Glioblastoma is the most malignant tumor occurring in the human central nervous system with overall median survival time <14.6 months. Current treatments such as chemotherapy and radiotherapy cannot reach an optimal remission since tumor resistance to therapy remains a challenge. Glioblastoma stem cells are considered to be responsible for tumor resistance in treating glioblastoma. Previous studies reported two subtypes, proneural and mesenchymal, of glioblastoma stem cells manifesting different sensitivity to radiotherapy or chemotherapy. Mesenchymal glioblastoma stem cells, as well as tumor cells generate from which, showed resistance to radiochemotherapies. Besides, two metabolic patterns, glutamine or glucose dependent, of mesenchymal glioblastoma stem cells also manifested different sensitivity to radiochemotherapies. Glutamine dependent mesenchymal glioblastoma stem cells are more sensitive to radiotherapy than glucose-dependent ones. Therefore, the transition between proneural and mesenchymal subtypes, or between glutamine-dependent and glucose-dependent, might lead to tumor resistance to radiochemotherapies. Moreover, neural stem cells were also hypothesized to participate in glioblastoma stem cells mediated tumor resistance to radiochemotherapies. In this review, we summarized the basic characteristics, adaptive transition and implications of glioblastoma stem cells in glioblastoma therapy.

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The adaptive transition of glioblastoma stem cells and its implications on treatments.

This study proposes a modular water monitoring IoT system that enables quantitative and qualitative measuring of water in terms of an upgraded version of the water infrastructure to sustain operational reliability. The proposed method could be used in urban and rural areas for consumption and quality monitoring, or eventually scaled up to a contemporary water infrastructure enabling water providers and/or decision makers (i.e., governmental authorities, global water organization, etc.) to supervise and drive optimal decisions in challenging times. The inherent resilience and agility that the proposed system presents, along with the maturity of IoT communications and infrastructure, can lay the foundation for a robust smart water metering solution. Introducing a modular system can also allow for optimal consumer profiling while alleviating the upfront adoption cost by providers, environmental stewardship and an optimal response to emergencies. The provided system addresses the urbanization and technological gap in the smart water metering domain by presenting a modular IoT architecture with consumption and quality meters, along with machine learning capabilities to facilitate smart billing and user profiling.

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An Intelligent Modular Water Monitoring IoT System for Real-Time Quantitative and Qualitative Measurements

Heat shock protein 27 (HSP27) is a protein that works as a chaperone and an antioxidant and is activated by heat shock, environmental stress, and pathophysiological stress. However, HSP27 dysregulation is a characteristic of many human cancers. HSP27 suppresses apoptosis and cytoskeletal reorganization. As a result, it is recognized as a critical therapeutic target for effective cancer therapy. Despite the effectiveness of multiple HSP27 inhibitors in pre-clinical investigations and clinical trials, no HSP27 inhibitor has progressed to the anticancer phase of the development. These difficulties have mostly been attributable to existing anticancer therapies’ inability to target oncogenic HSP27. Highly selective HSP27 inhibitors with higher effective-ness and low toxicity led to the development of combination techniques that include computer-aided assisted therapeutic discovery and design. This study emphasizes the most recent results and roles of HSP27 in cancer and the potential for utilizing an anticancer chemical database to uncover novel compounds to inhibit HSP27.

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Discovery of Novel HSP27 Inhibitors as Prospective Anti-Cancer Agents Utilizing Computer-Assisted Therapeutic Discovery Approaches

Simple Summary The primary characteristics of cancer cachexia are weakness, weight loss, atrophy, fat reduction, and systemic inflammation. Cachexia is strongly associated with cancers involving the lungs, pancreas, esophagus, stomach, and liver, which account for half of all cancer deaths. TGF-β, MSTN, activin, IGF-1/PI3K/AKT, and JAK-STAT signaling pathways are known to underlie muscle atrophy and cachexia. Anamorelin (appetite stimulation), megestrol acetate, eicosapentaenoic acid, phytocannabinoids, targeting MSTN/activin, and molecules targeting proinflammatory cytokines, such as TNF-α and IL-6, are being tested as treatment options for cancer cachexia. Abstract Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options.

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Molecular Mechanisms and Current Treatment Options for Cancer Cachexia

Oxidation reduction potential (ORP) has become a commonly used measurement to characterize functional beverages, specifically alkaline ionized water and hydrogen water. Numerous health benefits including antioxidant effects have been attributed to a negative ORP value. A greater negative ORP value is often incorrectly interpreted to mean a greater degree of health benefits and/or a high concentration of H2. Some hydrogen meters use the Nernst equation to calculate the concentration of H2 based on the measured ORP value. Unfortunately, due to the fundamental issues with the ORP meter, the calculated H2 value may be very inaccurate. Using the Nernst equation, we performed an in silico analysis of the ORP as a function of pH, temperature, and H2 concentration. Our analysis shows that a one unit increase in pH (e.g., 7–8) influences the ORP by as much as increasing the H2 concentration by 100 times (e.g., 1–100 mg/L). Similarly, at a saturated H2 concentration (1.57 mg/L) and pH 7, every ∆T of 20 °C changes the ORP by ≈ 30 mV. This is comparable to changing the H2 concentration by a factor of 10 (0.1 mg/L to 1 mg/L). Finally, to measure H2 within 0.1 mg/L, ORP meters need to have an accuracy of about 0.8 mV. However, ORP meters have an error range of at least ±10 mV, which corresponds to a potential error in measured H2 concentration of nearly 2 mg/L (≈125% error). This analysis shows that pH, temperature, and the intrinsic ORP errors can individually influence the ORP greater than the entire contribution of dissolved H2 within normally used ranges. In fact, this can easily result in a water sample with a greater negative ORP than another despite having significantly less H2. This makes it impossible to consistently determine if one water sample has more H2 than another water sample. Therefore, we can only conclude, based on a negative ORP reading, that, excluding the possibility of other reductive redox couples, some level of dissolved H2 is present in the water. Accordingly, ORP and ORP-based H2 meters are not recommended for testing or comparing the concentration of H2 in water. Experimental studies are warranted to determine if the ORP error is as great as or greater than what is predicted via this in silico analysis.

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ORP should not be used to estimate or compare concentrations of aqueous H2: An in silico analysis and narrative synopsis

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. A protein that helps relay signals within tumor cells provides a promising diagnostic biomarker and therapeutic target for the most deadly form of glioblastoma, a brain cancer. A research team in South Korea led by Myung-Jin Park from the Korea Institute of Radiological and Medical Sciences in Seoul and Yangsik Jeong from Yonsei University in Wonju showed that the gene encoding a nuclear receptor protein called PPARγ is exclusively expressed in glioblastoma stem cells taken from patients with the aggressive “mesenchymal” subtype of the disease, but not in stem cells from other glioblastomas with more favorable outcomes. In cell cultures and mouse models, the researchers found that elevated levels of the nuclear receptor promote cancer growth, but activation of PPARγ, either with drugs or by genetic means, has an opposite effect and suppresses tumor proliferation.

Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients

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.

The Search for the Elixir of Life: On the Therapeutic Potential of Alkaline Reduced Water in Metabolic Syndromes

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.

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Effects of Alkaline-Reduced Water on Exercise-Induced Oxidative Stress and Fatigue in Young Male Healthy Adults

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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Anti-Hyperglycemic Effect of Magnesium-Enhanced Alkaline-Reduced Water on High Glucose-Induced Oxidative Stress in Renal Tubular Epithelial Cells

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.

Alkaline reduced water attenuates oxidative stress-induced mitochondrial dysfunction and innate immune response triggered by intestinal epithelial dysfunction

Jayson M. Antonio

Papers

Peroxisome proliferator-activated receptor gamma as a theragnostic target for mesenchymal-type glioblastoma patients

The Search for the Elixir of Life: On the Therapeutic Potential of Alkaline Reduced Water in Metabolic Syndromes

Effects of Alkaline-Reduced Water on Exercise-Induced Oxidative Stress and Fatigue in Young Male Healthy Adults

Anti-Hyperglycemic Effect of Magnesium-Enhanced Alkaline-Reduced Water on High Glucose-Induced Oxidative Stress in Renal Tubular Epithelial Cells

Alkaline reduced water attenuates oxidative stress-induced mitochondrial dysfunction and innate immune response triggered by intestinal epithelial dysfunction