated with the Geriatric Nutritional Risk Index in elderly patients with poorly controlled type 2 diabetes mellitus.

AIMS/INTRODUCTION: Diabetes and sarcopenia have a two-way relationship with each other with advanced age. Additionally, malnutrition is correlated with a higher risk of sarcopenia in elderly patients. This study evaluated the association between sarcopenia and geriatric nutritional risk index (GNRI) in elderly patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Patients with type 2 diabetes mellitus aged ≥60 years were recruited from June 2018 to August 2020. This study analyzed 234 patients, who completed a physical performance test required for the diagnosis of sarcopenia. To investigate the effect of GNRI on sarcopenia, logistic regression analyses was used. RESULTS: Patients with sarcopenia were significantly older with a lower body mass index (BMI) and GNRI compared with normal patients. The GNRI showed a positive correlation with the skeletal muscle index (SMI) and handgrip strength (SMI: R = 0.486, P < 0.001 for male; R = 0.589, P < 0.001 for female, handgrip strength: R = 0.470, P < 0.001 for male, R = 0.364, P < 0.001 for female). In the multivariate logistic regression model, a higher GNRI was associated with a lower risk of sarcopenia in older men and women with diabetes (adjusted odds ratio [OR], 0.892; 95% confidence interval [CI], 0.839-0.948 for male; adjusted OR, 0.928; 95% CI, 0.876-0.982 for female). One year of diabetes treatment improved the GNRI in the sarcopenia group with type 2 diabetes mellitus. CONCLUSIONS: A low GNRI was associated with an increased risk of sarcopenia in elderly patients with type 2 diabetes mellitus. Treatment with glucose-lowering drugs improved the GNRI in the sarcopenia group.

Prevention of oxytosis-induced c-Raf down-regulation by (arylthio)cyclopentenone prostaglandins is neuroprotective.

Prolonged exposure to high concentrations of glutamate leads to cell type specific glutathione depletion and resulting oxidative stress, known as oxytosis. As a result of glutathione depletion, accumulation of reactive oxygen species and Ca2+ influx are increased; however, the specific target of oxytosis has yet to be identified. In the present study, we focused on the effect of glutamate-induced oxidative stress on the extracellular-regulated protein kinase (ERK) pathway using the murine hippocampal HT22 cell line. Although the contribution of the ERK pathway to glutamate-induced oxytosis in HT22 cells is controversial, Western blot analysis revealed that glutamate caused down-regulation of mitogen-activated protein kinase kinase kinase (c-Raf) and a resulting decrease in the phosphorylation of c-Raf, as well as of mitogen-activated protein kinase kinase1/2 (MEK1/2) and ERK1/2, downstream components of the c-Raf/MEK/ERK pathway. Furthermore, neuroprotective (arylthio)cyclopentenone prostaglandins prevented glutamate-induced c-Raf down-regulation and consequently maintained the basal activity of c-Raf and its downstream signaling components. A pull-down assay using biotin-labeled cyclopentenone prostaglandins revealed that they preferentially bound to c-Raf relative to other signaling molecules of the ERK pathway, including Ras, MEK1/2, and ERK. These results suggest that neuroprotective (arylthio)cyclopentenone prostaglandins directly bind to c-Raf protein and protect cells from down-regulation of the c-Raf protein itself, resulting in neuroprotection against oxidative stress.

Neuropeptide W stimulates adrenocorticotrophic hormone release via corticotrophin-releasing factor but not via arginine vasopressin.

Neuropeptide W (NPW) was isolated as an endogenous ligand for NPBWR1, an orphan G protein-coupled receptor localized in the rat brain, including the paraventricular nucleus. It has been reported that central administration of NPW stimulates corticosterone secretion in rats. We hypothesized that NPW activates the hypothalamic-pituitary-adrenal (HPA) axis via corticotrophin-releasing factor (CRF) and/or arginine vasopressin (AVP). NPW at 1 pM to 10 nM did not affect basal or ACTH-induced corticosterone release from dispersed rat adrenocortical cells, or basal and CRF-induced ACTH release from dispersed rat anterior pituitary cells. In conscious and unrestrained male rats, intravenous administration of 2.5 and 25 nmol NPW did not affect plasma ACTH levels. However, intracerebroventricular (icv) administration of 2.5 and 5.0 nmol NPW increased plasma ACTH levels in a dose-dependent manner at 15 min after stimulation (5.0 vs. 2.5 nmol NPW vs. vehicle: 1802 ± 349 vs. 1170 ± 204 vs. 151 ± 28 pg/mL, respectively, mean ± SEM). Pretreatment with astressin, a CRF receptor antagonist, inhibited the increase in plasma ACTH levels induced by icv administration of 2.5 nmol NPW at 15 min (453 ± 176 vs. 1532 ± 343 pg/mL, p<0.05) and at 30 min (564 ± 147 vs. 1214 ± 139 pg/mL, p<0.05) versus pretreatment with vehicle alone. However, pretreatment with [1-(ß-mercapto-ß, ß-cyclopentamethylenepropionic acid), 2-(Ο-methyl)tyrosine]-arg-vasopressin, a V1a/V1b receptor antagonist, did not affect icv NPW-induced ACTH release at any time (p>0.05). In conclusion, we suggest that central NPW activates the HPA axis by activating hypothalamic CRF but not AVP.

Neuroprotective effects of (arylthio)cyclopentenone derivatives on manganese-induced apoptosis in PC12 cells.

Parkinson's disease is characterized by degeneration of dopaminergic neurones in the substantia nigra. Chronic manganese poisoning shares many features of Parkinson's disease, and also induces extrapyramidal syndromes that resemble those of Parkinson's disease due to dopamine depletion in the central nervous system. This study was undertaken to develop novel neuroprotective drugs via the identification of compounds that inhibit manganese-induced apoptosis. Here, we report that (arylthio)cyclopentenone derivatives, which are synthetic analogs of cyclopentenone prostaglandins, prevent manganese-induced apoptosis in PC12 cells. A highly sensitive assay of caspase-3/7 activity was used for screening newly synthesized prostaglandin analogs. The results showed that some cyclopentenone derivatives (GIF-0642, GIF-0643, GIF-0644, GIF-0745, and GIF-0747) inhibit manganese-induced caspase-3/7 activation in a concentration-dependent manner. Effective compounds all have an arylthio group, indicating that this structure plays an important role in the anti-apoptotic effects of (arylthio)cyclopentenone derivatives. The anti-apoptotic effects of these compounds were confirmed by verifying their ability to inhibit the DNA fragmentation and caspase-9 activation induced by manganese. Furthermore, GIF-0747 prevented manganese-induced cytochrome c release from mitochondria. These results suggest that (arylthio)cyclopentenone derivatives may be good candidates for treating neurodegenerative diseases.

(Arylthio)cyclopentenones derivatives prevent glutamate-induced HT22 cell death through a PPAR gamma-dependent pathway.

We show that cyclopentenone derivatives, which are synthetic analogs of cyclopentenone prostaglandins, are neuroprotective against glutamate-induced oxidative stress in HT22 cells. This effect was antagonized by a peroxisome proliferator-activated receptor-gamma (PPAR gamma) antagonist, T0070907. Pull-down assays revealed that biotinylated (arylthio)cyclopentenone (GIF-0643-biotin) and other biotin-bound cyclopentenones bind to PPAR gamma. The results also indicate that the GIF-0643-biotin-PPAR gamma complex is localized to the nucleus. Moreover, retinoid X receptor-alpha (RXR) co-precipitated with the GIF-0643-biotin-PPAR gamma complex, indicating that (arylthio)cyclopentenone can activate PPAR gamma-RXR heterodimers. These findings suggest that (arylthio)cyclopentenone derivatives prevent excitotoxicity by modulating gene expression via activation of the PPAR gamma-RXR hetrodimer.

Synthesis of neuroprotective cyclopentenone prostaglandin analogs: suppression of manganese-induced apoptosis of PC12 cells.

The synthesis and evaluation for anti- and proapoptotic properties of cyclopentenone prostaglandin analogs are described. Novel J-type analogs of NEPP11 with a cross-conjugated cyclopentadienone moiety and a lipophilic omega-side chain suppressed manganese ion-induced apoptosis of PC12 cells at comparable levels to NEPP11, while monoenone derivatives were inactive. The proapoptotic activities of J-type analogs were much lower than that of NEPP11. Natural 15-deoxy-Delta(12,14)-PGJ(2) and Delta(7)-PGA(1) methyl ester were highly toxic, inducing apoptosis at lower concentrations.