Hydrogen Ion Dynamics as the Fundamental Link between Neurodegenerative Diseases and Cancer: Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis on Multiple Sclerosis.

The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this contribution, this recent oncological perspective has been laterally assessed for the first time in order to integrate neurodegeneration within the energetics of the cancer acid-base conceptual frame. At all levels of study (molecular, biochemical, metabolic, and clinical), the intimate nature of both processes appears to consist of opposite mechanisms occurring at the far ends of a physiopathological intracellular pH/extracellular pH (pHi/pHe) spectrum. This wide-ranging original approach now permits an increase in our understanding of these opposite processes, cancer and neurodegeneration, and, as a consequence, allows us to propose new avenues of treatment based upon the intracellular and microenvironmental hydrogen ion dynamics regulating and deregulating the biochemistry and metabolism of both cancer and neural cells. Under the same perspective, the etiopathogenesis and special characteristics of multiple sclerosis (MS) is an excellent model for the study of neurodegenerative diseases and, utilizing this pioneering approach, we find that MS appears to be a metabolic disease even before an autoimmune one. Furthermore, within this paradigm, several important aspects of MS, from mitochondrial failure to microbiota functional abnormalities, are analyzed in depth. Finally, and for the first time, a new and integrated model of treatment for MS can now be advanced.

The possible role of methylglyoxal metabolism in cancer.

Tumours reprogram their metabolism to acquire an evolutionary advantage over normal cells. However, not all such metabolic pathways support energy production. An example of these metabolic pathways is the Methylglyoxal (MG) one. This pathway helps maintain the redox state, and it might act as a phosphate sensor that monitors the intracellular phosphate levels. In this work, we discuss the biochemical step of the MG pathway and interrelate it with cancer.

Of mitochondrion and COVID-19.

COVID-19, a pandemic disease caused by a viral infection, is associated with a high mortality rate. Most of the signs and symptoms, e.g. cytokine storm, electrolytes imbalances, thromboembolism, etc., are related to mitochondrial dysfunction. Therefore, targeting mitochondrion will represent a more rational treatment of COVID-19. The current work outlines how COVID-19's signs and symptoms are related to the mitochondrion. Proper understanding of the underlying causes might enhance the opportunity to treat COVID-19.

Metabolic Shifts as the Hallmark of Most Common Diseases: The Quest for the Underlying Unity.

A hyper-specialization characterizes modern medicine with the consequence of classifying the various diseases of the body into unrelated categories. Such a broad diversification of medicine goes in the opposite direction of physics, which eagerly looks for unification. We argue that unification should also apply to medicine. In accordance with the second principle of thermodynamics, the cell must release its entropy either in the form of heat (catabolism) or biomass (anabolism). There is a decreased flow of entropy outside the body due to an age-related reduction in mitochondrial entropy yield resulting in increased release of entropy in the form of biomass. This shift toward anabolism has been known in oncology as Warburg-effect. The shift toward anabolism has been reported in most diseases. This quest for a single framework is reinforced by the fact that inflammation (also called the immune response) is involved in nearly every disease. This strongly suggests that despite their apparent disparity, there is an underlying unity in the diseases. This also offers guidelines for the repurposing of old drugs.

Integrin-Linked Kinase Links Integrin Activation to Invadopodia Function and Invasion via the p(T567)-Ezrin/NHERF1/NHE1 Pathway.

Tumor cell invasion depends largely on degradation of the extracellular matrix (ECM) by protease-rich structures called invadopodia, whose formation and activity requires the convergence of signaling pathways engaged in cell adhesion, actin assembly, membrane regulation and ECM proteolysis. It is known that ß1-integrin stimulates invadopodia function through an invadopodial p(T567)-ezrin/NHERF1/NHE1 signal complex that regulates NHE1-driven invadopodia proteolytic activity and invasion. However, the link between ß1-integrin and this signaling complex is unknown. In this study, in metastatic breast (MDA-MB-231) and prostate (PC-3) cancer cells, we report that integrin-linked kinase (ILK) integrates ß1-integrin with this signaling complex to regulate invadopodia activity and invasion. Proximity ligation assay experiments demonstrate that, in invadopodia, ILK associates with ß1-integrin, NHE1 and the scaffold proteins p(T567)-ezrin and NHERF1. Activation of ß1-integrin increased both invasion and invadopodia activity, which were specifically blocked by inhibition of either NHE1 or ILK. We conclude that ILK integrates ß1-integrin with the ECM proteolytic/invasion signal module to induce NHE1-driven invadopodial ECM proteolysis and cell invasion.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era.

A brand new approach to the understanding of breast cancer (BC) is urgently needed. In this contribution, the etiology, pathogenesis, and treatment of this disease is approached from the new pH-centric anticancer paradigm. Only this unitarian perspective, based upon the hydrogen ion (H+) dynamics of cancer, allows for the understanding and integration of the many dualisms, confusions, and paradoxes of the disease. The new H+-related, wide-ranging model can embrace, from a unique perspective, the many aspects of the disease and, at the same time, therapeutically interfere with most, if not all, of the hallmarks of cancer known to date. The pH-related armamentarium available for the treatment of BC reviewed here may be beneficial for all types and stages of the disease. In this vein, we have attempted a megasynthesis of traditional and new knowledge in the different areas of breast cancer research and treatment based upon the wide-ranging approach afforded by the hydrogen ion dynamics of cancer. The concerted utilization of the pH-related drugs that are available nowadays for the treatment of breast cancer is advanced.

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer Based upon Its Hydrogen Ion Dynamics.

Despite all efforts, the treatment of breast cancer (BC) cannot be considered to be a success story. The advances in surgery, chemotherapy and radiotherapy have not been sufficient at all. Indeed, the accumulated experience clearly indicates that new perspectives and non-main stream approaches are needed to better characterize the etiopathogenesis and treatment of this disease. This contribution deals with how the new pH-centric anticancer paradigm plays a fundamental role in reaching a more integral understanding of the etiology, pathogenesis, and treatment of this multifactorial disease. For the first time, the armamentarium available for the treatment of the different types and phases of BC is approached here from a Unitarian perspective-based upon the hydrogen ion dynamics of cancer. The wide-ranged pH-related molecular, biochemical and metabolic model is able to embrace most of the fields and subfields of breast cancer etiopathogenesis and treatment. This single and integrated approach allows advancing towards a unidirectional, concerted and synergistic program of treatment. Further efforts in this line are likely to first improve the therapeutics of each subtype of this tumor and every individual patient in every phase of the disease.

Hydrogen Ion Dynamics of Cancer and a New Molecular, Biochemical and Metabolic Approach to the Etiopathogenesis and Treatment of Brain Malignancies.

The treatment of cancer has been slowly but steadily progressing during the last fifty years. Some tumors with a high mortality in the past are curable nowadays. However, there is one striking exception: glioblastoma multiforme. No real breakthrough has been hitherto achieved with this tumor with ominous prognosis and very short survival. Glioblastomas, being highly glycolytic malignancies are strongly pH-dependent and driven by the sodium hydrogen exchanger 1 (NHE1) and other proton (H+) transporters. Therefore, this is one of those pathologies where the lessons recently learnt from the new pH-centered anticancer paradigm may soon bring a promising change to treatment. This contribution will discuss how the pH-centric molecular, biochemical and metabolic perspective may introduce some urgently needed and integral novel treatments. Such a prospective therapeutic approach for malignant brain tumors is developed here, either to be used alone or in combination with more standard therapies.

The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela

Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pHe) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pHi to ∆pHe) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs' cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism.

Out of Warburg effect: An effective cancer treatment targeting the tumor specific metabolism and dysregulated pH.

As stated by Otto Warburg nearly a century ago, cancer is a metabolic disease, a fermentation caused by malfunctioning mitochondria, resulting in increased anabolism and decreased catabolism. Treatment should, therefore, aim at restoring the energy yield. To decrease anabolism, glucose uptake should be reduced (ketogenic diet). To increase catabolism, the oxidative phosphorylation should be restored. Treatment with a combination of α-lipoic acid and hydroxycitrate has been shown to be effective in multiple animal models. This treatment, in combination with conventional chemotherapy, has yielded extremely encouraging results in glioblastoma, brain metastasis and lung cancer. Randomized trials are necessary to confirm these preliminary data. The major limitation is the fact that the combination of α-lipoic acid and hydroxycitrate can only be effective if the mitochondria are still present and/or functional. That may not be the case in the most aggressive tumors. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Concomitant correction of this alkalosis may be a very effective treatment in case of mitochondrial failure.

Cellular acidification as a new approach to cancer treatment and to the understanding and therapeutics of neurodegenerative diseases.

During the last few years, the understanding of the dysregulated hydrogen ion dynamics and reversed proton gradient of cancer cells has resulted in a new and integral pH-centric paradigm in oncology, a translational model embracing from cancer etiopathogenesis to treatment. The abnormalities of intracellular alkalinization along with extracellular acidification of all types of solid tumors and leukemic cells have never been described in any other disease and now appear to be a specific hallmark of malignancy. As a consequence of this intracellular acid-base homeostatic failure, the attempt to induce cellular acidification using proton transport inhibitors and other intracellular acidifiers of different origins is becoming a new therapeutic concept and selective target of cancer treatment, both as a metabolic mediator of apoptosis and in the overcoming of multiple drug resistance (MDR). Importantly, there is increasing data showing that different ion channels contribute to mediate significant aspects of cancer pH regulation and etiopathogenesis. Finally, we discuss the extension of this new pH-centric oncological paradigm into the opposite metabolic and homeostatic acid-base situation found in human neurodegenerative diseases (HNDDs), which opens novel concepts in the prevention and treatment of HNDDs through the utilization of a cohort of neural and non-neural derived hormones and human growth factors.

Tumor metabolism, cancer cell transporters, and microenvironmental resistance.

Cancer cells reprogram their metabolic machineries to enter into permanent glycolytic pathways. The full reason for such reprogramming takes place is unclear. However, this metabolic switch is not made in vain for the lactate that is generated and exported outside cells is reused by other cells. This results in the generation of a pH gradient between the low extracellular pH that is acidic (pHe) and the higher cytosolic alkaline or near neutral pH (pHi) environments that are tightly regulated by the overexpression of several pumps and ion channels (e.g. NHE-1, MCT-1, V-ATPase, CA9, and CA12). The generation of this unique pH gradient serves as a determining factor in defining "tumor fitness". Tumor fitness is the capacity of the tumor to invade and metastasize due to its ability to reduce the efficiency of the immune system and confer resistance to chemotherapy. In this article, we highlight the importance of tumor microenvironment in mediating the failure of chemotherapeutic agents.

Resistance to cancer chemotherapy: failure in drug response from ADME to P-gp.

Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor-related factors. However, most current research is focused on tumor-specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer.

Vascular measurements correlate with estrogen receptor status.

BACKGROUND: Breast carcinoma can be classified as either Estrogen Receptor (ER) positive or negative by immunohistochemical phenotyping, although ER expression may vary from 1 to 100% of malignant cells within an ER + tumor. This is similar to genetic variability observed in other tumor types and is generally viewed as a consequence of intratumoral evolution driven by random genetic mutations. Here we view cellular evolution within tumors as a classical Darwinian system in which variations in molecular properties represent predictable adaptations to spatially heterogeneous environmental selection forces. We hypothesize that ER expression is a successful adaptive strategy only if estrogen is present in the microenvironment. Since the dominant source of estrogen is blood flow, we hypothesized that, in general, intratumoral regions with higher blood flow would contain larger numbers of ER + cells when compared to areas of low blood flow and in turn necrosis. METHODS: This study used digital pathology whole slide image acquisition and advanced image analysis algorithms. We examined the spatial distribution of ER + and ER- cells, vascular density, vessel area, and tissue necrosis within histological sections of 24 breast cancer specimens. These data were correlated with the patients ER status and molecular pathology report findings. RESULTS: ANOVA analyses revealed a strong correlation between vascular area and ER expression and between high fractional necrosis and absent ER expression (R(2) = 39%; p < 0.003 and R(2) = 46%; p < 0.001), respectively). ER expression did not correlate with tumor grade or size. CONCLUSION: We conclude that ER expression can be understood as a Darwinian process and linked to variations in estrogen delivery by temporal and spatial heterogeneity in blood flow. This correlation suggests strategies to promote intratumoral blood flow or a cyclic introduction of estrogen in the treatment schedule could be explored as a counter-intuitive approach to increase the efficacy of anti-estrogen drugs.

The Prime and Integral Cause of Cancer in the Post-Warburg Era.

Back to beginnings. A century ago, Otto Warburg published that aerobic glycolysis and the respiratory impairment of cells were the prime cause of cancer, a phenomenon that since then has been known as "the Warburg effect". In his early studies, Warburg looked at the effects of hydrogen ions (H+), on glycolysis in anaerobic conditions, as well as of bicarbonate and glucose. He found that gassing with CO2 led to the acidification of the solutions, resulting in decreased rates of glycolysis. It appears that Warburg first interpreted the role of pH on glycolysis as a secondary phenomenon, a side effect that was there just to compensate for the effect of bicarbonate. However, later on, while talking about glycolysis in a seminar at the Rockefeller Foundation, he said: "Special attention should be drawn to the remarkable influence of the bicarbonate…". Departing from the very beginnings of this metabolic cancer research in the 1920s, our perspective advances an analytic as well as the synthetic approach to the new "pH-related paradigm of cancer", while at the same time addressing the most fundamental and recent changing concepts in cancer metabolic etiology and its potential therapeutic implications.

Epidemiological Characteristics and Outcomes Predictors for Intensive Care Unit COVID-19 Patients in Al-Madinah, Saudi Arabia. Retrospective Cohort Study.

Introduction: The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) increased the demand for intensive care unit (ICU) services. Mortality and morbidity rates among ICU COVID-19 patients are affected by several factors, such as severity, comorbidities, and coinfections. In this study, we describe the demographic characteristics of COVID-19 patients admitted to an ICU in Saudi Arabia, and we determined the predictors for mortality and prolonged ICU length of stay. Additionally, we determined the prevalence of bacterial coinfection and its effect on the outcomes for ICU COVID-19 patients. Methods: We retrospectively studied the medical records of 142 COVID-19 patients admitted to the ICU at a tertiary hospital in Madinah, Saudi Arabia. Data on demographics, medical history, mortality, length of stay, and presence of coinfection were collected for each patient. Results: Neutrophil-to-Lymphocyte ratio (NLR) and intubation were reliable predictors of mortality and ICU length of stay among these ICU COVID-19 patients. Moreover, bacterial coinfections were detected in 23.2% of the patients and significantly (p < 0.001) prolonged their ICU length of stay, explaining the 10% increase in the length of stay for these patients. Furthermore, mortality reached 70% among the coinfected patients, and 60.8% of the isolated coinfecting pathogens were multidrug-resistant (MDR) strains of Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococcus aureus. Conclusion: Increased NLR and intubation are predictors of mortality and prolonged length of stay in COVID-19 patients admitted to the ICU. Coinfection with MDR bacterial strains potentially results in complications and is a high-risk factor for prolonged ICU length of stay.

Low prevalence of community-acquired influenza coinfections among COVID-19 patients in Al-Madinah, Saudi Arabia: A retrospective cohort study.

BACKGROUND: Coinfections with respiratory viruses among SARS CoV-2 patients have been reported by several studies during the current COVID-19 pandemic. Most of these studies designated these coinfections as being hospital-acquired infections; however, there is inadequate knowledge about community-acquired respiratory coinfections among SARS CoV-2 patients. METHODS: In this retrospective cohort study, we investigated the seroprevalence of influenza A, influenza B, and parainfluenza-2 among newly hospitalized patients with confirmed COVID-19 infections (n = 163). The study was conducted during the early phase of the COVID-19 pandemic in Saudi Arabia (from April to October 2020). The patients' serum samples were subjected to commercial immunoglobulin M (IgM) antibody tests against the three aforementioned viruses. RESULTS: Seropositivity for influenza A and B and parainfluenza-2 occurred only in 4.2% (7/163) of COVID-19 patients, indicating simultaneous acute infections of these three viruses with SARS CoV-2 infection. All coinfection cases were mild and misdiagnosed during the care period in the hospital. CONCLUSION: This study highlights the low prevalence of community-acquired respiratory infections among COVID-19 patients in the current pandemic and we discussed the possible factors for this finding. During newly emerging epidemics or pandemics, considering other respiratory viruses circulating in the community is essential to avoid their misdiagnosis and account for their possible negative effects on pandemic disease management and prognosis.

Serostatus and Epidemiological Characteristics for Atypical Pneumonia Causative Bacteria among Healthy Individuals in Medina, Saudi Arabia, a Retrospective Study.

Background: Community-acquired atypical pneumonia is generally a mild and self-limiting infection. Still, it may lead to hospitalization and progressive clinical complications in some cases, particularly among the elderly and individuals with chronic diseases. Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae are the community's main causative agents of atypical pneumonia. However, most published studies evaluated their incidence in the hospital setting, and little is known about their prevalence among healthy individuals. This work aims to assess the seroprevalence of these bacteria among healthy people to determine the status of immunity against these bacteria in the community. Methodology: Two hundred and eighty-three serum samples from a multicenter in Medina, Saudi Arabia, were collected in this study. Serum samples were subjected to indirect enzyme-linked immunosorbent assays (ELISAs) to detect IgG antibodies against C. pneumoniae, L. pneumophila, and M. pneumoniae to investigate the seroprevalence of these bacteria and their distribution among different genders and age groups of healthy people. Results: IgG seropositivity for at least one of the three atypical pneumonia-causative bacteria occurred in 85.8% (n= 243/283) of the sample population. IgG seropositivity for C. pneumoniae occurred in 80.6% (228/283) of the population, followed by 37.5% for L. pneumophila and 23% for M. pneumoniae (66/283). In addition, the IgG seropositivity rates for the three bacteria were observed predominantly among male participants. Furthermore, no significant difference in IgG seropositivity distribution occurred between different age groups of healthy people for C. pneumoniae, L. pneumophila and M. pneumoniae. Conclusions: The current study found that C. pneumoniae, L. pneumophila, and M. pneumoniae tended to be highly prevalent among healthy people and more common among males than females. Additionally, their pattern of distribution among healthy individuals seemed to be predominant among young adults (aged 20−40 years), which differs from their predominant distribution among elderly patients in hospital settings (>50 years).

Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma: A Physiopathologic and Pharmacologic Review.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.

Acute Helicobacter pylori Infection Prevalence Among Renal Failure Patients and Its Potential Roles with Other Chronic Diseases: A Retrospective Cohort Study.

Background: Helicobacter pylori (H. pylori) infection is relevant to several chronic human diseases, from digestive diseases to renal, metabolic, and cancer diseases. H. pylori infections and chronic kidney diseases are in increasing, global records; if not well controlled in a specific population, these diseases might lead to more clinical complications. Methods: In this retrospective study, we investigated the prevalence of acute H. pylori infections among 127 dialysis patients via subjecting their serums to the enzyme-linked immunosorbent assay (ELISA) to detect the human Immunoglobulin M (IgM) against H. pylori infections. Samples were from dialysis patients in a single hemodialysis center in Medina, Saudi Arabia, from January to August 2021. Results: Our results indicated the significant prevalence of H. pylori acute infections among 33.1% of renal failure patients recruited in this study, chi-squared: 14.559, p-value: 0.0001. In addition, no significant occurrence of acute H. pylori infection among males and females, chi-squared: 1.823, p-value: 0.177. Furthermore, the prevalence of acute H. pylori infection was not significant in different age groups of renal failure patients. Chi-squared: 6.803, p-value: 0.147, despite H. pylori-infected cases predominantly represented in patients above 51 years. Moreover, we noticed that hypertension, followed by diabetes, was the most prevalent underlying medical condition among acute infected H. pylori and renal failure patients. Conclusion: We documented the significant prevalence of acute H. pylori infection among renal failure patients. We also highlighted and discussed the possible potential roles of H. pylori in renal failure and other chronic diseases. Routine screening and treatment for acute H. pylori infection for chronic kidney diseases, hypertension, and diabetes patients would positively reduce the bacterium's progressive effects on them. They might even improve the control of these diseases.