Inhibition Of Glucose Transport Research Articles

Effects of the SGLT2 inhibitor ipragliflozin and metformin on hepatic steatosis and liver fibrosis: Sub-analysis of a randomized controlled study.

To compare the effects of ipragliflozin, a sodium-dependent glucose transporter-2 inhibitor, and those of metformin on the visceral fat area (VFA), a prospective, multi-centre, open-label, blinded-endpoint, randomized, controlled study was undertaken. The generated data were used to examine the effects of ipragliflozin and metformin on indices of hepatic steatosis and liver fibrosis. In total, 103 Japanese patients with type-2 diabetes (T2D), body mass index (BMI) of ≥22 kg/m2 and glycated haemoglobin level of 7%-10% were randomly administered ipragliflozin 50 mg or metformin 1000 mg for 24 weeks. Various parameters, including hepatic steatosis indices, fatty liver index (FLI), hepatic steatosis index (HSI), non-alcoholic fatty liver disease-liver fat score (NAFLD-LFS), liver fibrosis indices, AST to platelet ratio index (APRI) and fibrosis-4 (FIB-4) index, were compared in the sub-analyses. The correlations between changes in each index and VFA were evaluated. At baseline, patients demonstrated moderate hepatic steatosis, with FLI scores of 52.9 ± 26.6 and 57.8 ± 29.0 in the ipragliflozin and metformin groups, respectively. At 24 weeks, compared with metformin, ipragliflozin showed improvements in hepatic steatosis indices: FLI (-9.24 ± 10.7 vs. -3.45 ± 11.8, p = 0.013), HSI (-1.45 ± 2.32 vs. -0.45 ± 1.87, p = 0.021), NAFLD-LFS (-0.70 ± 1.46 vs. -0.04 ± 0.98, p = 0.011) and liver fibrosis index: APRI (-0.110 ± 0.323 vs. 0.033 ± 0.181, p = 0.010). In the ipragliflozin group, changes in FLI and HSI were correlated with VFA reduction (r = 0.340, p = 0.024; r = 0.367, p = 0.011, respectively). Compared with metformin, ipragliflozin improved multiple hepatic steatosis and liver fibrosis indices, suggesting that ipragliflozin exerts potential hepatoprotective effects in early-stage liver disease associated with T2D.

A MEF2C transcription factor network regulates proliferation of glomerular endothelial cells in diabetic kidney disease.

The maintenance of a healthy epithelial-endothelial juxtaposition requires cross-talk within glomerular cellular niches. We sought to understand the spatially-anchored regulation and transition of endothelial and mesangial cells from health to injury in DKD. From 74 human kidney samples, an integrated multi-omics approach was leveraged to identify cellular niches, cell-cell communication, cell injury trajectories, and regulatory transcription factor (TF) networks in glomerular capillary endothelial (EC-GC) and mesangial cells. Data were culled from single nucleus RNA and ATAC sequencing and three orthogonal spatial transcriptomic technologies for correlation with histopathological and clinical trial data. We identified a cellular niche in diabetic glomeruli enriched in a proliferative endothelial cell subtype (prEC) and altered vascular smooth muscle cells (VSMCs). Cellular communication within this niche maintained pro-angiogenic signaling with loss of anti-angiogenic factors. We identified a TF network of MEF2C, MEF2A, and TRPS1 which regulated SEMA6A and PLXNA2, a receptor-ligand pair opposing angiogenesis. In silico knockout of the TF network accelerated the transition from healthy EC-GCs toward a degenerative (injury) endothelial phenotype, with concomitant disruption of EC-GC and prEC expression patterns. Glomeruli enriched in the prEC niche had histologic evidence of neovascularization. MEF2C activity was increased in diabetic glomeruli with nodular mesangial sclerosis. The gene regulatory network (GRN) of MEF2C was dysregulated in EC-GCs of patients with DKD, but sodium glucose transporter-2 inhibitor (SGLT2i) treatment reversed the MEF2C GRN effects of DKD. The MEF2C, MEF2A, and TRPS1 TF network carefully balances the fate of the EC-GC in DKD. When the TF network is "on" or over-expressed in DKD, EC-GCs may progress to a prEC state, while TF suppression leads to cell death. SGLT2i therapy may restore the balance of MEF2C activity.

4-Furanylvinylquinoline derivative as a new scaffold for the design of oxidative stress initiator and glucose transporter inhibitor drugs

In the present study, a detailed analysis of the effect of a substitution at the C4 position of the quinoline ring by styryl or furanylvinyl substituents on the structure-antitumour activity relationship was conducted. After analysing a library of derivatives from the styrylquinoline and furanylvinylquinoline groups, we selected the most active (IC50 below 100 nM) derivative 13, which contained the strongly electron-withdrawing nitro group in the furan substituent. The mechanism of action of this compound was studied on cell lines that differed in their p53 protein status. For this derivative, both cell cycle arrest (in G2/M phase in both HCT 116 cell lines and S phase for U-251 cell line) and the induction of apoptosis (up to 66% for U-251 cell line) were revealed. These studies were then confirmed by other methods at the gene and protein levels. Interestingly, we observed differences in the mechanism of action depending on the presence and mutation of the p53 protein, thus confirming its key role in cellular processes. Incubation with derivative 13 resulted in the induction of oxidative stress and triggered a cascade of cellular defence proteins that failed in the face of such an active compound. In addition, the results showed an inhibition of the GLUT-1 glucose transporter, which is extremely important in the context of anti-cancer activity.

Oxygen sensing in the kidney.

The kidneys fulfil several essential homeostatic functions for the body. One of them is the maintenance of sufficient oxygen supply to the organs. For this purpose, the kidneys control the formation of red blood cells by the production of the hormone erythropoietin. This control of red cell formation is not only relevant to prevent states of oxygen deficiency but also to prevent an unwanted increase of red cell numbers causing thromboembolic risks. The adequate production of erythropoietin requires a sensing of the arterial oxygen content and transduction to hormone production. This oxygen sensing is a two-step process which includes a translation of the arterial oxygen content to respective oxygen tension in the tubulointerstitium and a perception of the resulting local interstitial oxygen tension to translate them into specific cellular responses such as the production of erythropoietin. This contribution will describe these steps of oxygen sensing for the healthy kidney and for the changes occurring during states of chronic renal disease, which are commonly associated with anemia. In this context a special focus will also be set on intrarenal hypoxia and oxygen sensing in the diabetic kidney including the treatment with tubular glucose transport (SGLT-2) inhibitors which might influence the oxygen sensing in the kidney. Finally, we will consider the effects of prolylhydroxylase inhibitors (PHD-I), which fundamentally interfere with the cellular oxygen sensing and which are meanwhile treatment options in renal anemia.

Exploring Antidiabetic Properties of Medicinal Plants in Malaria-Affected Regions

This study investigates the potential antidiabetic properties of medicinal plants commonly used in malaria-affected regions. Diabetes and malaria, both prevalent in tropical and subtropical regions, often co-occur, posing unique challenges for healthcare management. Traditional remedies, including medicinal plants, have been widely employed to treat both diseases. This paper reviews the ethnobotanical use of plants with antidiabetic properties in areas where malaria is endemic, analyzing their pharmacological mechanisms, such as glucose transport inhibition and insulin sensitization. The synergistic relationship between malaria and diabetes is also examined, with an emphasis on shared pathophysiological mechanisms, such as oxidative stress and altered blood flow. The paper highlights the need for further clinical research to standardize the use of these plants and enhance their therapeutic potential. Keywords: Antidiabetic properties, medicinal plants, malaria, diabetes, ethnobotany.

A novel approach to regulate glucose uptake in an anaplastic thyroid cancer cell line.

Curcumin's function in affecting cancer metabolic reprogramming remains poorly understood. Herein, we aimed to elucidate a novel link between Curcumin and the glucose uptake metabolism and glucose transporters (GLUTs) status in SW1736 cell line derived from anaplastic thyroid cancer. TheMTT test and flow cytometry was employed to test cell viability and cell death. For glucose uptake detection, ''GOD-PAP'' enzymatic colorimetric assay was applied to measure the direct glucose levels inside of the cells. Determination of GLUT1 and GLUT3 mRNA and protein expression in SW1736 cells was performed by qRT-PCR and western blotting. Also, the scratch wound healing assay was conducted for cell migration. The data indicated that Curcumin-induced cell death is independent of apoptosis in this type of thyroid cancer cell line. Furthermore, significantly reduced GLUT1 and GLUT3 expression was observed after treatment with Curcumin, resulting in the inhibition of glucose uptake (p < 0.05). Scratch assay indicated the inhibition of cell migration in SW1736 cells treated by Curcumin (p < 0.05). It can be concluded that GLUTs as metabolic targets can be blocked specifically by Curcumin for thyroid cancer prevention. Curcumin, as a promising anti-cancer agent, inhibits the growth of SW1736 anaplastic thyroid cancer cell line by regulating glucose uptake pathway and cell death. Altogether, these results suggest that the glucose pathway may be an important target for therapeutic intervention to sensitize tumor cells to cell death process by inhibition of glucose transporters.

“Resource-Conserving” engineered nanoparticles Mediate disulfidptosis by overcoming resistance to ferroptosis for antitumor immunotherapy

The highly reducing and immunosuppressive environment within solid tumors limits the application of ferroptosis and immunotherapy in clinical treatment. Elevated SLC7A11 transporter expression can strengthen tumor cells’ resistance to ferroptosis, but induce disulfidptosis under glucose starvation conditions. Here, using the ferroptosis resistance mechanism of tumor cells, we created a multifunctional nanoparticle (BZTFH) to induce disulfidptosis and accelerate ferroptosis, eventually causing immunogenic cell death (ICD) of tumor cells for synergistic cancer immunotherapy. After cellular internalization, the metal polyphenol network releases iron ions under acidic conditions, and then ZnO2 is degraded into Zn2+ and H2O2. The iron ions and H2O2 generate a sustained and powerful ROS storm through the Fenton reaction. Consequently, ferroptosis resistance is activated. Finally, the released glucose transporter inhibitor depletes the intracellular NADPH pool, and accumulates a large amount of intracellular disulfide molecules, thereby inducing cell disulfidptosis. The destruction of the reducing environment, along with the occurrence of disulfidptosis and ferroptosis, promotes the ICD effect. Simultaneously, Zn2+ causes STING activation, which in turn stimulate particular T cell responses, thereby reducing immunosuppression within the tumor microenvironment (TME). In short, we have successfully integrated ferroptosis and disulfidptosis for immunotherapy for the first time, presenting a potential therapeutic strategy for clinical application.

Effectiveness and mechanisms of sodium-dependent glucose transporter 2 inhibitors in type 2 diabetes and heart failure patients.

We comment on an article by Grubić Rotkvić et al published in the recent issue of the World Journal of Cardiology. We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) and their impact on comorbidities. SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys, lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine. Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control. In addition, SGLT2i has been shown to be effective in anti-apoptosis, weight loss, and cardiovascular protection. Accordingly, it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.

Disulfidptosis-related subtype and prognostic signature in prostate cancer

BackgroundDisulfidptosis refers to cell death caused by the accumulation and bonding of disulfide in the cytoskeleton protein of SLC7A11-high level cells under glucose deprivation. However, the role of disulfidptosis-related genes (DRGs) in prostate cancer (PCa) classification and regulation of the tumor microenvironment remains unclear.MethodsFirstly, we analyzed the expression and mutation landscape of DRGs in PCa. We observed the expression levels of SLC7A11 in PCa cells through in vitro experiments and assessed the inhibitory effect of the glucose transporter inhibitor BAY-876 on SLC7A11-high cells using CCK-8 assay. Subsequently, we performed unsupervised clustering of the PCa population and analyzed the differentially expressed genes (DEGs) between clusters. Using machine learning techniques to select a minimal gene set and developed disulfidoptosis-related risk signatures for PCa. We analyzed the tumor immune microenvironment and the sensitivity to immunotherapy in different risk groups. Finally, we validated the accuracy of the prognostic signatures genes using single-cell sequencing, qPCR, and western blot.ResultsAlthough SLC7A11 can increase the migration ability of tumor cells, BAY-876 effectively suppressed the viability of prostate cancer cells, particularly those with high SLC7A11 expression. Based on the DRGs, PCa patients were categorized into two clusters (A and B). The risk label, consisting of a minimal gene set derived from DEGs, included four genes. The expression levels of these genes in PCa were initially validated through in vitro experiments, and the accuracy of the risk label was confirmed in an external dataset. Cluster-B exhibited higher expression levels of DRG, representing lower risk, better prognosis, higher immune cell infiltration, and greater sensitivity to immune checkpoint blockade, whereas Cluster A showed the opposite results. These findings suggest that DRGs may serve as targets for PCa classification and treatment. Additionally, we constructed a nomogram that incorporates DRGs and clinical pathological features, providing clinicians with a quantitative method to assess the prognosis of PCa patients.ConclusionThis study analyzed the potential connection between disulfidptosis and PCa, and established a prognostic model related to disulfidptosis, which holds promise as a valuable tool for the management and treatment of PCa patients.

Efficacy of Metformin plus Sodium Glucose Transporter-2 inhibitors (SGLT-2i) in Obese Type 2

Efficacy of Metformin plus Sodium Glucose Transporter-2 inhibitors (SGLT-2i) in Obese Type 2

Abstract P227: Potential roles of vascular glucose transporter 1 in development of abdominal aortic aneurysm induced by angiotensin II

It has been reported that pharmacological inhibition of glycolysis attenuated abdominal aortic aneurysm (AAA) development in mice. Glucose transporters (GLUTs) incorporate glucose as a first step of glycolysis. GLUT1 over-expression in vascular smooth muscle cell (VSMC) appears to enhance atherosclerosis in a mouse model. In angiotensin II (AngII) plus BAPN model of mouse AAA, silencing of VSMC AngII type 1 rec receptors attenuated AAA development and rupture which was associated with less immune cell infiltration to the aortas. However, the role of VSMC GLUT1 in AAA remains elusive. Here we tested our hypothesis that VSMC GLUT1 deletion attenuates AAA development and rupture in mice. Rat aortic VSMC were obtained by the explant method. Media glucose consumption of cultured VSMCs was evaluated in the presence or absence of angiotensin II (AngII, 100 nM) stimulation and GLUT1 inhibitor BAY-876. GLUT1 floxed mice were crossed with tamoxifen-inducible SMMHC-Cre mice. At 6 weeks of age, mice were injected with 2 mg/kg tamoxifen for 5 days. Significant vascular GLUT1 silencing was confimed with immunofluorescent chemistry. As a control, tamoxifen-treated SMMHC-Cre male mice were utilized. At 8 weeks, AngII (1 μg/kg/min) was delivered for 4 weeks. In addition, mice were received 1 mg/mL BAPN during the first 2 weeks of AngII infusion. After 4weeks, all animals were euthanized and maximal external diameter of the abdominal aorta was measured. In cultured VSMC, glucose consumption increased by AngII was attenuated by pretreatment of 100 nM BAY-876. AngII plus BAPN significantly developed AAA in control mice. However, silencing of VSMC GLUT1 did not affect AAA development by AngII plus BAPN. The survival rate due to aortic rupture in VSMC GLUT1 silenced mice and control mice treated with BAPN and AngII were 60.0% and 57.1%, respectively. AngII induced hypertension in control mice and VSMC GLUT1 silenced mice. Although GLUT1 may be a primary VSMC GLUT to enhance glucose utilization in response to AngII stimulation, VSMC GLUT1 silencing did not alter AngII-dependent AAA development or rupture in a mouse model. Since pharmacological inhibition of GLUT attenuated AAA and associated macrophage infiltration, it is possible that GLUT1 or other GLUT expressed in macrophages may contribute to development of AAA. In conclusion, VSMC GLUT1 silencing did not alter AngII-dependent AAA development or rupture in a mouse model.

Hepatocyte MMP14 mediates liver and inter-organ inflammatory responses to diet-induced liver injury.

The matrix metalloproteinase MMP14 is a ubiquitously expressed, membrane-bound, secreted endopeptidase that proteolyzes substrates to regulate development, signaling, and metabolism. However, the spatial and contextual events inciting MMP14 activation and its metabolic sequelae are not fully understood. Here, we introduce an inducible, hepatocyte-specific MMP14-deficient model (MMP14LKO mice) to elucidate cell-intrinsic and systemic MMP14 function. We show that hepatocyte MMP14 mediates diet-induced body weight gain, peripheral adiposity, and impaired glucose homeostasis and drives diet-induced liver triglyceride accumulation and induction of hepatic inflammatory and fibrotic gene expression. Single-nucleus RNA sequencing revealed that hepatocyte MMP14 mediates Kupffer cell and T-cell accumulation and promotes diet-induced hepatocellular subpopulation shifts toward protection against lipid absorption. MMP14 co-immunoprecipitation and proteomic analyses revealed MMP14 substrate binding across both inflammatory and cytokine signaling, as well as metabolic pathways. Strikingly, hepatocyte MMP14 loss-of-function suppressed skeletal muscle and adipose inflammation in vivo, and in a reductionist adipose-hepatocyte co-culture model. Finally, we reveal that trehalose-type glucose transporter inhibitors decrease hepatocyte MMP14 gene expression and nominate these inhibitors as translatable therapeutic metabolic agents. We conclude that hepatocyte MMP14 drives liver and inter-organ inflammatory and metabolic sequelae of obesogenic dietary insult. Modulating MMP14 activation and blockade thus represents a targetable node in the pathogenesis of hepatic inflammation.

Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis

Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted that the absence of hypoxia signaling through hypoxia-inducible factor (HIF)-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy. We sought to define the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation processes and barrier function in EoE. In RNA sequencing of EoE patient biopsy samples, we observed the expression pattern of key genes involved in mitochondrial metabolism/oxidative phosphorylation (OXPHOS) and glycolysis. Seahorse bioenergetics analysis was performed on EPC2-hTERT cells to decipher the metabolic processes involved in epithelial differentiation processes. In addition, air-liquid interface cultures were used to delineate metabolic dependency mechanisms required for epithelial differentiation. Transcriptomic analysis identified an increase in genes associated with OXPHOS in patients with EoE. Epithelial origin of this signature was confirmed by complex V immunofluorescence of patient biopsy samples. Bioenergetic analysis invitro revealed that differentiated epithelium was less reliant on OXPHOS compared with undifferentiated epithelium. Increased OXPHOS potential and reduced glycolytic capacity was mirrored in HIF1A-knockdown EPC2-hTERT cells that exhibited a significant absence of terminal markers of epithelial differentiation, including involucrin. Pharmacologic glucose transport inhibition phenocopied this, while rescue of the HIF-1α-deficient phenotype using the pan-prolyl hydroxylase inhibitor dimethyloxalylglycine resulted in restored expression of epithelial differentiation markers. An OXPHOS-dominated metabolic pattern in EoE patients, brought about largely by the absence of HIF-1α-mediated glycolysis, is linked with the deficit in esophageal epithelial differentiation.

A Potential Neurotoxic Mechanism: Bisphenol S-Induced Inhibition of Glucose Transporter 1 Leads to ATP Excitotoxicity in the Zebrafish Brain.

Many environmental pollutants have neurotoxic effects, but the initial molecular events involved in these effects are unclear. Here, zebrafish were exposed to the neurotoxicant bisphenol S (BPS, 1, 10, or 100 μg/L) from the embryonic stage to the larval stage to explore the ability of BPS to interfere with energy metabolism in the brain. BPS, which is similar to a glucose transporter 1 (GLUT1) inhibitor, inhibited GLUT1 function but increased mitochondrial activity in the brains of larval zebrafish. Interestingly, GLUT1 inhibitor treatment and BPS exposure did not reduce energy production in the brain; instead, they increased ATP production by inducing the preferential use of ketone bodies. Moreover, BPS promoted the protein expression of the purinergic 2X receptor but inhibited the purinergic 2Y-mediated phosphatidylinositol signaling pathway, indicating that excess ATP acts as a neurotransmitter to activate the purinergic 2X receptor under the BPS-induced restriction of GLUT1 function. BPS-induced inhibition of GLUT1 increased the number of neurons but promoted apoptosis by activating ATP-purinergic 2X receptors in the brain, causing ATP excitatory neurotoxicity. Our data reveal a potential neurotoxic mechanism induced by BPS that may represent a new adverse outcome pathway.

Effects of 6-month administration of tofogliflozin on cardiac function in elderly patients with heart failure with preserved ejection fraction: A retrospective study of a patient cohort.

Patients with type 2 diabetes mellitus are frequently hospitalized for heart failure. The ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/e'), measured by echocardiography, is a simple and convenient indicator of diastolic dysfunction. Various large clinical trials have reported that sodium glucose transporter-2 inhibitor therapy reduced cardiovascular events and hospitalizations in heart failure patients. We examined the effect of tofogliflozin on various physiological and cardiac function. A retrospective analysis was performed on elderly patients aged 65 years or older with type 2 diabetes mellitus attending Himi Municipal Hospital who were taking oral tofogliflozin 20 mg/day. Measurement of physiological and hormonal variables, blood sampling, and echocardiographic evaluations at 0, 1, 3, and 6 months were performed on those with ejection fraction (EF) of 40% or greater at the time of treatment. Statistical analysis was performed using t-tests and mixed-effects models, with brain natriuretic peptide less than or not less than 100 pg/mL, estimated glomerular filtration rate (eGFR) less than or not less than 50 mL/min/1.73 m2, and diuretics administered or not. Hypoglycemic effects were observed at 0, 1, 3, and 6 months. At each time point, EF was retained and E/e' was significantly reduced. On the other hand, most physiological parameters and laboratory results showed no clinical abnormalities. Mixed-effects models showed time-dependent reduction of E/e' in high/low brain natriuretic peptide, high/low eGFR, with or without diuretics between baseline and at 6 months. The interaction with time was significant in high/low eGFR. Tofogliflozin was shown to improve E/e', a measure of diastolic function, while maintaining EF, with hypoglycemic effects and no clinical side effects.

Complex actions of sodium glucose transporter-2 inhibitors on lipids, calcific atherosclerosis, and bone density.

Inhibitors of sodium-glucose cotransporter-2 (SGLT2) lower renal glucose reabsorption and, thus, are used to treat patients with type 2 diabetes mellitus. Clinical trials coincidentally showed that SGLT2 inhibitors also benefitted patients with heart failure. This review explores the impact of SGLT2 inhibitors on other aspects of cardiovascular disease and skeletal health. In some, but not all, clinical and preclinical studies, SGLT2 inhibitors are found to reduce serum levels of free fatty acids and triglycerides. Their effects on total and low-density lipoprotein cholesterol and cardiac function also vary. However, SGLT2 inhibitors reduce lipid accumulation in the liver, kidney, and heart, and alter expression of lipid metabolism genes. Effects on free fatty acid uptake in abdominal fat depots depend on the location of adipose tissue. In male, but not female, mice, SGLT2 inhibitors reduce the atherosclerotic lesions and aortic calcium deposition. With respect to skeletal health, recent literature has reported conflicting associations with the risks of fracture and amputation. Studies suggest that SGLT2 inhibitors reduce tissue lipid accumulation, and in a sex-dependent manner, atherosclerosis and vascular calcification. However, their effects on lipid levels and bone health are complex and remain to be established.

Flying‐Saucer‐Shaped Nanoheterojunctions with Enhanced Colorectal Tumor Accumulation for Increased Oxidative Stress and Immunometabolic Regulation

AbstractThe treatment outcomes of nanomedicines against colorectal cancer are severely restricted by their insufficient accumulation in the tumor tissues, unsatisfactory antitumor effect, and weak immunometabolic modulation. To address these issues, flying‐saucer‐shaped nanoheterojunctions by coating copper oxide (CuxO) onto the surface of PEGylated zinc oxide (ZnO) nanoparticles are constructed. When exposed to ultrasound, the resultant CuxO@ZnO nanoheterojunctions exhibit increased locomotor activities, facilitating colorectal mucus infiltration, deep tumor penetration, and tumor cell internalization. The decoration of CuxO suppresses the rapid recombination of electrons and holes in CuxO@ZnO exposed to ultrasound, promoting the production of singlet oxygen and hydroxyl radical, which are generated by CuxO through a Fenton‐like chemodynamic reaction and CuxO@ZnO through sonodynamic reaction. After rectal administration, the sono‐chemodynamic CuxO@ZnO plus PD‐L1 antibodies effectively inhibit the growth of orthotopic and distant tumors. It elicits immunometabolic responses by inducing immunogenic cell death, activating the interferon genes signaling pathway stimulator, and inhibiting glucose transport and the glycolytic signaling pathways. This combined modality also increases the proportion of beneficial microbes (e.g., Bifidobacterium) and decreases the abundance of harmful microorganisms (e.g., Romboutsia) in the intestine. This treatment modality (CuxO@ZnO plus ultrasound and PD‐L1 antibodies) is a promising strategy for the synergistic treatment of colorectal cancer.

Warburg Effect and Type II Glucose Transporter Inhibitors as a Potential Targeted Therapy for Liver Cancer: A Review

Warburg Effect and Type II Glucose Transporter Inhibitors as a Potential Targeted Therapy for Liver Cancer: A Review

Hypertension and Heart Failure: From Pathophysiology to Treatment.

Hypertension represents one of the primary and most common risk factors leading to the development of heart failure (HF) across the entire spectrum of left ventricular ejection fraction. A large body of evidence has demonstrated that adequate blood pressure (BP) control can reduce cardiovascular events, including the development of HF. Although the pathophysiological and epidemiological role of hypertension in the development of HF is well and largely known, some critical issues still deserve to be clarified, including BP targets, particularly in HF patients. Indeed, the management of hypertension in HF relies on the extrapolation of findings from high-risk hypertensive patients in the general population and not from specifically designed studies in HF populations. In patients with hypertension and HF with reduced ejection fraction (HFrEF), it is recommended to combine drugs with documented outcome benefits and BP-lowering effects. In patients with HF with preserved EF (HFpEF), a therapeutic strategy with all major antihypertensive drug classes is recommended. Besides commonly used antihypertensive drugs, different evidence suggests that other drugs recommended in HF for the beneficial effect on cardiovascular outcomes exert advantageous blood pressure-lowering actions. In this regard, type 2 sodium glucose transporter inhibitors (SGLT2i) have been shown to induce BP-lowering actions that favorably affect cardiac afterload, ventricular arterial coupling, cardiac efficiency, and cardiac reverse remodeling. More recently, it has been demonstrated that finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Other proposed agents, such as endothelin receptor antagonists, have provided contrasting results in the management of hypertension and HF. A novel, promising strategy could be represented by small interfering RNA, whose actions are under investigation in ongoing clinical trials.

GLUT1 mediates bronchial epithelial E-cadherin disruption in TDI-induced steroid-insensitive asthma

Objective Down-regulation of bronchial epithelial E-cadherin is an important of feature of severe asthma, including steroid-insensitive asthma. Yet, the mechanisms involved in E-cadherin disruption are not fully understood. This study was aimed to investigate the role of glucose transporter 1 (GLUT1) in dysregulation of E-cadherin in toluene diisocyanate (TDI)-induced steroid-insensitive asthma. Methods A murine model of steroid-insensitive asthma was established by TDI sensitization and aerosol inhalation. Selective GLUT1 antagonists WZB117 and BAY876 were given to BALB/c mice after airway challenge. In vitro, primary human bronchial epithelial cells (HBECs) cultured in an airway-liquid interface (ALI) were exposed to TDI. Results TDI exposure markedly up-regulated GLUT1 in murine lungs and HBECs. Pharmacological inhibition of GLUT1 with BAY876 decreased airway hyperresponsiveness, neutrophil and eosinophil accumulation, as well as type 2 inflammation in vivo. Besides, the TDI-induced down-regulated expression of full-length E-cadherin was also partly recovered, accompanied by inhibited secretion of soluble E-cadherin (sE-cadherin). WZB117 also exhibited mild therapeutic effects, though not significant. In vitro, treatment with GLUT1 inhibitor relieved the TDI-induced disruption of E-cadherin in HBECs. Conclusions Taken together, our data demonstrated that GLUT1 modulates bronchial epithelial E-cadherin dysfunction production in TDI-induced steroid-insensitive asthma.