Acetamide Electrosynthesis from CO2 and Nitrite in Water.

Renewable electricity driven electrocatalytic CO2 reduction reaction (CO2 RR) is a promising solution to carbon neutralization, which mainly generate simple carbon products. It is of great importance to produce more valuable C-N chemicals from CO2 and nitrogen species. However, it is challenging to co-reduce CO2 and NO3 - /NO2 - to generate aldoxime an important intermediate in the electrocatalytic C-N coupling process. Herein, we report the successful electrochemical conversion of CO2 and NO2 - to acetamide for the first time over copper catalysts under alkaline condition through a gas diffusion electrode. Operando spectroelectrochemical characterizations and DFT calculations, suggest acetaldehyde and hydroxylamine identified as key intermediates undergo a nucleophilic addition reaction to produce acetaldoxime, which is then dehydrated to acetonitrile and followed by hydrolysis to give acetamide under highly local alkaline environment and electric field. Moreover, the above mechanism was successfully extended to the formation of phenylacetamide. This study provides a new strategy to synthesize highly valued amides from CO2 and wastewater.

Role of Exosomal Non-Coding RNA in the Tumour Microenvironment of Genitourinary System Tumours.

In recent years, genitourinary system tumors are common in people of all ages, seriously affecting the quality of life of patients, the pathogenesis and treatment of these diseases are constantly being updated and improved. Exosomes, with a lipid bilayer that enable delivery of their contents into body fluids or other cells. Exosomes can regulate the tumor microenvironment, and play an important role in tumor development. In turn, cellular and non-cellular components of tumor microenvironment also affect the occurrence, progression, invasion and metastasis of tumor. Non-coding RNAs have been shown to be able to be ingested and released by exosomes, and are seen as a potential tool in cancer diagnosis and treatment. Here, we summarize the effect of non-coding RNAs of exosome contents on the tumor microenvironment of genitourinary system tumor, expound the significance of non-coding RNAs of exosome in the occurrence, development, diagnosis and treatment of cancers.

Dexmedetomidine Preserves Activity of Neurons in Primary Somatosensory Cortex Compared to Propofol and Ketamine.

General anesthesia has been shown to induce significant changes in the functional connectivity of the cerebral cortex. However, traditional methods such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) lack the spatial resolution to study the effects of general anesthesia on individual cortical neurons. This study aimed to use high-resolution two-photon imaging, which can provide single-neuron resolution, to investigate the characteristics of consciousness under general anesthesia. We used C57BL/6J and Thy1-GCamp6s mice and found that at similar levels of sedation, as measured by EEG, dexmedetomidine did not significantly inhibit the spontaneous activity of neuronal somata in the S1 cortex, but preserved the frequency of calcium events in neuronal spines. In contrast, propofol and ketamine dramatically inhibited the spontaneous activity of both neuronal somata and spines. The S1 cortex still responded to whisker stimulation under dexmedetomidine anesthesia, but not under propofol or ketamine anesthesia. Our results suggest that dexmedetomidine anesthesia has unique neuronal properties associated with its ability to facilitate easy awakening in the clinic. These findings provide insights into the development of more effective strategies for monitoring consciousness during general anesthesia.

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone.

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with immature hydroxyapatite. Arsenic-manganese nanocrystals (around 14 nm) were loaded in osteogenic niche-targeted PEG-PLGA nanoparticles with an acidic environment-triggered arsenic release. Arsenic formulations greatly reduced 4T1 cell adhesion to mesenchymal stem cells (MSCs)/preosteoblasts (pre-OBs) and osteogenic differentiation of osteoblastic cells. Arsenic formulations also prevented tumor cell colonization and dormancy via altering the direct interaction between 4T1 cells and MSCs/pre-OBs. The chemotactic migration of 4T1 cells toward osteogenic cells was blocked by arsenic in mimic 3D osteogenic niche. Systemic administration of osteogenic niche-targeted arsenic nanoparticles significantly extended the survival of mice with 4T1 syngeneic bone metastasis. Our findings provide an effective approach for osteogenic niche-specific drug delivery and suggest that bone metastasis can be effectively inhibited by blockage of tumor cell colonization in the bone microenvironment.

Protective Effects of Raspberry Crude Polysaccharides on UVB-Induced Photodamage in HaCaT Cells / 中国生物化学与分子生物学报

Polysaccharide is one of the functional components of the raspberry, which has various pharmacological effects such as anti-inflammatory, antioxidant, anti-fatigue, hypoglycemic and immunomodulatory. However, whether raspberry polysaccharides have protective effects on UV-induced photodamage to skin cells has not been reported. This study aims to investigate the protective effect of Raspberry Crude Polysaccharide on Ultraviolet B (UVB) -induced photodamage of human immortalized keratinocytes (H a C a T). The photodamage model of HaCaT cells was established by UVB irradiation. To evaluate the anti-UVB activity of R C P, the cell viability was determined by the CCK-8 method, and the Enzyme-linked immunosorbent assays (ELISA) and microplate method were used to measure the contents of matrix metalloproteinase, inflammatory and antioxidant factors in the photodamaged HaCaT cells. The antioxidant activity of RCP was detected by radical scavenging assays against D P P H radical (D P P H •) and ABTS radical (ABTS •

Recent advances in the contribution of circRNAs to cisplatin chemotherapy resistance in cancers.

Worldwide, cancer is a serious threat to the health of citizens of every country, with the incidence and mortality increasing year by year. Cisplatin is the first-line anticancer drug commonly used in clinics and is widely used for the treatment of solid tumors including lung, gastric, liver, bladder, and ovarian cancer. Although cisplatin-based chemotherapy has a high clinical response efficacy, patients will inevitably develop drug resistance after repeated use, leading to severe restrictions of its application. Circular RNAs (circRNAs) are a promising class of non-coding RNAs capable of promoting or suppressing cancer via functioning as miRNAs sponges. Recently, an increasing amount of evidence shows that circRNAs are closely related to the cisplatin resistance of cancers. Therefore, standing at the perspective of the cisplatin chemotherapy resistance, this paper reviews the research progress of circRNAs related to cisplatin resistance of various cancers.

Discovery of sertraline and its derivatives able to combat drug-resistant gastric cancer cell via inducing apoptosis.

Resistance phenomena during chemotherapy of tumor has been severely hampering the applications of chemotherapeutics. Due to advantage of drug repurposing, discovery of new chemosensitizers based on approved drugs is an effect strategy to find new candidates. Herein, we found antidepressant drug - sertraline, could sensitize drug-resistant gastric cancer cell (SGC-7901/DDP) with the IC50 value of 18.73 µM. To understand the structure-activity relationship and improve the activity, 30 derivatives were synthesized and evaluated. The IC50 value of the best compound was improved to 5.2 µM. Moreover, we found apoptosis induction and cell cycle arrest was the reason for the cell death of the drug-resistant cells after treatment of sertraline and derivatives, and PI3K/Akt/mTOR pathway was involved.

Charging effects of SiO2 thin film on Si substrate irradiated by penetrating electron beam.

In this work, the charging effect and induced conductivity of SiO2 thin films on Si substrate irradiated by penetrating electron beam (e-beam) are investigated based on numerical calculation and experiment. The numerical model is performed by considering the electron scattering, trapping, drift, diffusion and recombination, and solved by the Monte Carlo and finite difference method. The results show that, under e-beam irradiation, due to emission of secondary electrons (SEs) from the surface, the net charge density is positive near the surface, but negative inside the film. The net charge density and resulting negative charging intensity decrease under e-beam irradiation because of high electron mobility. With e-beam irradiation, the free electrons drift and diffuse to the meter and thus the sample current increases. Meanwhile, the transmission current remains unchanged due to the weak charging intensity. With the increasing beam energy, the transmission current increases to the beam current. The sample current and the induced current gain reach the maximum at the beam energy of 15 keV. The sample current and the induced conductivity at the steady state increase linearly with beam current. The induced current gain increases with the rising positive bias voltage. The influence of film parameters on the charge effect is also analyzed.

Autocorrected preconditioning regularization inversion algorithm for an atmospheric turbulence profile.

Atmospheric turbulence profiles have great significance for adaptive optics, astronomical observations, laser propagation in atmospheres, and free space optical communications. The two-aperture differential scintillation method is a recent approach for analyzing remote-sensing atmospheric turbulence profiles that utilizes active beacons to make it suitable for different measurement situations. The relationship between differential scintillation and atmospheric turbulence profiles can be modeled using the Fredholm integral equation. To address this ill-posed integration problem, the discrete forward observation equation is first analyzed to obtain better integration intervals and measurement intervals needed for inversion. Then an autocorrected preconditioning conjugate gradient normal residual (PCGNR) algorithm is proposed to acquire atmospheric turbulence profiles. The algorithm contains a developed autocorrection strategy that incorporates incremental differences, adaptive thresholds, and weighted averages to correct for artefacts and marginal errors that arise from the PCGNR method. Compared with other regularized methods, the proposed autocorrected PCGNR method is more accurate and robust in the presence of noise.

Docetaxel-Loaded Chitosan-Cholesterol Conjugate-Based Self-Assembled Nanoparticles for Overcoming Multidrug Resistance in Cancer Cells.

Cholesteryl hemisuccinate (CHS)-conjugated chitosan (CS)-based self-assembled nanoparticles (NPs) were developed for enhancing the intracellular uptake of docetaxel in multidrug resistance (MDR)-acquired cancer cells. CHS-CS was successfully synthesized and self-aggregation, particle size, zeta potential, drug entrapment efficiency, and in vitro drug release of docetaxel-loaded CHS-CS NPs were tested. The optimized NPs had a mean hydrodynamic diameter of 303 nm, positive zeta potential of 21.3 mV, and spherical shape. The in vitro release of docetaxel from the optimized CHS-CS NPs in different pH medium (pH 6.0 and 7.4) revealed that the release was improved in a more acidic condition (pH 6.0), representing a tumor cell's environment. The superior MDR-overcoming effect of docetaxel-loaded CHS-CS NPs, compared with docetaxel solution, was verified in anti-proliferation and cellular accumulation studies in MDR-acquired KBV20C cells. Thus, CHS-CS NPs could be potentially used for overcoming the MDR effect in anticancer drug delivery.

Role of adenylate kinase 1 in the integument development of Schistosoma japonicum schistosomula.

Schistosomula antigens play an important role in the growth and development of Schistosoma japonicum. We investigated the role of S. japonicum adenylate kinase 1 (SjAK1) in the growth and development of schistosomula. Quantitative real-time PCR showed that SjAK1 mRNA was expressed in all schistosomula stages, but increased gradually with the development of S. japonicum schistosomula. Using immunohistochemical techniques, the AK1 protein was found to be mainly distributed in the tegument and in some parenchymal tissues of the schistosomula. Double-stranded RNA-mediated knockdown of AK1 reduced AK1 mRNA transcripts by more than 90%; western blot analysis demonstrated that AK1 protein expression decreased by 66%. Scanning electron microscopy following RNA-mediated AK1 knockdown demonstrated that the sensory papillae degenerated significantly. Transmission electron microscopy demonstrated that the mean thickness of the tegument in the SjAK1 interference group was lower than that in the negative control group. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) suggested that, compared with the negative control group, apoptosis increased in the interference group. These results show that AK1 may be involved in the growth and development of S. japonicum schistosomula, and thus may be a target when developing treatments for schistosomiasis.

Dual oligopeptides modification mediates arsenic trioxide containing nanoparticles to eliminate primitive chronic myeloid leukemia cells inside bone marrow niches.

Chronic myeloid leukemia (CML) is one type of hematopoietic stem cell diseases. Although BCR-ABL1 tyrosine kinase inhibitors are remarkably effective in inducing remission in chronic phase patients, they are not curative in a majority of patients due to their failure to eradicate residual CML stem/progenitor cells, which reside in bone marrow niches. Here, we presented novel dual oligopeptides-conjugated nanoparticles and demonstrated their effective delivery of arsenic trioxide in bone marrow niches for the elimination of primitive CML cells. We encapsulated As-Ni transitional metal compounds into polymeric nanoparticles based on the reverse micelle rationale. The loading density and stability of arsenic trioxide in nanoparticles were improved. In vitro experiments demonstrated that dual oligopeptides conjugated nanoparticles could deliver arsenic trioxide into bone marrow niches including endosteal niches and vascular niches. The colony-forming activity of CML cells was remarkably restrained in the presence of metaphyseal bone fragments pre-incubated with bone marrow niche targeted arsenic nanoparticles. The in vitro vascular niche model suggested that CML cell proliferation was also successfully inhibited through a tight contact with HUVECs, which were pre-treated using niche-targeted arsenic nanoparticles. This bone marrow niche targeted delivery strategy has a potential usage for the treatment of CML and other malignant hematologic disorders originated from the bone marrow.

(3 + 1) Annulation/Rearrangement Cascade of C,N-Cyclic Azomethine Imines and 3-Chlorooxindoles: Construction of Hexahydroindeno[2,1-c]pyrazole Spirooxindole Frameworks.

The Brønsted base promoted (3 + 1) annulation reaction of C,N-cyclic azomethine imines and 3-chlorooxindoles was investigated, finally delivering complex hexahydroindeno[2,1-c] pyrazoles incorporating a spirocyclic oxindole motif after an unexpected rearrangement process. The asymmetric version of this new transformation could be accomplished, but slow racemization of the chiral product was observed at ambient temperature. Experiments and DFT calculations were further conducted to elucidate the reaction process and racemization mechanism.

Feasibility and safety of robotic PCI in China: first in man experience in Asia.

OBJECTIVES: To evaluate the feasibility and safety of a second generation robotic percutaneous coronary intervention (R-PCI) system in China. BACKGROUND: Robotic PCI has been shown to be an effective method for conducting coronary interventions. It has further benefits of more accurate lesion measurement, improved stent deployment, reduced incidence of geographic miss and reduction of operator radiation exposure. METHODS: This single center evaluation enrolled 10 consecutive patients who had been selected for PCI. Clinical success was defined as residual stenosis < 30% and no in-hospital major adverse cardiovascular events. Learning curve effect was assessed by comparing efficiency metrics of early vs. later cases. RESULTS: Eleven lesions were treated all successfully without manual interruption or MACE events. Most lesions (63%) were ACC/AHA class B2 and C. Mean procedure time was 57.7 ± 26.4 min, however two procedures were part of live demonstrations. Excluding the two live cases, the mean procedure time was 51.8 ± 23.7 min. Procedural efficiency tended to improve from early cases to later cases based on PCI time (48.3 ± 32.9 vs. 25.5 ± 13.0 min, P = 0.27), fluoroscopy time (20.3 ± 8.2 vs. 12.5 ± 4.6 min, P = 0.16), contrast volume (145.0 ± 28.9 vs. 102.5 ± 17.1 mL, P = 0.05) and Air Kerma dose (1932 ± 978 vs. 1007 ± 70 mGy, P = 0.31). CONCLUSIONS: Second generation robotic PCI was safe, effective and there were trends toward improvements in procedural efficiency during this early experience in China.

Analysis of anomalous origin of coronary arteries by coronary angiography in Chinese patients with coronary artery disease.

With the development of coronary angiography for the diagnosis of coronary artery disease, its clinical significance in detecting coronary artery anomalies and evaluating the seriousness is attracting more attention. In the study we aimed to assess the prevalence of anomalous origin of coronary arteries in a Chinese population who underwent coronary angiography for coronary artery disease, and explore any patterns in the common variants and typical anomalies, especially the potentially serious ones. Patients who underwent coronary angiography from January 2013 to December 2016 in Fuwai Hospital were included. Baseline characteristics and angiographic data were collected, the incidence of anomalous origin of coronary arteries was calculated, and the typical patterns were analyzed. Comparisons between the present results and those of existing reports were also conducted. A total of 110,158 patients were included in the study, among which 0.76% (835 cases) had anomalous origin of coronary arteries. Among the anomalies, the incidences of anomalous origin of the right coronary artery (RCA), the left coronary artery (LCA), both the RCA and LCA, single coronary artery (SCA) and dextrocardia were 76.76% (641 cases), 14.61% (122 cases), 1.80% (15 cases), 4.67% (39 cases) and 2.16% (18 cases), respectively. Moreover, 47.54% (397 cases) of the anomalies were shown to be potentially serious, and an RCA arising from the left sinus of Valsalva (LSV) was the most common subtype (39.28%, 328 cases). Although anomalous origin of coronary arteries is not quite common, more clinical attention should be paid to this condition due to the potential risk of serious sequelae.

Effect of ß-elemene on the kinetics of intracellular transport of d-luciferin potassium salt (ABC substrate) in doxorubicin-resistant breast cancer cells and the associated molecular mechanism.

In order to explore the mechanism of the reversing multidrug resistance (MDR) phenotypes by ß-elemene (ß-ELE) in doxorubicin (DOX)-resistant breast cancer cells (MCF-7/DOX), both the functionality and quantity of the ABC transporters in MCF-7/DOX were studied. Bioluminescence imaging (BLI) was used to study the efflux of d-luciferin potassium salt, the substrate of ATP-binding cassette transporters (ABC transporters), in MCF-7/DOX cells treated by ß-ELE. At the same time three major ABC transport proteins and genes-related MDR, P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 1 (MRP, ABCC1) as well as breast cancer resistance protein (BCRP, ABCG2) were analyzed by q-PCR and Western blot. To investigate the efflux functionality of ABC transporters, MCF-7/DOXFluc cell line with stably-overexpressed luciferase was established. BLI was then used to real-time monitor the efflux kinetics of d-luciferin potassium salt before and after MCF-7/DOXFluc cells being treated with ß-ELE or not. The results showed that the efflux of d-luciferin potassium salt from MCF-7/DOXFluc was lessened when pretreated with ß-ELE, which means that ß-ELE may dampen the functionality of ABC transporters, thus decrease the efflux of d-fluorescein potassium or other chemotherapies which also serve as the substrates of ABC transporters. As the effect of ß-ELE on the expression of ABC transporters, the results of q-PCR and Western blot showed that gene and protein expression of ABC transporters such as P-gp, MRP, and BCRP were down-regulated after the treatment of ß-ELE. To verify the efficacy of ß-ELE on reversing MDR, MCF-7/DOX cells were treated with the combination of DOX and ß-ELE. MTT assay showed that ß-ELE increased the inhibitory effect of DOX on the proliferation of MCF-7/DOX, and the IC50 of the combination group was much lower than that of the single DOX or ß-ELE treatment. In all, ß-ELE may reverse MDR through the substrates of ABC transporters by two ways, to lessen the ABC protein efflux by weakening their functionality, or to reduce the quantity of ABC gene and protein expression.

Targeted drug delivery for tumor therapy inside the bone marrow.

Bone marrow is the primary hematopoietic organ, which is involved in multiple malignant diseases including acute and chronic leukemia, multiple myeloma, myelodysplastic syndromes, and bone metastases from solid tumors. These malignancies affect normal homeostasis and reshape the bone marrow microenvironment. There are limited treatment options for them because of their inevitable aggravation. The current systemic administration of anticancer agents is difficult to achieve ideal therapeutic dose to suppress tumor growth at bone marrow diseased sites, and is always associated with a high incidence of relapse and severe side effects. The limitations of current treatments urge scientists to develop bone marrow targeted drug delivery systems intended for the treatment of diseased bone marrow, which can improve the efficacy of therapeutic agents and reduce their dose-limiting systemic side effects on healthy tissues. In this review we first present the current opinions on bone marrow vasculature, as well as the molecular and structural interactions between tumor cells and the diseased bone marrow. In the second part, we highlight the different design rationales and strategies of bone marrow delivery systems and their therapeutic applications for the treatment of malignancies inside the bone marrow.

Association between Prevalence of Thyroid Nodule and Metabolic Parameters in Population over 40 / 中山大学学报(医学科学版)

[Objective] The aim of our study is to examine nodule prevalence in a population over 40 years old in order to explore the relation between prevalence of thyroid nodules and metabolic parameters.[Methods] A total of 1875 individuals who were over 40 years of age were received the questionnaire and underwent thyroid ultrasonography examinations.Height,weight,waist circumference,blood pressure were measured.Levels of fasting blood glucose,fasting serum insulin,glycated hemoglobin,blood lipids,thyroid stimulating hormone and free T4 were detected.Body mass index (BMI) and homeostasis model assessment-insulin resistance (HOMA-IR) were calculated.[Result] The study included a total of 1875 subjects (513 men and 1362 women).The age of subjects were between 41 and 113 years old,and the mean age was 57.4±7.1 years old.The prevalence of thyroid nodules was 51.2％,and the prevalence of thyroid nodules in women was significantly higher than that in men (53.4％ vs.45.2％,P=0.002).The prevalence of thyroid nodules was significantly higher in subjects with hypertriglyceridemia (59.2％ vs.49.5％,P=0.009) and hypertension (56.5％ vs.47.8％,P＜ 0.001).Result of multivariate binary logistic regression revealed that hypertension (OR=1.405,P=0.002),female sex (OR=1.490,P=0.001),older age (OR=1.028,P＜0.001),and hypertriglyceridemia (OR=1.589,P=0.005) were independent risk factors for thyroid nodules.The prevalence of thyroid nodules increased along with age,systolic blood pressure and serum triglyceride level.[Conclusion] The prevalence of thyroid nodules and metabolism-related diseases were high in population over 40 years old.After adjusted for age and sex,hypertriglyceridemia and hypertension were possible independent risk factors for thyroid nodules especially in women.In general,hypertriglyceridemia and hypertension might play an important role in the pathological process of thyroid nodules.

Preparation of mixed monoterpenes edge activated PEGylated transfersomes to improve the in vivo transdermal delivery efficiency of sinomenine hydrochloride.

Surfactants generally have been used as edge activators of transfersomes. However, surfactants edge activated transfersomes frequently lead to cutaneous irritation, skin lipid loss and other side effects after dermal administration. In this study, mixed monoterpenes edge activated PEGylated transfersomes (MMPTs) were prepared by ethanol injection process with sinomenine hydrochloride as a model drug. The formulation of MMPTs was optimized by an orthogonal design. We investigated skin permeation/deposition characteristics and pharmacokinetics of sinomenine hydrochloride loaded in MMPTs by comparing with liposomes using in vitro skin tests and in vivo cutaneous microdialysis. In in vitro study, the accumulative skin permeated quantity (ASPQ) and skin permeation rate (SPR) of simonenine (SIN) in the optimized MMPTs were prominently higher than that in the other MMPTs. The optimized MMPTs had a SIN ASPQ of over three times of SIN ASPQ in the liposomes and much larger SPR of SIN compared with the latter. In contrast, the drug deposition of the optimized MMPTs in the stratum corneum was much less than that of the conventional liposomes. It was noteworthy that the drug deposition curve in the whole skin (stratum corneum-stripped skin, either) for the optimized MMPTs increased initially and then decreased with an obvious peak deposition amount at 12h, while, a relatively steady curve was observed for the liposomes. In in vivo cutaneous pharmacokinetic study, the steady state concentration (Css) and the area under the curve (AUC0→t) of SIN from the optimized MMPTs was 8.7 and 8.2 folds higher than those from the liposomes, respectively. Moreover, the MRT0-inf of SIN from optimal MMPTs got shorter than that from the liposomes. It can be concluded that the optimized MMPTs obviously enhance the percutaneous absorption of sinomenine.

Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice.

Metformin (MET) is the first-line drug for treating type 2 diabetes mellitus (T2DM). However, MET increases blood lactate levels in patients with T2DM. Lactate possesses proinflammatory properties and causes insulin resistance (IR). Oxamate (OXA), a lactate dehydrogenase inhibitor, can decrease tissue lactate production and blood lactate levels. This study was conducted to examine the effects of the combination of OXA and MET on inflammation, and IR in diabetic db/db mice. Supplementation of OXA to MET led to lowered tissue lactate production and serum lactate levels compared to MET alone, accompanied with further decreased tissue and blood levels of pro-inflammatory cytokines, along with better insulin sensitivity, beta-cell mass, and glycemic control in diabetic db/db mice. These results show that OXA enhances the anti-inflammatory and insulin-sensitizing effects of MET through the inhibition of tissue lactate production in db/db mice.