The Efficacy and Safety of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors in Real-World Clinical Practice: Potential Cautionary Use in Elderly Patients with Type 2 Diabetes (T2D).

INTRODUCTION: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown safe and therapeutic efficacy in randomized controlled trials (RCT) to reduce adverse cardiorenal events in high-risk patients with type 2 diabetes (T2D). In this study, we investigated the efficacy and safety of SGLT2 intervention in patients with T2D in a real-world clinical practice to confirm the validity of the RCT results. METHODS: As a retrospective study, we evaluated medical records from 596 patients with T2D treated with SGLT2 inhibitors (dapagliflozin or empagliflozin) in addition to their prior drug regimen to improve glucose control between 2015 and 2019 in the Endocrinology Department at Chungbuk National University Hospital. No control arm was evaluated to compare the effects of adding SGLT inhibitors to the pre-existing regimen. The primary objective was the measurement of glycated hemoglobin (HbA1c) from each individual patient over a 36-month period at 6-month intervals. The secondary parameters were the measurement of fasting plasma glucose (FPG) and body weight (Bwt) changes, as well as the monitoring of adverse events (AEs) and determining the reasons for drug discontinuation. RESULTS: HbA1c levels were reduced at each of the time points throughout the 36-month period and were significantly reduced by 12.5% (P < 0.01) from time 0 (8.8 ± 1.3%) to 36 months (7.7 ± 1.0%). FPG levels [from basal (180 ± 60 mg/dL) to 36 months (138 ± 38 mg/dL)] and Bwt [from basal (74 ± 15 kg) to 36 months (72 ± 15 kg)] were also significantly reduced (P < 0.01) for both measurements in the SGLT2 inhibitor add-on group. Similar to HbA1c profile, the FPG and Bwt were measured at a consistently lower level at 6 months until the end of the study. The most common AEs were hypoglycemia (n = 57), genitourinary infection (GUI) (n = 31), and polyuria (n = 28). In the elderly population (≥ 75 years old), AEs (31%) were generally more prevalent (P < 0.001) than those (21%) in the adult (< 75 years old) patients. Over the study period, 211 (35%) patients either dropped or completely discontinued the use of the SGLT2 inhibitor, and the elderly patients tended to have a higher discontinuation rate (52%; P = 0.005) than the adults (33%). CONCLUSIONS: In this study, we demonstrated that SGLT2 inhibitors are an effective and durable hypoglycemic agent to control blood glucose levels with reduced maintenance of Bwt, but their use in the elderly (≥ 75 years old) patients with T2D may warrant some additional caution due to increased probability of AEs and discontinuation of drug use.

Up to a 15-Year Survival Rate and Marginal Bone Resorption of 1780 Implants with or without Microthreads: A Multi Center Retrospective Study.

The effect of microthreads at the implant neck on the amount of marginal bone resorption is controversial. This multicenter retrospective study compared the implant survival rate and amount of marginal bone resorption between two platform-switching internal connection implant systems with or without microthreads. Patient-related (age and sex), surgery-related (implant installation site, type, diameter, and length), and prosthesis-related (prosthesis type) data were collected from patient charts from the implant placement surgery to the final recall visit. A total of 1780 implants, including 1379 with microthreads and 401 without microthreads, were placed in 804 patients. For implants with and without microthreads, the longest follow-up period after prosthesis delivery was 15 and 6 years, respectively. Twenty implants failed during the 15-year follow-up period (98.8% survival rate) due to failed osseointegration, peri-implantitis, implant fractures, and non-functioning implants. The mean marginal bone loss was < 0.1 mm for both implant systems at the 1-year follow-up and 0.18 mm and 0.09 mm at the 4-year follow-up for implants with and without microthreads, respectively, without statistical significance. Microthreads did not significantly affect the amount of marginal bone loss or the implant survival rate for implants with an internal connection with a platform-switching design.

Proteomic and metabolomic profiling reveals the involvement of apoptosis in meat quality characteristics of ovine M. longissimus from different callipyge genotypes.

Proteome and metabolome changes in muscles from callipyge mutation (+/C) and non-callipyge phenotype (+/+, C/+, and C/C) lambs were profiled to provide insight into the biochemical changes affecting meat quality attributes. M. longissimus thoracis from lambs with all four possible callipyge genotype (n = 4, C/+, C/C, +/C, and +/+) were collected after 3d aging and analyzed using mass-spectrometry based platforms. Among identified proteomes, cytochrome c (pro-apoptotic protein) was detected with significantly lower abundances in +/C. Anti-apoptotic HSP70, BAG3, and PARK7 were over-abundant in +/C, which could result in delayed apoptosis and possibly attributed to tougher meat in callipyge lambs. Eight glycolysis enzymes were overabundant in +/C lambs, whereas 3 enzymes involved in TCA cycle were overabundant in non-callipyge ones (C/C and/or C/+). Twenty-five metabolites were affected by genotypes (P < .05), including metabolic co-factors, polyphenols, and AA/short peptides. Our omics results provided insightful information for revealing the differences in biochemical attributes caused by callipyge mutation.

The new designer drug buphedrone produces rewarding properties via dopamine D1 receptor activation.

Substituted cathinones are synthetic analogs of the active components of natural products and are widely abused worldwide. However, the rewarding properties of these agents have not yet been evaluated. In this study, we investigated the abuse potential of buphedrone [2-(methylamino)-1-phenylbutan-1-one, α-methylamino-butyrophenone] and its effects on the mesolimbic dopaminergic system in mice using conditioned place preference (CPP) analysis, a self-administration test, a locomotor activity test, a behavioral sensitization test and Western blot analysis. Treatment with buphedrone supported CPP and self-administration, enhanced locomotor activity and produced behavioral sensitization when mice were challenged with methamphetamine. SCH23390, a D1 dopamine antagonist, prevented buphedrone-induced CPP, whereas raclopride, a D2 dopamine antagonist, had no effect. SCH23390 also blocked locomotor activity increase by buphedrone, while raclopride partially attenuated locomotor activation. Western blot analysis revealed that repeated buphedrone treatment increased D1 dopamine receptor expression in the dorsal striatum and nucleus accumbens in mice. Collectively, these findings suggest the abuse potential of buphedrone and demonstrate the involvement of the dopaminergic system in the establishment of its rewarding properties.

Metabolomics Profiling to Determine the Effect of Postmortem Aging on Color and Lipid Oxidative Stabilities of Different Bovine Muscles.

The objective of this study was to identify metabolites that could be associated with oxidative stability of aged bovine muscles. Three muscles (longissimus lumbrum (LL), semimembranosus (SM), and psoas major (PM)) from seven beef carcasses at 1 day postmortem were divided into three sections and assigned to three aging periods (9, 16, and 23 days). Although an increase in discoloration was found in all muscles with aging, LL was the most color/lipid oxidative stable, followed by SM and PM (P < 0.05). Lower myoglobin and nonheme iron contents were observed in LL compared to those in SM and PM (P < 0.05). The HPLC-ESI-MS-based metabolomics analysis identified metabolites that were significantly responsive to aging and/or muscle type, such as acyl carnitines, free amino acids, nucleotides, nucleosides, and glucuronides. The results from the current study suggest that color and oxidative stability could be associated with aging but are also muscle-specific. Further studies determining the exact role of the identified metabolites in the color and oxidative stability of beef muscles are warranted.

The new stimulant designer compound pentedrone exhibits rewarding properties and affects dopaminergic activity.

Cathinone derivatives are new recreational drugs known to produce psychostimulant effects. However, unlike other psychostimulants, the addictive potential of cathinone derivatives has not been widely studied. Here, we investigated the effects of pentedrone, a type of cathinone derivative, on the dopaminergic system using reverse transcription polymerase chain reaction and Western blot. We also evaluated the addictive potential of pentedrone using conditioned place preference and self-administration. We found that pentedrone increased the mRNA expression of dopamine 1 receptor, dopamine 2 receptor and dopamine transporter, as well as induced phosphorylation of cAMP response element-binding protein in PC-12 cells. Additionally, pentedrone at 3 and 10 mg/kg significantly increased conditioned place preference in mice, while pentedrone at 0.3 mg/kg/infusion significantly increased self-administration in rats. Finally, we found that acute administration of pentedrone enhanced locomotor activity in a dose-dependent manner. Collectively, these data suggest that the addictive properties of pentedrone may be due to its effects on the dopaminergic system.

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages.

Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces "mitochondrial priming" by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.

Eucommia ulmoides Oliv. Bark. protects against hydrogen peroxide-induced neuronal cell death in SH-SY5Y cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Eucommia ulmoides Oliv. Bark. (EUE), has commonly been used to fortify the muscles and lungs, lower blood pressure, prevent miscarriage, improve the tone of liver and kidneys, and promote longevity the traditional tonic medicines of Korea, China, and Japan. AIM OF THE STUDY: In this study, we investigated that the neuroprotective activities and possible mechanisms of EUE aqueous extract in hydrogen peroxide (H(2)O(2))-induced neuronal cell death in human SH-SY5Y neuroblastoma cells. MATERIAL AND METHOD: We examined the effects of EUE against H(2)O(2)-induced cytotoxicity, DNA condensation, the production of reactive oxygen species (ROS), loss of mitochondria membrane potential (MMP), the proteolysis of cleaved poly-ADP-ribose polymerase (PARP), and the expression of Bcl-2, Bcl-xL, cleaved caspase-3, and release of cytochrome c. Moreover, we attempted to determine whether EUE suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), and phosphoinositide 3-kinase (PI3K)/Akt. RESULTS: Pretreatment with EUE increased cell viability and inhibited cytotoxicity and DNA condensation. EUE also attenuated the increase in ROS production and MMP reduction. Western blot data revealed that EUE inhibited H(2)O(2)-induced up- or down-regulation of cleaved PARP, cleaved caspase-3, Bcl-2, and Bcl-xL. The EUE inhibited release of cytochrome c from mitochondria to the cytosol, and significantly attenuated H(2)O(2)-induced phosphorylation of JNK, p38 MAPK, ERK 1/2, and PI3K/Akt. CONCLUSION: The potent neuroprotective capacity of EUE, shown in these experiments, may potentially be applied in the prevention or treatment of neurodegenerative diseases such as Alzheimer's disease (AD).