Uncovering novel therapeutic targets in glucose, nucleotides and lipids metabolism during cancer and neurological diseases.

BACKGROUND: Cell metabolism functions without a stop in normal and pathological cells. Different metabolic changes occur in the disease. Cell metabolism influences biochemical and metabolic processes, signaling pathways, and gene regulation. Knowledge regarding disease metabolism is limited. OBJECTIVE: The review examines the cell metabolism of glucose, nucleotides, and lipids during homeostatic and pathological conditions of neurotoxicity, neuroimmunological disease, Parkinson's disease, thymoma in myasthenia gravis, and colorectal cancer. METHODS: Data collection includes electronic databases, the National Center for Biotechnology Information, and Google Scholar, with several inclusion criteria: cell metabolism, glucose metabolism, nucleotide metabolism, and lipid metabolism in health and disease patients suffering from neurotoxicity, neuroinflammation, Parkinson's disease, thymoma in myasthenia gravis. The initial number of collected and analyzed papers is 250. The final analysis included 150 studies out of 94 selected papers. After the selection process, 62.67% remains useful. RESULTS AND CONCLUSION: A literature search shows that signaling molecules are involved in metabolic changes in cells. Differences between cancer and neuroimmunological diseases are present in the result section. Our finding enables insight into novel therapeutic targets and the development of scientific approaches for cancer and neurological disease onset, outcome, progression, and treatment, highlighting the importance of metabolic dysregulation. Current understanding, emerging research technologies and potential therapeutic interventions in metabolic programming is disucussed and highlighted.

Probiotic Supplementation during Pregnancy: Evaluating the Current Clinical Evidence Against Gestational Diabetes Mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) constitutes a common metabolic disorder that could lead to deleterious short- and long-term complications in both the mother and her infant. Probiotic supplementation seems to exert diverse, healthy effects by acting as a preventive agent against various human diseases, including GDM. OBJECTIVE: The purpose of the current narrative review was to critically summarize and scrutinize the available clinical studies during the last 15 years (2008-2023) concerning the use of probiotic supplementation during pregnancy as a protecting agent against GDM. METHODS: A thorough and in-depth search was performed in the most accurate scientific databases, e.g., PubMed., Scopus, Web of Science, and Google Scholar applying effective, and relevant keywords. RESULTS: There are currently some clinical studies suggesting the potential beneficial impact of probiotic supplementation in the prevention and/or co-treatment of GDM. Nevertheless, there is a high heterogeneity amongst the available clinical studies concerning the dosage, the administration duration, the probiotic species types, the method designs and protocols, and the study populations. CONCLUSION: Probiotic supplementation at conventional dosages and in combination with a balanced healthy diet, and lifestyle seems to reduce the the risk of developing GDM, while ameliorating the severity of its symptoms. Further clinical studies taking into account the above considerations should be performed to establish conclusive results, while the future meta-analyses should include studies with the feasibly lowest heterogeneity.

Exogenous γ-aminobutyric acid strengthens phenylpropanoid and nitrogen metabolism to enhance the contents of flavonoids, amino acids, and the derivatives in edamame.

γ-aminobutyric acid (GABA) has been reported to improve stress resistance in plants. Nonetheless, little is known about the effects of GABA on the nutritional quality and regulatory mechanisms of edamame. Therefore, we analyzed the flavonoid and amino acid (AA) metabolism and the effects of GABA on the nutrient content of edamame seeds through physiological and metabolomic analyses. Exogenous GABA increased endogenous GABA metabolism and GABA transaminase activity and enhanced the oxoglutarate content, which entered into nitrogen metabolism and increased the activity and expression of nitrogen metabolism-related enzymes, to accumulate AAs and bioactive peptides. Meanwhile, exogenous GABA induced the metabolism of flavonoids, including total flavonoids, anthocyanins, 6''-o-malonyglycitin, glycitin, ononin, cyanin, and ginkgetin, by increasing the activity and expression of flavonoid biosynthetic enzymes. This is the first study to reveal that GABA effectively improves the nutritional quality of edamame through the accumulation of AAs, bioactive peptides, isoflavones, anthocyanins, sugars, and organic acids.

Screening of Gestational Diabetes and Its Risk Factors: Pregnancy Outcome of Women with Gestational Diabetes Risk Factors According to Glycose Tolerance Test Results.

Background: Gestational diabetes mellitus (GDM) can cause maternal and neonatal health problems, and its prevalence is increasing worldwide. We assessed the screening of GDM during a 7-year period and compared the outcome of pregnancies at high risk for GDM. Methods: We analyzed non-selected pregnant women (n = 5021) receiving antenatal care in Tartu University Hospital, Estonia in 2012-2018. Pregnant women were classified based on the absence or presence of GDM risk factors as low risk (n = 2302) or high risk for GDM (n = 2719), respectively. The latter were divided into subgroups after the oral glycose tolerance test (OGTT): GDM (n = 423), normal result (n = 1357) and not tested (n = 939). Results: The proportion of women with GDM risk factors increased from 43.5% in 2012 to 57.8% in 2018, and the diagnosis of GDM more than doubled (5.2% vs. 13.7%). Pregnancies predisposed to GDM but with normal OGTT results were accompanied by an excessive gestational weight gain and increased odds to deliver a LGA baby (AOR 2.3 (CI 1.8-3.0)). Conclusions: An increasing number of pregnancies presenting GDM risk factors are diagnosed with GDM. Pregnant women with GDM risk factors are, despite normal OGTT, at risk of increased weight gain and LGA newborns.

Flavonoid Metabolism in Tetrastigma hemsleyanum Diels et Gilg Based on Metabolome Analysis and Transcriptome Sequencing.

Tetrastigma hemsleyanum Diels et Gilg, known as a "plant antibiotic", possesses several attractive properties including anti-inflammatory, anti-tumor, and antioxidant effects, with its efficacy being attributed to flavonoids. However, the flavonoid biosynthesis of T. hemsleyanum has rarely been studied. In this study, we investigated the flavonoid metabolism of T. hemsleyanum through metabolome analysis and transcriptome sequencing. The metabolomic results showed differences in the flavonoids of the leaves and root tubers of T. hemsleyanum. A total of 22 flavonoids was detected, and the concentrations of most flavonoids in the leaves were higher than those in the root tubers. Transcriptome analysis revealed that differentially expressed genes (DEGs) in the leaves and root tubers were enriched in photosynthesis-antenna proteins. Pearson correlation analysis indicated that the expression levels of chalcone isomerase (CHI) and UDP-glycose flavonoid glycosyltransferase (UFGT) were highly correlated with the concentrations of most flavonoids. Further, this study found that the photosynthesis-antenna proteins essentially contributed to the difference in the flavonoids in T. hemsleyanum. The gene expressions and concentrations of the total flavonoids of leaves and root tubers in Hangzhou, Jinhua, Lishui, and Taizhou in Zhejiang Province, China, showed that CHI (CL6715.Contig1_All, Unigene19431_All, CL921.Contig4_All) and UFGT (CL11556.Contig3_All, CL11775.Contig1_All) were the potential key genes of accumulation of most flavonoids in T. hemsleyanum.

Effect of vitamin D supplementation on glycose homeostasis and islet function in vitamin D deficient or insufficient diabetes and prediabetes: a systematic review and meta-analysis.

Objective of the present study was to evaluate the effect of vitamin D supplementation on glycose homeostasis, islet function, and diabetes progress. Literatures were searched via electronic databases, websites, and previous reviews from the earliest available time to the end of May 2020. Randomized controlled trials initially designed for diabetes and prediabetes with 25-dihydroxyvitamin D [25(OH)D]<30 ng/ml were included. All data were analyzed and presented based on the Cochrane guidelines and PRISMA guidelines. In total, 27 articles (n = 1,932) were enrolled in this study. Vitamin D supplementation significantly improved fasting blood glucose, postprandial blood glucose, and quantitative insulin sensitivity check index in diabetes and prediabetes with baseline 25(OH)D<30 ng/ml. Higher percentages regressing from prediabetes to normal glucose status [1.60 (1.19, 2.17), p = 0.002, n = 564] and lower percentage progressing from prediabetes to diabetes [0.68 (0.36, 1.27), p = 0.23, n = 569] were found in the supplementation group. The positive effects of vitamin D supplementation on body mass index, waist, HDL-C, LDL-C, and CRP were also demonstrated. In conclusion, modest improvements in vitamin D supplementation on short-term glycose homeostasis, insulin sensitivity, and disease development in diabetes and prediabetes with 25(OH)D<30 ng/ml were demonstrated, but more research needs to be conducted in the future to support the clinical application. (Register ID: CRD42020186004).

Short-Chain Fatty Acids and Their Association with Signalling Pathways in Inflammation, Glucose and Lipid Metabolism.

Short-chain fatty acids (SCFAs), particularly acetate, propionate and butyrate, are mainly produced by anaerobic fermentation of gut microbes. SCFAs play an important role in regulating energy metabolism and energy supply, as well as maintaining the homeostasis of the intestinal environment. In recent years, many studies have shown that SCFAs demonstrate physiologically beneficial effects, and the signalling pathways related to SCFA production, absorption, metabolism, and intestinal effects have been discovered. Two major signalling pathways concerning SCFAs, G-protein-coupled receptors (GPRCs) and histone deacetylases (HDACs), are well recognized. In this review, we summarize the recent advances concerning the biological properties of SCFAs and the signalling pathways in inflammation and glucose and lipid metabolism.

Antitumor Effect of a Novel Photodynamic Therapy With Acetylated Glucose-conjugated Chlorin for Gastrointestinal Cancers.

BACKGROUND/AIM: We previously synthesized a glucose-conjugated chlorin compound e6 (G-chlorin e6), and reported that it has very strong antitumor effects. The aim of the present study was to synthesize acetylated glucose-conjugated chlorin (AcN003HP) and evaluate its antitumor effect and excretion. MATERIALS AND METHODS: To evaluate the antitumor effect of AcN003HP, its IC50 was calculated as well as its accumulation in cancer cells was examined by flow cytometry. Confocal microscopy was used to observe the intracellular localization of AcN003HP. The excretion and antitumor effects of AcN003HP were also evaluated in vivo. RESULTS: AcN003HP showed stronger antitumor effects and accumulation into cancer cells compared to talaporfin sodium, a conventional photosensitizer. AcN003HP was localized in the endoplasmic reticulum. In a xenograft tumor mouse model, AcN003HP showed longer excretion time from the body than G-chlorin e6, and photodynamic therapy using AcN003HP showed very strong antitumor effects. CONCLUSION: The safety, improved controllability, and robust antitumor effects suggest AcN003HP as a good next-generation photosensitizer.

Inhibition of aerobic glycolysis enhances the anti-tumor efficacy of Zoptarelin Doxorubicin in triple-negative breast cancer cells.

AIM: A characteristic of cancer cells including triple-negative breast cancers (TNBC) is an increased aerobic glycolysis for ATP production representing a selective therapeutic target. More than 70% of TNBC express gonadotropin-releasing hormone receptors (GnRH-R). These receptors can be used for targeted chemotherapy with cytotoxic GnRH agonists such as Zoptarelin Doxorubicin, in which doxorubicin is covalently linked to [D-Lys6 ]GnRH. In this study, we have analyzed whether inhibition of aerobic glycolysis can enhance the antitumor efficacy of GnRH-R-targeted chemotherapy using Zoptarelin Doxorubicin. METHODS: Triple-negative breast cancers cell lines MDA-MB-231 and HCC1806 were treated with Zoptarelin Doxorubicin, glycolysis inhibitor 2-deoxy-D-glucose (2DG) or the combination of both agents. Cell viability was measured using Alamar blue. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted MDA-MB-231 tumors. RESULTS: Treatment of TNBC cells with Zoptarelin Doxorubicin or with 2DG resulted in a significant decrease of cell viability and a significant increase of apoptosis. Treatment with Zoptarelin Doxorubicin in combination with 2DG resulted in significantly reduced viability and enhanced apoptosis compared with single-agent treatments. Combinational index (CI) analysis revealed the co-treatment effect as a synergistic. The antitumor effects of Zoptarelin Doxorubicin or 2DG were confirmed in nude mice. The tumor reducing effects of Zoptarelin Doxorubicin were enhanced by combination with 2DG. CONCLUSION: The glycolytic phenotype of TNBC can be used to improve antitumor therapies. Co-treatment of Zoptarelin Doxorubicin with glycolysis inhibitor 2DG might be a suitable therapeutic option for GnRH receptor-positive TNBC.

Abnormal glucose and lipid metabolism and oral squamous cell carcinoma / 口腔疾病防治

@#Epidemiological studies have shown that abnormal glucose and lipid metabolism is associated with a variety of malignant tumors, including oral squamous cell carcinoma. In this paper, the role of abnormal glucose and lipid metabolism, especially diabetes mellitus and obesity, in the occurrence and development of oral squamous cell carcinoma and its pathogenesis are reviewed based on the research results of our group and the literature. Hyperglycemia and insulinemia in diabetes mellitus are the main mechanisms that increase the risk of cancer. Our research shows that hyperglycemia can promote the proliferation, invasion and metastasis of tongue squamous cell carcinoma through the glycolytic enzyme M2 pyruvate kinase (PKM2) and hexokinase 2 (HK2). Hyperinsulinemia can promote the proliferation, invasion and metastasis of tongue squamous cell carcinoma by activating the insulin-like growth factor signal transduction system. Obese patients are often accompanied by increased serum adipokine Chemerin (Chem). Our study shows that serum Chem concentrations in obese patients with tongue cancer are significantly higher compared with nonobese patients. Chem can regulate the proliferation, invasion and migration of tongue squamous cell carcinoma cells through the SOD2-H2O2 signaling pathway. These results provide a basis for the prevention of oral squamous cell carcinoma, provide a new iqdea for the precise treatment of oral squamous cell carcinoma, and suggest that the treatment of oral squamous cell carcinoma should also actively treat patients with diabetes and obesity.

Impact of neonatal hypoxia-ischaemia on oligodendrocyte survival, maturation and myelinating potential.

Hypoxic-ischaemic episodes experienced at the perinatal period commonly lead to a development of neurological disabilities and cognitive impairments in neonates or later in childhood. Clinical symptoms often are associated with the observed alterations in white matter in the brains of diseased children, suggesting contribution of triggered oligodendrocyte/myelin pathology to the resulting disorders. To date, the processes initiated by perinatal asphyxia remain unclear, hampering the ability to develop preventions. To address the issue, the effects of temporal hypoxia-ischaemia on survival, proliferation and the myelinating potential of oligodendrocytes were evaluated ex vivo using cultures of hippocampal organotypic slices and in vivo in rat model of perinatal asphyxia. The potential engagement of gelatinases in oligodendrocyte maturation was assessed as well. The results pointed to a significant decrease in the number of oligodendrocyte progenitor cells (OPCs), which is compensated for to a certain extent by the increased rate of OPC proliferation. Oligodendrocyte maturation seemed however to be significantly altered. An ultrastructural examination of selected brain regions performed several weeks after the insult showed however that the process of developing central nervous system myelination proceeds efficiently resulting in enwrapping the majority of axons in compact myelin. The increased angiogenesis in response to neonatal hypoxic-ischaemic insult was also noticed. In conclusion, the study shows that hypoxic-ischaemic episodes experienced during the most active period of nervous system development might be efficiently compensated for by the oligodendroglial cell response triggered by the insult. The main obstacle seems to be the inflammatory process modulating the local microenvironment.

The association between impaired glucose tolerance and soluble CD40 ligand: a 15-year prospective cohort study.

BACKGROUND AND AIMS: The aim of the present study was to assess soluble CD40 Ligand (sCD40L) levels in relation to impaired glucose tolerance (IGT) at population level. METHODS: This study is part of a prospective, population-based cohort study, carried out from 1990 to 2008 in northern Finland. Study members, born in 1935 and living in the City of Oulu, underwent oral glucose tolerance test (OGTT) and measurement of plasma sCD40L at three different time points during the 15-year follow-up. The total number of study members who underwent OGTT was 768 at the baseline, 557 at the first and 467 at the second follow-up. SCD40L levels in patients with IGT were compared with those in subjects with normal glucose tolerance or impaired fasting glucose (non-IGT). RESULTS: Geometric mean level of sCD40L was significantly higher in the IGT group compared with the non-IGT group at the baseline (0.42 vs. 0.27 ng/mL) and at the first follow-up (1.50 vs. 0.36 ng/mL) (repeated measures mixed models ANOVA, p < 0.05). At the second follow-up (age 72-73 years), however, the difference was not statistically significant (9.44 vs. 7.24 ng/mL). During the entire follow-up, the levels of sCD40L increased significantly both in IGT and non-IGT groups. CONCLUSION: We found that plasma sCD40L level increases with age as well as there are elevated levels of plasma sCD40L in subjects with IGT compared with non-IGT. This may indicate an increased cardiovascular risk in older age and in subjects with IGT.

Riboflavin inhibited ischemia brain damage in rats / 中国药理学通报

Aim To investigate the protective effect of riboflavin on ischemia brain damage and the mecha-nism.Methods The in vivo experiments were pro-cessed in male SD rats .Rats were randomly arranged into control group , model group and riboflavin group . The rats in riboflavin group were intraperitoneally in-jected riboflavin at the dose of 1 mg? kg -1 for seven consecutive days .Then the rats in model and riboflavin groups were carried out middle cerebral artery occlu-sion( MCAO) operation.After 24 h, all rats were sacri-ficed and the brain tissue was dissected to observe the infarct area, the edema and the ultrastructure damage . The brain tissue was dyed by triphenyl tetrazolium chloride .The brain edema was observed by the weight of ischemia-side semi-brain.The ultrastructure was ob-served by electron microscope .The in vitro experiments were processed in primary culture neurons by exposed to oxygen and glycose deprivation ( OGD) .The viability of neurons was assayed by MTT method .The enzyme activity of superoxide dismutase ( SOD) , catalase ( CAT)and glutathione peroxidase ( GSH-Px ) was assayed to explore the mechanism .Results Riboflavin signifi-cantly decreased the infarct area ( P<0.01 ) , inhibited the brain edema ( P <0.01 ) and inhibited the ultra-structure damage in rats after MCAO;riboflavin protec-ted the viability ( P <0.01 ) and the ultrastructure of neurons exposed to OGD .The enzyme activity of an-tioxidant SOD1 ( P <0.01 ) , CAT ( P <0.01 ) and GSH-Px ( P <0.01 ) was protected by riboflavin in MCAO model .No difference was found in the activity of SOD2 . Conclusion Riboflavin inhibits ischemia brain damage , and the protection of the activity of an-tioxidants is involved in the mechanism .

Effects of nateglinide and acarbose on glycemic excursions in standardized carbohydrate and mixed-meal tests in drug-naïve type 2 diabetic patients.

The aim of this study was to compare the effects of nateglinide and acarbose on glycemic excursions and postprandial glucose profiles with different types of meals (standardized carbohydrate and mixed meals) in drug-naïve type 2 diabetic patients. A randomized, parallel-group prospective design clinical trial was conducted and a total of 39 drug-naïve patients (16 males and 23 females, aged 56.7±10.2 years) were enrolled. The patients were randomly divided into group A [nateglinide 120 mg three times daily (t.i.d.), n=19] and group B (acarbose 50 mg t.i.d., n=20). The standardized carbohydrate and mixed-meal tests were performed at baseline and at the end of study. Continuous glucose monitoring system (CGMS) data were recorded. Various parameters that measure glucose variability were derived from the CGMS data. In the standardized carbohydrate meal tests, the postprandial glucose excursions (PPGEs) were significantly decreased in the two groups after 12 weeks of treatment (P<0.05), whereas the decrease was more prominent in the acarbose compared to the nateglinide group (P=0.138). In the mixed-meal tests, the mean sensor glucose values [24-h mean blood glucose (MBG)] were significantly decreased in the two groups after 12 weeks of treatment (P<0.05) and the parameters of glucose excursions, including standardized deviation (SD), largest amplitude of glycemic excursion (LAGE), mean of daily differences (MODD) and mean amplitude of glycemic excursion (MAGE), were reduced in the two groups. However, the decreases in SD and LAGE in the nateglinide group were statistically significant, whereas in the acarbose group only the decreases in LAGE were statistically significant. The efficiency of nateglinide or acarbose in lowering postprandial 120-min hyperglycemia were similar in the standardized carbohydrate meal test. However, acarbose was more efficient in lowering postprandial 30- and 60-min hyperglycemia (P<0.05) compared to nateglinide. The fasting and postprandial total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) had a tendency to decrease from the baseline after 12 weeks of treatment with nateglinide, whereas fasting and postprandial high-density lipoprotein cholesterol (HDL-C) had a tendency to increase. Acarbose did not affect the fasting or postprandial lipid profiles after 12 weeks of treatment (P>0.05). In conclusion, nateglinide and acarbose effectively improved postprandial glycemic control, although acarbose was shown to be more efficient in controlling early (30 and 60 min) postprandial glucose excursions in the carbohydrate meal test, whereas nateglinide was shown to be superior to acarbose in controlling postprandial glucose excursions in the mixed-meal test.

Efeito do manejo pré-abate sobre alguns parâmetros fisiológicos em fêmeas suínas pesadas / Effect of pre-slaughter management on physiological parameters of heavy-weight female pigs

O objetivo neste trabalho foi avaliar o efeito do período de descanso (3, 5, 7 e 9 horas) dos suínos no frigorífico (PDF) e da localização dos suínos na carroceria do caminhão (PBO), quando transportados, no inverno ou verão, sobre alguns parâmetros fisiológicos avaliados em 64 fêmeas, com peso médio de 130kg para abate, durante o manejo pré-abate. Para a análise estatística, foram considerados, no modelo de análise da variância, os efeitos de bloco, PDF, PBO e da interação (bloco x PDF), entre outros. O PDF influenciou, significativamente, as concentrações de lactato no sangue e cortisol na saliva. Suínos que descansaram 5 e 7 horas apresentaram maior concentração de lactato em relação aos animais que descansaram 3 e 9 horas. No transporte, a freqüência cardíaca foi muito maior em relação aos demais locais avaliados. Concluiu-se que o incremento do PDF não promove mudanças na freqüência cardíaca, nas concentrações de glicose e CPK no sangue e cortisol na saliva, mas interfere na concentração de lactato no sangue dos suínos.

The aim of the research was to evaluate the effect of pig lairage time (PDF=3, 5, 7 and 9 hours) and evaluate the effect of pig position into the truck (PBO) during transportation to slaughterhouse, in winter or summer conditions, on some physiologic parameters evaluated on 64 heavyweight females with mean liveweight of 130kg during pre-slaughter events. The following effects were considered in the statistical analysis of variance model: block (BL=summer farm or winter farm), PDF, PBO and interaction (Block x PDF), under other factors. The PDF influenced significativelly blood lactate and saliva cortisol levels. Pig submitted to 5 and 7 hours of lairage had higher levels of lactate when compared to pigs submitted to 3 and 9 hours of lairage. During transport the heart rate were higher than in other pre-slaughter events. It is concluded that increasing PDF above 3 hours had no effects on heart frequency, glucose and CPK levels and salivary cortisol levels but affects the blood lactate levels.