Glioblastomas (GBMs) are characterized by four subtypes, proneural (PN), neural, classical, and mesenchymal (MES) GBMs, and they all have distinct activated signaling pathways. Among the subtypes, PN and MES GBMs show mutually exclusive genetic signatures, and the MES phenotype is, in general, believed to be associated with more aggressive features of GBM: tumor recurrence and drug resistance. Therefore, targeting MES GBMs would improve the overall prognosis of patients with fatal tumors. In this study, we propose peroxisome proliferator-activated receptor gamma (PPARγ) as a potential diagnostic and prognostic biomarker as well as therapeutic target for MES GBM; we used multiple approaches to assess PPARγ, including biostatistics analysis and assessment of preclinical studies. First, we found that PPARγ was exclusively expressed in MES glioblastoma stem cells (GSCs), and ligand activation of endogenous PPARγ suppressed cell growth and stemness in MES GSCs. Further in vivo studies involving orthotopic and heterotopic xenograft mouse models confirmed the therapeutic efficacy of targeting PPARγ; compared to control mice, those that received ligand treatment exhibited longer survival as well as decreased tumor burden. Mechanistically, PPARγ activation suppressed proneural–mesenchymal transition (PMT) by inhibiting the STAT3 signaling pathway. Biostatistical analysis using The Cancer Genomics Atlas (TCGA, n = 206) and REMBRANDT (n = 329) revealed that PPARγ upregulation is linked to poor overall survival and disease-free survival of GBM patients. Analysis was performed on prospective (n = 2) and retrospective (n = 6) GBM patient tissues, and we finally confirmed that PPARγ expression was distinctly upregulated in MES GBM. Collectively, this study provides insight into PPARγ as a potential therapeutic target for patients with MES GBM.

Our body composition is enormously influenced by our lifestyle choices, which affect our health and longevity. Nutrition and physical activities both impact overall metabolic condition, thus, a positive energy balance causes oxidative stress and inflammation, hastening the development of metabolic syndrome. With this knowledge, boosting endogenous and exogenous antioxidants has emerged as a therapeutic strategy for combating metabolic disorders. One of the promising therapeutic inventions is the use of alkaline reduced water (ARW). Aside from its hydrating and non-caloric properties, ARW has demonstrated strong antioxidant and anti-inflammatory properties that can help stabilize physiologic turmoil caused by oxidative stress and inflammation. This review article is a synthesis of studies where we elaborate on the intra- and extracellular effects of drinking ARW, and relate these to the pathophysiology of common metabolic disorders, such as obesity, diabetes mellitus, non-alcoholic fatty liver disease, and some cancers. Highlighting the health-promoting benefits of ARW, we also emphasize the importance of maintaining a healthy lifestyle by incorporating exercise and practicing a balanced diet as forms of habit.

Regular physical activity confers health benefits and improves the general quality of life. Recently, alkaline-reduced water (ARW) consumption has garnered increasing attention in the field of sports. ARW effectively inhibits the oxidative stress generated in cells during high-intensity exercises; however, whether it exerts similar effects during exhaustive exercises remains unknown. This study was designed as a randomized, controlled, crossover, double-blind clinical trial with a single intervention of ARW intake (pH 9.5, 10 mL/kg body weight) after intense exercise. The participants were divided into two groups, wherein they consumed either purified water (PW group) or ARW (ARW group). Blood samples were collected before exercise, immediately after exercise, and 15 min after drinking water. The serum levels of oxidative stress markers and fatigue markers were determined. The results showed that ROS (p < 0.01) and NO levels (p < 0.001) were significantly decreased after ARW intake, and the reduction was more pronounced than that in the PW group. Interestingly, the increase in GPx and MDA levels was mediated by ARW intake (both p < 0.05) after exercise. The levels of fatigue markers, such as lactate (p < 0.001), lactate dehydrogenase (p < 0.001), and phosphate (p < 0.001), were significantly reduced in both groups, with ARW intervention showing more decreased markers. The correlation analysis results showed that ARW may help maintain homeostatic conditions for ROS, antioxidant systems, and fatigue markers. These findings indicate that ARW consumption is effective in reducing oxidative stress and fatigue following exhaustive exercise and that ARW could be used as an antioxidant and anti-fatigue supplement after exhaustive physical exercise.

Redox imbalance in intestinal epithelial cells is critical in the early phases of intestinal injury. Dysfunction of the intestinal barrier can result in immunological imbalance and inflammation, thus leading to intestinal syndromes and associated illnesses. Several antioxidants have been discovered to be beneficial in resolving intestinal barrier dysfunction. Of these antioxidants, the effects of alkaline reduced water (ARW) in oxidative stress of intestinal epithelial cells and its immunokine modulation in vitro is unknown. In this study, we utilized ARW-enriched media to investigate its cytoprotective effect against H2O2-induced oxidative stress in DLD1 cells. We found that ARW rescued DLD1 from oxidative stress by diluting the influence of H2O2 on oxidative stress-activated MAPK signaling and mitochondrial dysfunction. Further, intestinal oxidative stress significantly affects immunokine profiles of Raw 264.7 cells (IL-6, IL-10, MCP, TNF-a, RANTES), which can be reversed by ARW. Collectively, ARW shields intestinal epithelial cells from oxidative stress, reducing the immunological mayhem caused by barrier failure.

Diabetes is coupled with hyperglycemia, a state in which elevated glucose levels trigger oxidative stress (OS) in various body functions. One of the organs most afflicted by diabetes is the kidney. Despite this, specific treatments to mitigate the harmful effects of hyperglycemia-induced OS in the kidney have not been extensively explored. This study evaluates the anti-hyperglycemic efficacy of magnesium-enhanced alkaline-reduced water (MARW) in human kidney-2 (HK-2) cells. OS, mitogen-activated protein kinase (MAPK) signaling and fibrosis markers were assessed in high glucose (HG)-induced HK-2 cells, followed by treatment with experimental water for 24 h. Surprisingly, MARW rescued the vitality of HG-induced HK-2 cells, in contrast to that seen with other experimental waters. Additionally, MARW maintained reactive oxygen species, nitric oxide, catalase, glutathione peroxidase, hepatocyte growth factor and glucose uptake in HG-induced HK-2 cells but not in tap water and mineral water. Similarly, MARW downregulated the expression of MAPK and fibrosis-linked signaling proteins such as p-p38, phospho-c-Jun N-terminal kinase, α-smooth muscle actin, matrix metalloproteinase-3 and cleaved caspase 3 in HG-induced HK-2 cells. In conclusion, MARW protects HK-2 cells from the deleterious effects of HG by stabilizing antioxidant defenses and by signaling cascades related to metabolism, apoptosis and fibrosis.

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Diabetes, a chronic metabolic disorder, affects glucose consumption in the body and leads to severe kidney damage, known as diabetic nephropathy, where oxidative stress (OS) plays a vital role in disease pathogenesis. Electrolyzed weakly alkaline reduced water (EWARW) is known to have anti-oxidative functions in vitro due to its bioactive properties. However, there is an increasing need for adequate research on EWARW-specific therapies to minimize the negative consequences of hyperglycemia-induced OS in the kidney. This study aimed to determine the anti-oxidative and anti-diabetic effects of EWARW at pH 8.5 on human kidney-2 (HK-2) cells. Here, HK-2 cells were treated with 71.68 mM glucose to induce OS and then treated with 10% tap water (TW)_7.7, electrolyzed alkaline reduced water (EARW)_9.5, or EARW_8.5 for 24 h. After treatment, cell viability, OS and apoptotic markers, glucose uptake, adenosine triphosphate (ATP) content, and inflammatory markers were assessed to determine the effect of EARW_8.5. Our results revealed that EARW_8.5 rescued cell viability in comparison to the high glucose (HG) only and TW_7.7 groups. In addition, EARW_8.5 was effective in reducing OS markers (ROS, NO, and CAT), apoptotic markers (cleaved caspase-3), mitogen-activated protein kinase (MAPK) markers (p-JNK and p-p38), diabetic markers (glucose uptake), and inflammatory markers (p-STAT1, p-STAT3, IL-1β, and IL-6). Furthermore, we found EARW_8.5 treatment enhanced GPx and ATP content in HG-induced HK-2 cells compared to the HG-only and TW_7.7 groups. Collectively, EARW_8.5 stabilized antioxidant defenses and modulated inflammation, improving cellular metabolism and rescuing HG-induced harmful effects in HK-2 cells.