Under oxygen availability, normal cells undergo mitochondrial oxidative phosphorylation to metabolize glucose and yield up to 36 ATPs per glucose molecule for cellular functions, and undergo non-oxidative metabolism (glycolysis) under hypoxic and proliferating conditions to yield 2 ATP per glucose. These cells metabolize glucose to pyruvate via glycolysis followed by conversion of pyruvate to lactate via lactate dehydrogenase. However, cancer cells have the ability to undergo glycolysis and ferment glucose to lactate regardless of oxygen availability; a phenomenon first addressed by Otto Warburg and called, ”Warburg effect”. Numerous glycolytic genes/proteins have been identified in tumors; that include glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase-M2 splice isoform (PKM2), and lactate dehydrogenase (LDH-A). Histone deacetylase sirtuin 6 (SIRT6), an epigenetic regulator, is highly expressed in various cancers. SIRT6 plays an important role in Warburg effect by regulating many glycolytic genes. Loss of SIRT6 enhances tumor growth via enhancing glycolysis. This review is mainly concerned with exploring the most recent advances in understanding the roles of the metabolic genes (GLUT1, HK2, PKM2, and LDH-A) and the epigenetic regulator SIRT6 in cancer metabolism and how SIRT6 can modulate these metabolic genes expression and its possible use as a therapeutic target for cancer treatment.

Type 2 diabetes mellitus is a chronic disease that occurs among the general population. The insulin-lowering and homeostasis model assessment of insulin resistance-improving effects of inulin are unconfirmed. We conducted this meta-analysis to examine the efficiency and safety of inulin for improving insulin control, homeostasis model assessment of insulin resistance and HbA1c in patients with type 2 diabetes mellitus. We searched the Web of Science, PubMed, Embase and Cochrane Library databases for relevant articles published before June 1, 2019. In total, 225 randomized controlled trials regarding the efficiency of inulin for the treatment of type 2 diabetes mellitus compared to the efficacy of placebo or other treatments were examined. According to the inclusion and exclusion criteria, 9 trials with a total of 661 participants were included. We concluded that inulin supplementation can significantly improve fasting plasma glucose (SMD = −0.55, 95% CI –0.73 to −0.36, p = 0), HOMA-IR (SMD = −0.81, 95% CI –1.59 to −0.03, p = 0.042) and HbA1c (SMD = −0.69, 95% CI −0.92 to −0.46, p = 0). Further subgroup analyses revealed a significant role of inulin supplementation for treatment durations ≥8 weeks (p = 0.038 for insulin, p = 0.002 for HOMA-IR, p = 0.032 for FPG, p = 0 for HbA1c).

Several secretagogues, such as lubiprostone, have been developed for the treatment of constipation in the last 10 years. It is unclear whether the efficacy of lubiprostone for spontaneous bowel movement (SBM) and the adverse events are similar between idiopathic and opioid-induced constipation and between East-Asian and Western populations. We conducted a meta-analysis to compare efficacy and safety of lubiprostone in two populations with idiopathic vs opioid-induced constipation. The PubMed and Cochrane databases were searched for relevant randomized control trials (RCTs) investigating the efficacy and safety that were published in English up to March 2019. Compared with the placebo groups in idiopathic and opioid-induced constipation, the lubiprostone groups significantly improved in 24-h SBM frequency [relative risk: 1.28, 95% confidence interval, 1.11–1.49, and 1.23, 1.14–1.32] and weekly frequency >3 SBM/week (1.68, 1.41–2.01, and 1.43, 1.01–2.04), respectively. Although the incidence of adverse events was similar between idiopathic and opioid-induced constipation, the incidence of nausea in Western populations with idiopathic constipation was significantly higher (29.2%) than that in East-Asian populations (10.0%, p<0.001). In conclusion, lubiprostone effectively improved SBM frequency, irrespective of the etiology of constipation and population. The incidence of nausea was significantly higher in Western populations.

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly used as an antipyretic analgesic owing to its strong anti-inflammatory action in clinical treatment. However, diclofenac can cause injury, with gastrointestinal mucosal lesions and skin photosensitivity as the main side effects. In general, photosensitive drugs contain photosensitive chemical sites, and form free radicals under ultraviolet irradiation, leading to phototoxic reactions. Therefore, this study focuses on free radical production in photosensitive reactions of diclofenac. The free radical production mechanism of diclofenac under ultraviolet irradiation, which might result in photo-toxicity, was clarified using a direct electron spin resonance method. When diclofenac was irradiated with ultraviolet light (254 nm), diclofenac radicals were generated depending on the ultraviolet irradiation time and stably present for 30 min at room temperature. Diclofenac radicals were produced by the ultraviolet irradiation system depending on the dose of diclofenac until 2 mM. Therefore, diclofenac radicals might directly or indirectly react with various biomolecules to cause phototoxicity, other side effects, and new diclofenac pharmacology owing to its stability of diclofenac radicals.

In the present study, we investigated the beneficial and risky effects of exercise intended to prevent or treat lifestyle-related diseases on insulin sensitivity, lactic acid utilization, lipid metabolism, hepatic and renal oxidative stress, hepatic selenoprotein P and renal function in obese and glucose-intolerant rats with renal failure. We fed normal rats a 20% casein diet while the glucose-intolerant, obese rats received a high-fructose diet, and after then rats received single injection of vancomycin at a dose of 400 mg/kg for constructing the duplicative state of renal failure and diabetes mellitus. They were forced to run for 1 h/day, 6 days/week, for 10 weeks. Exercise reduced visceral fat and ameliorated insulin sensitivity in the high-fructose group, improved lactic acid usage efficiency, however, increased hepatic oxidative stress and complicated renal dysfunction in the normal and high-fructose fed groups with renal failure. Additionally, exercise upregulated hepatic selenoprotein P expression and enhanced renal antioxidative system in both groups. It is concluded that strictly controlled exercise conditions must be adapted to patient health states especially in view of kidney protection, and supplemental therapy is also recommended in parallel with exercise, using nutrients and vitamins for kidney protection.

There is great interest in using natural supplements to treat various medical conditions. In this study, we evaluated the anti-oxidative and stem cell differentiation effects of a mixture of vitamin D, Lactobacillus rhamnosus, ginger, curcumin, and Boswellia extract. The calcein acetoxymethyl assay after H₂O₂ treatment showed that combined natural supplement had an anti-oxidative effect. NS-J also increased calcium deposition, as shown by Alizarin Red S staining, indicating bone formation activity. The contents of type II collagen and glycosaminoglycans, which are biomarkers of cartilage, were higher in mesenchymal stem cells treated with combined natural supplement than in cells treated with individual ingredients of the formula. In mesenchymal stem cells treated with human osteoarthritis synovial fluids, combined natural supplement enhanced the expression of type II collagen and PPAR-δ, overcoming the anti-chondrogenic effect of inflammatory conditions. Combined natural supplement also inhibited Oil Red O staining in cells, which indicates inhibited adipogenesis. Thus, combined natural supplement, a formula comprising vitamin D, Lactobacillus rhamnosus, ginger, curcumin and Boswellia extract, reduced oxidative stress, enhanced osteogenesis and chondrogenesis, and inhibited adipogenesis in mesenchymal stem cells to a greater extent than the individual ingredients, indicating synergistic interaction. In addition, combined natural supplement increased the expression PPAR-δ, suggesting that these effects correlate with the PPAR-δ pathway.

Mesenchymal stem cells, which have the potential to be used in regenerative medicine, require improvements in quality for patient use. To maintain stemness of cultured bone marrow-derived mesenchymal stem cells, we focused on the bone marrow microenvironment, generated a conditioned medium of whole bone marrow cells (BMC-CM), and assessed its effects on bone marrow-derived mesenchymal stem cells. BMC-CM suppressed morphological deterioration and proliferative decline in cultured bone marrow-derived mesenchymal stem cells, suppressed mitochondrial oxidative phosphorylation activity, a stemness indicator, and upregulated suppressors of oxidative phosphorylation such as hypoxia-inducible factor-1 alpha, Sirtuin 3, 4, and 5. Furthermore, BMC-CM upregulated TNF-stimulated gene 6 and ameliorated the therapeutic effects of cells on liver injury in carbon tetrachloride-administered rats. Since the elimination of 20–220-nm particles attenuated the effects of BMC-CM, we further analyzed exosomal microRNAs produced by whole bone marrow cells. Among the 49 microRNAs observed to be upregulated during the preparation of BMC-CM, several were identified that were associated with suppression of oxidative phosphorylation, upregulation of TNF-stimulated gene 6, and the pathogenesis of liver diseases. Thus, bone marrow-derived humoral factors including exosomal microRNAs may help to improve the therapeutic quality of bone marrow-derived mesenchymal stem cells for liver regenerative therapy.

Oxidative stress induced by decreases in tear volume and excessive tear evaporation is a key factor in dry eye disease (DED). Previously, we reported that desiccation stress induces reactive oxygen species generation and up-regulated expression of age-related markers such as p53, p21 and p16. We also showed that the antioxidant astaxanthin prepared as a liposomal formulation could suppress these phenomena in the in vitro DED model. In this study, we evaluated the protective effect of liposomes encapsulating astaxanthin against superficial punctate keratopathy (SPK) in the in vivo rat DED model. This model of DED was characterized by decreased tear volume and increased fluorescein score as an indicator of SPK as well as upregulated expression of age-related markers. Repeat-dose of liposomal astaxanthin prevented increases in the fluorescein score and up-regulation of age-related markers. Liposomes bearing a slight positive surface charge had superior effects and higher affinity compared to neutral liposomes. Furthermore, fluorescence intensities in rat corneal epithelium after administration of high-affinity liposomes labeled with fluorescent dye were higher than those for neutral liposomes. In conclusion, we developed the high-affinity liposomal formulation that can prevent DED and promote antioxidative effects of astaxanthin.

Omega-3 fatty acids intake is important to maintain muscle mass. However, the relationship between omega-3 fatty acids intake and sarcopenia in elderly patients with type 2 diabetes has been unclear. We used the brief-type self-administered diet history questionnaire for the assessment of habitual food and nutrient intake. Body composition of patients was evaluated using bioimpedance analysis. To investigate the effect of energy intake on the presence of sarcopenia, we performed logistic regression analyses. Among the patients, 45 patients (13.2%) were diagnosed as sarcopenia. Patients with sarcopenia were aged [74.2 (5.7) vs 71.4 (5.9) years, p = 0.003] and lower body mass index [21.2 (3.5) vs 24.3 (4.6) kg/m², p<0.001] than those without. In addition, omega-3 fatty acids intake of patients with sarcopenia was lower than that without [2.6 (1.0) vs 3.0 (1.2) kcal/day, p = 0.046]. Omega-3 fatty acids intake was negatively associated with the presence of sarcopenia (odds ratio: 0.29, 95% confidence interval: 0.14–0.60, p<0.001) after adjusting for age, sex, exercise, smoking status, diabetes duration, hemoglobin A1c, energy intake, protein intake, fat intake and omega-3 fatty acids intake. Omega-3 fatty acids intake was negatively associated with the presence of sarcopenia in elderly patients with type 2 diabetes.

We examined the effects of increasing physical activity on arterial stiffness during hyperglycemia. Nineteen glucose-intolerant elderly participated in the study. We randomly assigned 10 participants to increase their daily activity in everyday life, regardless of the time or intensity, for 1 month (PAI group) (age, 74.6 ± 1.3 years; mean ± SE) and nine participants to maintain their level of activity (CON group) (age, 79.2 ± 2.1 years; mean ± SE). The 75-g oral glucose tolerance test was conducted in each participant in both groups before and after the start of the intervention to confirm glucose intolerance. Brachial­ankle pulse wave velocity and cardio-ankle vascular index significantly increased from baseline at 30, 60, and 90 min after the 75-g glucose ingestion after the intervention in the CON group (p<0.05), but not in the PAI group. Heart­brachial pulse wave velocity did not change compared to baseline after the 75-g glucose ingestion in either group and did not change from baseline at 30, 60, and 90 min after the 75-g glucose ingestion before and after the intervention in both groups. The present findings indicate that a short-term increase in physical activity suppresses the increase in arterial stiffness after glucose intake.

The recently approved direct-acting antivirals (DAA) agents are effective in terms of sustained virologic response (SVR) rates and are well tolerated in most hepatitis C virus (HCV) patients. This study aimed to analyze the association between serum zinc levels in patients who developed hepatocellular carcinoma (HCC) following HCV eradication after DAA treatment. The retrospective study included 769 HCV-infected patients who achieved SVR after DAA treatment. We calculated the annual incidence rate of HCC and identified risk factors associated with HCC development. We also assessed serum zinc and clinical factors at both baseline and end of treatment (EOT). During follow-up (median duration 35 months), HCC occurred in 18/769 (2.3%) patients. From the multivariate analysis, serum zinc <60 µg/dl [hazard ratio (HR) 5.936] and AFP ≥6.0 ng/dl (HR 5.862) at baseline, baseline-zinc <60 µg/dl (HR 6.283), EOT-serum zinc <63 µg/dl (HR 6.011), baseline-AFP ≥6.0 ng/dl (HR 8.163), and EOT-M2BPGi ≥2.5 (HR 12.194) at baseline and EOT were independently associated with increased HCC risk. In patients who achieved HCV eradication following DAA treatment, serum zinc levels before and at EOT could be a risk factor for developing HCC.

This study aimed to analyze the association between serum zinc levels and major subjective symptoms in zinc deficiency patients with chronic liver disease. 578 patients with chronic liver disease were enrolled. The patients, whose serum zinc level of <80 µg/dl, completed a questionnaire to determine whether they had subjective symptoms of the five conditions (taste disorder, aphthous stomatitis, dermatitis, alopecia, and anorexia). Then, the association between these subjective symptoms and serum zinc levels was analyzed. In total, 193 patients (33.4%) experienced any subjective symptoms. The prevalence of each symptom was as follows: 36 patients with taste disorder (6.2%), 46 with aphthous stomatitis (8.0%), 77 with dermatitis (13.3%), 46 with alopecia (8.0%), and 53 with anorexia (9.2%). In total, 70.8%, 34.1%, and 26.1% patients with serum zinc levels of <40, ≥40 to <60, and ≥60 to <80 µg/dl, respectively, had these symptoms. When zinc deficiency was defined as a serum zinc level of <80 µg/dl, approximately one-third of patients displayed symptoms presumably originating from zinc deficiency. As serum zinc levels decreased, the prevalence of these symptoms increased. Dermatitis, especially, was relevant to zinc.