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Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED 50 (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam-pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic pain is a common public health problem and remains an unmet medical need. Currently available analgesics usually have limited efficacy for the treatment of chronic pain, including neuropathic pain and persistent inflammatory pain, or they are accompanied by many adverse side effects. The voltage-gated calcium channel blocker (pregabalin) and potassium channel openers (flupirtine and retigabine) have been widely used for the management of chronic pain, but their effectiveness in combination is unclear. In this research, we evaluated the antinociceptive effects of pregabalin in combination with flupirtine or retigabine in carrageenan-induced inflammatory pain and paclitaxel-induced peripheral neuropathy in mice using the von Frey test. Isobolographic analysis indicated that pregabalin exerted synergistic antinociceptive effects when combined with flupirtine or retigabine in neuropathic and inflammatory pain models. Furthermore, the antinociceptive effects of pregabalin, flupirtine/retigabine, and their combinations were significantly attenuated by the Kv7 channel blocker XE991. The favored dose ratio between pregabalin and flupirtine/retigabine in combinations was also investigated. Finally, we evaluated the motor coordination of their combinations using the rotarod test, and the outcomes underpinned their safety. Collectively, our results support the potential use of pregabalin in combination with flupirtine or retigabine to alleviate chronic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Atherosclerosis involves the proliferation and migration of vascular smooth muscle cells (VSMCs). The migration of VSMCs from the media into the intima and their subsequent proliferation are important processes in neointima formation in atherosclerosis and restenosis after percutaneous coronary interventions. Acarbose, an alpha-glucosidase inhibitor, has been demonstrated to not affect serum levels of glucose and decrease the progression of intima-media thickening in rabbits fed with a high cholesterol diet (HCD). We previously showed that increased Ras protein levels enhanced the migration of TNF-α treated A7r5 cells. The aim of this study was to determine the inhibitory effects of acarbose on Ras expression in A7r5 cells. Acarbose also inhibited the phosphorylation of focal adhesion kinase (FAK) and Akt, activities of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, and protein expressions of small G proteins (Ras, Cdc42, RhoA, and Rac1) in a dose-dependent manner. We also found that acarbose could effectively inhibit the proliferation and migration of Ras G12V A7r5 cells by blocking small G proteins and phosphoinositide-3-kinase (PI3K)/Akt signaling. These studies demonstrated that acarbose could theoretically decrease atherosclerosis by targeting Ras signaling., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To determine whether percutaneous nephrolithotomy or ureteroscopic lithotripsy leads to the development of hypertension, using the Taiwan National Health Insurance database., Methods: Data were sourced from the Longitudinal Health Insurance Database (LHID2000) of Taiwan, Republic of China, compiled by the Taiwan National Health Insurance database from 1996 to 2010. Percutaneous nephrolithotomy and ureteroscopic lithotripsy were studied as time-dependent covariates in a Cox proportional hazard model to estimate the hazard ratio for the effect of new-onset hypertension., Results: A total of 2552 patients were included, with 232 PNL percutaneous nephrolithotomy, 1160 ureteroscopic lithotripsy patients, and 1160 comparison patients. There was a significant difference between the incidence of new-onset hypertension between the percutaneous nephrolithotomy and comparison groups (adjusted hazard ratio 1.48, 95% confidence interval 1.13-1.95, P = .005). The percutaneous nephrolithotomy group also had a higher incidence of new-onset hypertension than the ureteroscopic lithotripsy group (adjusted hazard ratio 1.39, 95% confidence interval 1.06-1.83, P = .018). The incidence rate of new hypertension during the follow-up period was 44.5 per 1000 person-years in the percutaneous nephrolithotomy group, 33.0 per 1000 person-years in the ureteroscopic lithotripsy group, and 30.2 per 1000 person-years in the comparison group., Conclusion: An association exists between nephrolithiasis patients who were treated with percutaneous nephrolithotomy and subsequent hypertension diagnosis. Although the exact mechanisms for this phenomenon are not clear, patients who undergo percutaneous nephrolithotomy may need close monitoring of blood pressure during postoperative follow-up., (Copyright © 2016. Published by Elsevier Inc.)

Microglia are the primary immune cells that contribute to neuroinflammation by releasing various proinflammatory cytokines and neurotoxins in the brain. Microglia-mediated neuroinflammation is one of the key characteristics of Alzheimer's disease (AD). Therefore, inhibitory reagents that prevent microglial activation may be used as potential therapeutic agents for treating AD. Recently, many studies have been performed to determine the bioactivities of green tea polyphenol epigallocatechin-3-gallate (EGCG), an efficient antioxidant that prevents neuroinflammation. However, limited information is available on the effects of EGCG on microglia-mediated neuroinflammation. In this study, we investigated the inhibitory effects of EGCG on amyloid β (Aβ)-induced microglial activation and neurotoxicity. Our results indicated that EGCG significantly suppressed the expression of tumor necrosis factor α (TNFα), interleukin-1β, interleukin-6, and inducible nitric oxide synthase (iNOS) in Aβ-stimulated EOC 13.31 microglia. EGCG also restored the levels of intracellular antioxidants nuclear erythroid-2 related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), thus inhibiting reactive oxygen species-induced nuclear factor-κB (NF-κB) activation after Aβ treatment. Furthermore, EGCG effectively protected neuro-2a neuronal cells from Aβ-mediated, microglia-induced cytotoxicity by inhibiting mitogen-activated protein kinase-dependent, Aβ-induced release of TNFα. Taken together, our findings suggested that EGCG suppressed Aβ-induced neuroinflammatory response of microglia and protected against indirect neurotoxicity. These results suggest that EGCG is a possible therapeutic agent for preventing Aβ-induced inflammatory neurodegeneration., (Copyright © 2015 Elsevier B.V. All rights reserved.)

We report the case of a 56-year-old man who in a motor vehicle collision developed a pelvic fracture and complete urethra rupture. Sudden onset of intermittent severe urethral bleeding occurred and it led to life-threatening blood pressure drop and dyspnea. An angiography of internal iliac artery showed a pseudoaneurysm involving the right obturator artery. Super-selective embolization of the feeding vessel was performed with cessation of the blood flow immediately., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Objectives: Deficiency and/or decreased activity of methyltetrahydrofolate reductase (MTHFR) resulted from MTHFR variants are associated with hyperhomocysteinemia, an independent risk factor for vasculopathies in diabetic patients. The aim of this study was to examine MTHFR genotypes between healthy and type 2 diabetes mellitus (T2DM) subjects., Design and Methods: MTHFR C677T and A1298C genotypes were analyzed in 56 T2DM and 62 healthy subjects by PCR-RFLP. Association between MTHFR genotypes and T2DM as well as the lipid/glucose metabolic indexes among T2DM subjects was statistically analyzed., Results: No significance in the distribution of MTHFR genotypes between healthy and T2DM subjects is found. Besides, no significant associations between lipid/glucose metabolic indexes with MTHFR genotypes among diabetic patients are observed., Conclusions: These data indicate the previous observation that MTHFR polymorphisms may play some roles in the pathogenesis and complications of T2DM in Caucasians are unlikely to be applied in Taiwanese patients., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Inhibitory effects of oleanolic acid (OA) and ursolic acid (UA) on aldose reductase (AR) and glycative products in kidney of diabetic mice were examined. OA or UA at 0.05, 0.1 or 0.2% was supplied for 10 weeks. Diabetic mice with 0.1 or 0.2% OA or UA treatments had significantly higher body weight and lower kidney weight at weeks 5 and 10 (P<0.05). OA or UA intake at 0.1 or 0.2% increased their content in the kidney, dose-dependently decreased plasma glucose, HbA1c, renal N(epsilon)-(carboxymethyl)lysine, urinary glycated albumin and urinary albumin levels; elevated plasma insulin and renal creatinine clearance levels; as well as decreased renal sorbitol and fructose concentrations (P<0.05). OA or UA treatments at 0.1 and 0.2% also significantly diminished renal AR activity and dose-dependently down-regulated renal AR mRNA expression (P<0.05). These two compounds at 0.2% significantly reduced renal sorbitol dehydrogenase activity (P<0.05). OA, not UA, treatments at 0.1 or 0.2% dose-dependently enhanced renal glyoxalase I (GLI) activity, up-regulated renal GLI mRNA expression and lowered renal methylglyoxal level (P<0.05). Based on these marked anti-glycative effects, the supplement of OA or UA might be helpful for the prevention or alleviation of glycation associated renal diseases.

Objective: The aim of the current study was to investigate whether changes in post- to pre-overnight sleep systolic blood pressure (SSBP) are associated with sleep respiratory disturbance, pro-inflammatory state, and metabolic situation in patients with sleep-disordered breathing (SDB)., Methods: Anthropometry, sleep polysomnography, biochemical markers, and pre- and post-overnight sleep BP were measured from 263 SDB patients. All SDB patients were further subgrouped into MORNING SURGE (% changes from post- to pre-overnight SSBP >+1SD of this cohort), MORNING DROP (% changes <-1SD), CONSTANT HIGH (% changes within+/-1SD, averaged SSBP>130mmHg) and CONSTANT LOW (% changes within+/-1SD, averaged SSBP<130mmHg)., Results: BMI, neck circumference, waistline circumference, respiratory disturbance index, arousal index, lowest oxygen saturation, duration of SaO(2)<90%, blood glucose, hs-CRP, and metabolic syndrome score in MORNING SURGE and CONSTANT HIGH were significantly greater than those in CONSTANT LOW. Except metabolic syndrome score, all other parameters in MORNING DROP were similar to those in CONSTANT LOW., Conclusion: Patients with SDB whose post- to pre-overnight SSBPs were elevated or maintained a constant high have more sleep respiratory disturbance, more pro-inflammatory state, and higher metabolic syndrome indices than the rest. Without subdividing into CONSTANT LOW, MORNING DROP, CONSTANT HIGH, and MORNING SURGE, the important pathophysiologic points of SDB patients will possibly be missed.

Objectives: This study aimed to examine the association between promoter polymorphisms of Th1 and Th2 cytokine genes [interleukin-4 (IL-4 T-34C, A-81G, C-285T and T-589C), IL-6 (G-174C), IL-10 (A-592C and T-819C) and tumour necrosis factor-alpha (TNF-alpha G-238A and G-308A)] and Graves' disease (GD) in Taiwanese population., Design and Methods: Genomic DNA was extracted from peripheral blood cells of 137 GD patients and 189 control subjects. Cytokine gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism., Results: Genotype frequencies of TNF-alpha G-238A or G-308A between control and GD subjects were significantly different. Frequencies of the high TNF-alpha secreting alleles (-238*A and -308*A) and IL-10 -819*C allele were significantly increased in GD patients. No significant differences regarding IL-4 or IL-6 gene polymorphisms between GD patients and control subjects were found., Conclusions: Our data demonstrated that TNF-alpha G-238A and G-308A genotypes were strongly associated with GD incidence.