The inhibitory and transcriptional effects of the epigenetic repurposed drugs hydralazine and valproate in lymphoma cells.

Lymphoma is a disease that affects countless lives each year. In order to combat this disease, researchers have been exploring the potential of DNMTi and HDACi drugs. These drugs target the cellular processes that contribute to lymphomagenesis and treatment resistance. Our research evaluated the effectiveness of a combination of two such drugs, hydralazine (DNMTi) and valproate (HDACi), in B-cell and T-cell lymphoma cell lines. Here we show that the combination of hydralazine and valproate decreased the viability of cells over time, leading to the arrest of cell-cycle and apoptosis in both B and T-cells. This combination of drugs proved to be synergistic, with each drug showing significant growth inhibition individually. Microarray analyses of HuT 78 and Raji cells showed that the combination of hydralazine and valproate resulted in the up-regulation of 562 and 850 genes, respectively, while down-regulating 152 and 650 genes. Several proapoptotic and cell cycle-related genes were found to be up-regulated. Notably, three and five of the ten most up-regulated genes in HuT 78 and Raji cells, respectively, were related to immune function. In summary, our study suggests that the combination of hydralazine and valproate is an effective treatment option for both B- and T-lymphomas. These findings are highly encouraging, and we urge further clinical evaluation to validate our research and potentially improve lymphoma treatment.

Chronic kidney disease, dialysis and climate change.

Chronic Kidney Disease is a serious public health problem and in clear relation to Climate Change and ecosystem maintenance. Renal health is particularly vulnerable to the impacts of climate change, and dialysis therapy (hemodialysis and PD) has a significant environmental footprint, conditioned by energy consumption and greenhouse gas production. In the last 50 years, people have changed ecosystems faster and more extensively than in any other period in human history. It is a consequence of ever-increasing demand for food, fresh water, fuel, industry, etc. and the result has been a substantial and largely irreversible loss of the diversity of life on Earth. Since 1979, human activities have caused the extinction of 60% of mammals, birds, fish and reptiles. There is an urgent need to adopt "Green Nephrology" measures by developing sustainable environmental solutions for the prevention and treatment of kidney diseases.

Galectin-8 counteracts folic acid-induced acute kidney injury and prevents its transition to fibrosis.

Acute kidney injury (AKI), characterized by a sudden decline in kidney function involving tubular damage and epithelial cell death, can lead to progressive tissue fibrosis and chronic kidney disease due to interstitial fibroblast activation and tissue repair failures that lack direct treatments. After an AKI episode, surviving renal tubular cells undergo cycles of dedifferentiation, proliferation and redifferentiation while fibroblast activity increases and then declines to avoid an exaggerated extracellular matrix deposition. Appropriate tissue recovery versus pathogenic fibrotic progression depends on fine-tuning all these processes. Identifying endogenous factors able to affect any of them may offer new therapeutic opportunities to improve AKI outcomes. Galectin-8 (Gal-8) is an endogenous carbohydrate-binding protein that is secreted through an unconventional mechanism, binds to glycosylated proteins at the cell surface and modifies various cellular activities, including cell proliferation and survival against stress conditions. Here, using a mouse model of AKI induced by folic acid, we show that pre-treatment with Gal-8 protects against cell death, promotes epithelial cell redifferentiation and improves renal function. In addition, Gal-8 decreases fibroblast activation, resulting in less expression of fibrotic genes. Gal-8 added after AKI induction is also effective in maintaining renal function against damage, improving epithelial cell survival. The ability to protect kidneys from injury during both pre- and post-treatments, coupled with its anti-fibrotic effect, highlights Gal-8 as an endogenous factor to be considered in therapeutic strategies aimed at improving renal function and mitigating chronic pathogenic progression.

Multitargeted polypharmacotherapy for cancer treatment. theoretical concepts and proposals.

INTRODUCTION: The pharmacological treatment of cancer has evolved from cytotoxic to molecular targeted therapy. The median survival gains of 124 drugs approved by the FDA from 2003 to 2021 is 2.8 months. Targeted therapy is based on the somatic mutation theory, which has some paradoxes and limitations. While efforts of targeted therapy must continue, we must study newer approaches that could advance therapy and affordability for patients. AREAS COVERED: This work briefly overviews how cancer therapy has evolved from cytotoxic chemotherapy to current molecular-targeted therapy. The limitations of the one-target, one-drug approach considering cancer as a robust system and the basis for multitargeting approach with polypharmacotherapy using repurposing drugs. EXPERT OPINION: Multitargeted polypharmacotherapy for cancer with repurposed drugs should be systematically investigated in preclinical and clinical studies. Remarkably, most of these proposed drugs already have a long history in the clinical setting, and their safety is known. In principle, the risk of their simultaneous administration should not be greater than that of a first-in-human phase I study as long as the protocol is developed with strict vigilance to detect early possible side effects from their potential interactions. Research on cancer therapy should go beyond the prevailing paradigm targeted therapy.

Efficacy and safety of biological treatment for inflammatory bowel disease in elderly patients: Results from a GETECCU cohort.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.

Use of Tirzepatide in Adults with Type 2 Diabetes Mellitus: Scientific Evidence and Practical Aspects.

Tirzepatide is a novel antidiabetic medication a single-molecule, agonist to the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors. It is approved in the USA and EU for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Due to the potential novelty represented by incorporating tirzepatide to clinical practice, we aim to review practical aspects of tirzepatide use in T2DM and the supporting scientific evidence. A group of ten endocrinologists involved as investigators in the phase 3 SURPASS clinical trial program followed a nominal group technique, a qualitative research methodology designed as a semi-structured group discussion to reach a consensus on the selection of a set of practical aspects. The scientific evidence for tirzepatide has been reviewed with respect to a number of patients' clinical profiles and care goals. Information of interest related to adverse events, special warnings and precautions, and other considerations for tirzepatide use has been included. Finally, information provided to the patients has been summarized. The practical aspects reported herein may be helpful in guiding physicians in the use of tirzepatide and contribute to optimizing the management of T2DM.

Chronic Exposure to Arsenic and Fluoride Starting at Gestation Alters Liver Mitochondrial Protein Expression and Induces Early Onset of Liver Fibrosis in Male Mouse Offspring.

The presence of arsenic (As) and fluoride (F-) in drinking water is of concern due to the enormous number of individuals exposed to this condition worldwide. Studies in cultured cells and animal models have shown that As- or F-induced hepatotoxicity is primarily associated with redox disturbance and altered mitochondrial homeostasis. To explore the hepatotoxic effects of chronic combined exposure to As and F- in drinking water, pregnant CD-1 mice were exposed to 2 mg/L As (sodium arsenite) and/or 25 mg/L F- (sodium fluoride). The male offspring continued the exposure treatment up to 30 (P30) or 90 (P90) postnatal days. GSH levels, cysteine synthesis enzyme activities, and cysteine transporter levels were investigated in liver homogenates, as well as the expression of biomarkers of ferroptosis and mitochondrial biogenesis-related proteins. Serum transaminase levels and Hematoxylin-Eosin and Masson trichrome-stained liver tissue slices were examined. Combined exposure at P30 significantly reduced GSH levels and the mitochondrial transcription factor A (TFAM) expression while increasing lipid peroxidation, free Fe 2+, p53 expression, and serum ALT activity. At P90, the upregulation of cysteine uptake and synthesis was associated with a recovery of GSH levels. Nevertheless, the downregulation of TFAM continued and was now associated with a downstream inhibition of the expression of MT-CO2 and reduced levels of mtDNA and fibrotic liver damage. Our experimental approach using human-relevant doses gives evidence of the increased risk for early liver damage associated with elevated levels of As and F- in the diet during intrauterine and postnatal period.

Galectins in epithelial-mesenchymal transition: roles and mechanisms contributing to tissue repair, fibrosis and cancer metastasis.

Galectins are soluble glycan-binding proteins that interact with a wide range of glycoproteins and glycolipids and modulate a broad spectrum of physiological and pathological processes. The expression and subcellular localization of different galectins vary among tissues and cell types and change during processes of tissue repair, fibrosis and cancer where epithelial cells loss differentiation while acquiring migratory mesenchymal phenotypes. The epithelial-mesenchymal transition (EMT) that occurs in the context of these processes can include modifications of glycosylation patterns of glycolipids and glycoproteins affecting their interactions with galectins. Moreover, overexpression of certain galectins has been involved in the development and different outcomes of EMT. This review focuses on the roles and mechanisms of Galectin-1 (Gal-1), Gal-3, Gal-4, Gal-7 and Gal-8, which have been involved in physiologic and pathogenic EMT contexts.

Progress and Challenge of Sensors for Dairy Food Safety Monitoring.

One of the most consumed foods is milk and milk products, and guaranteeing the suitability of these products is one of the major concerns in our society. This has led to the development of numerous sensors to enhance quality controls in the food chain. However, this is not a simple task, because it is necessary to establish the parameters to be analyzed and often, not only one compound is responsible for food contamination or degradation. To attempt to address this problem, a multiplex analysis together with a non-directed (e.g., general parameters such as pH) analysis are the most relevant alternatives to identifying the safety of dairy food. In recent years, the use of new technologies in the development of devices/platforms with optical or electrochemical signals has accelerated and intensified the pursuit of systems that provide a simple, rapid, cost-effective, and/or multiparametric response to the presence of contaminants, markers of various diseases, and/or indicators of safety levels. However, achieving the simultaneous determination of two or more analytes in situ, in a single measurement, and in real time, using only one working 'real sensor', remains one of the most daunting challenges, primarily due to the complexity of the sample matrix. To address these requirements, different approaches have been explored. The state of the art on food safety sensors will be summarized in this review including optical, electrochemical, and other sensor-based detection methods such as magnetoelastic or mass-based sensors.

Strategy for the Enzymatic Acylation of the Apple Flavonoid Phloretin Based on Prior α-Glucosylation.

The acylation of flavonoids serves as a means to alter their physicochemical properties, enhance their stability, and improve their bioactivity. Compared with natural flavonoid glycosides, the acylation of nonglycosylated flavonoids presents greater challenges since they contain fewer reactive sites. In this work, we propose an efficient strategy to solve this problem based on a first α-glucosylation step catalyzed by a sucrose phosphorylase, followed by acylation using a lipase. The method was applied to phloretin, a bioactive dihydrochalcone mainly present in apples. Phloretin underwent initial glucosylation at the 4'-OH position, followed by subsequent (and quantitative) acylation with C8, C12, and C16 acyl chains employing an immobilized lipase from Thermomyces lanuginosus. Electrospray ionization-mass spectrometry (ESI-MS) and two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) confirmed that the acylation took place at 6-OH of glucose. The water solubility of C8 acyl glucoside closely resembled that of aglycone, but for C12 and C16 derivatives, it was approximately 3 times lower. Compared with phloretin, the radical scavenging capacity of the new derivatives slightly decreased with 2,2-diphenyl-1-picrylhydrazyl (DPPH) and was similar to 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+). Interestingly, C12 acyl-α-glucoside displayed an enhanced (3-fold) transdermal absorption (using pig skin biopsies) compared to phloretin and its α-glucoside.

Selection of clinically relevant drug concentrations for in vitro studies of candidates drugs for cancer repurposing: a proposal.

Drug repurposing of widely prescribed patent-off and cheap drugs may provide affordable drugs for cancer treatment. Nevertheless, many preclinical studies of cancer drug repurposing candidates use in vitro drug concentrations too high to have clinical relevance. Hence, preclinical studies must use clinically achievable drug concentrations. In this work, several FDA-approved cancer drugs are analyzed regarding the correlation between the drug inhibitory concentrations 50% (IC50) tested in cancer cell lines and their corresponding peak serum concentration (Cmax) and area under the curve (AUC) reported in clinical studies of these drugs. We found that for most targeted cancer drugs, the AUC and not the Cmax is closest to the IC50; therefore, we suggest that the initial testing of candidate drugs for repurposing could select the AUC pharmacokinetic parameter and not the Cmax as the translated drug concentration for in vitro testing. Nevertheless, this is a suggestion only as experimental evidence does not exist to prove this concept. Studies on this issue are required to advance in cancer drug repurposing.

Chronic exposure to inorganic arsenic and fluoride induces redox imbalance, inhibits the transsulfuration pathway, and alters glutamate receptor expression in the brain, resulting in memory impairment in adult male mouse offspring.

Exposure to toxic elements in drinking water, such as arsenic (As) and fluoride (F), starts at gestation and has been associated with memory and learning deficits in children. Studies in which rodents underwent mechanistic single exposure to As or F showed that the neurotoxic effects are associated with their capacity to disrupt redox balance, mainly by diminishing glutathione (GSH) levels, altering glutamate disposal, and altering glutamate receptor expression, which disrupts synaptic transmission. Elevated levels of As and F are common in groundwater worldwide. To explore the neurotoxicity of chronic exposure to As and F in drinking water, pregnant CD-1 mice were exposed to 2 mg/L As (sodium arsenite) and 25 mg/L F (sodium fluoride) alone or in combination. The male litter continued to receive exposure up to 30 or 90 days after birth. The effects of chronic exposure on GSH levels, transsulfuration pathway enzymatic activity, expression of cysteine/cystine transporters, glutamate transporters, and ionotropic glutamate receptor subunits as well as behavioral performance in the object recognition memory task were assessed. Combined exposure resulted in a significant reduction in GSH levels in the cortex and hippocampus at different times, decreased transsulfuration pathway enzyme activity, as well as diminished xCT protein expression. Altered glutamate receptor expression in the cortex and hippocampus and decreased transaminase enzyme activity were observed. These molecular alterations were associated with memory impairment in the object recognition task, which relies on these brain regions.

BDNF and Cognitive Function in Chilean Schizophrenic Patients.

Despite cognitive symptoms being very important in schizophrenia, not every schizophrenic patient has a significant cognitive deficit. The molecular mechanisms underlying the different degrees of cognitive functioning in schizophrenic patients are not sufficiently understood. We studied the relation between brain-derived neurotrophic factor (BDNF) and cognitive functioning in two groups of schizophrenic patients with different cognitive statuses. According to the Montreal Cognitive Assessment (MoCA) results, the schizophrenic patients were classified into two subgroups: normal cognition (26 or more) and cognitive deficit (25 or less). We measured their plasma BDNF levels using ELISAs. The statistical analyses were performed using Spearman's Rho and Kruskal-Wallis tests. We found a statistically significant positive correlation between the plasma BDNF levels and MoCA score (p = 0.04) in the subgroup of schizophrenic patients with a cognitive deficit (n = 29). However, this correlation was not observed in the patients with normal cognition (n = 11) and was not observed in the total patient group (n = 40). These results support a significant role for BDNF in the cognitive functioning of schizophrenics with some degree of cognitive deficit, but suggest that BDNF may not be crucial in patients with a normal cognitive status. These findings provide information about the molecular basis underlying cognitive deficits in this illness.

Transoral removal of submandibular hilar lithiasis: results on the salivary duct system, glandular parenchyma, and quality-of-life recovery.

OBJECTIVE(S): To confirm that hilar transoral submandibular sialolitectomy (TOSL) is the first treatment option for submandibular hilar lithiasis (SHL) in terms of glandular parenchyma recovery, salivary system restoration, and patient quality of life (QoL) improvement. METHODS: Depending on whether the stone was easily palpable, TOSL was carried out with or without sialendoscopy. For the first time in the literature, Magnetic Resonance Sialography (MR-Si) was performed before and after TOSL, to evaluate stone characteristics, glandular parenchyma status, hilum dilation and main duct recanalization. Radiological data was examined independently by two radiologists. COSQ, a recently validated and specific questionnaire, was used to assess associated QoL. RESULTS: Between 2017 and 2022, 29 TOSL patients were examined. With a high interobserver correlation, MR-Si was confirmed as a very useful radiological test in the pre- and post-surgical evaluation of SHL. The salivary main duct was completely recanalized in all cases. The presence of lithiasis was found in 4 patients (13.8%). After surgery, the majority of patients (79.31%) had hilum dilation. There was a statistically significant improvement in parenchyma status, but no significant progression to glandular atrophy. After surgery, COSQ mean values always improved (22.5 to 4.5). CONCLUSIONS: TOSL is the ideal surgical technique for the management of SHL, resulting in improved parenchymal inflammatory changes, recanalization of Wharton's duct, and enhancement patients' QoL. As a result, before removing the submandibular gland, TOSL should be considered as the first treatment option for SHL.

Transforming an esterase into an enantioselective catecholase through bioconjugation of a versatile metal-chelating inhibitor.

Metal complexes introduced into protein scaffolds can generate versatile biomimetic catalysts endowed with a variety of catalytic properties. Here, we synthesized and covalently bound a bipyridinyl derivative to the active centre of an esterase to generate a biomimetic catalyst that shows catecholase activity and enantioselective catalytic oxidation of (+)-catechin.

PaSTe. Blockade of the Lipid Phenotype of Prostate Cancer as Metabolic Therapy: A Theoretical Proposal.

BACKGROUND: Prostate cancer is the most frequently diagnosed malignancy in 112 countries and is the leading cause of death in eighteen. In addition to continuing research on prevention and early diagnosis, improving treatments and making them more affordable is imperative. In this sense, the therapeutic repurposing of low-cost and widely available drugs could reduce global mortality from this disease. The malignant metabolic phenotype is becoming increasingly important due to its therapeutic implications. Cancer generally is characterized by hyperactivation of glycolysis, glutaminolysis, and fatty acid synthesis. However, prostate cancer is particularly lipidic; it exhibits increased activity in the pathways for synthesizing fatty acids, cholesterol, and fatty acid oxidation (FAO). OBJECTIVE: Based on a literature review, we propose the PaSTe regimen (Pantoprazole, Simvastatin, Trimetazidine) as a metabolic therapy for prostate cancer. Pantoprazole and simvastatin inhibit the enzymes fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), therefore, blocking the synthesis of fatty acids and cholesterol, respectively. In contrast, trimetazidine inhibits the enzyme 3-b-Ketoacyl-CoA thiolase (3-KAT), an enzyme that catalyzes the oxidation of fatty acids (FAO). It is known that the pharmacological or genetic depletion of any of these enzymes has antitumor effects in prostatic cancer. RESULTS: Based on this information, we hypothesize that the PaSTe regimen will have increased antitumor effects and may impede the metabolic reprogramming shift. Existing knowledge shows that enzyme inhibition occurs at molar concentrations achieved in plasma at standard doses of these drugs. CONCLUSION: We conclude that this regimen deserves to be preclinically evaluated because of its clinical potential for the treatment of prostate cancer.

In vivo effect of mouthwashes on viable viral load of SARS-CoV-2 in saliva: a pilot study.

Current data on the efficacy of antiseptic mouthwashes to reduce viral load are contradictory. Firstly, in vitro data indicate very strong virucidal effects that are not replicated in clinical studies. Secondly, most clinical studies identify a limited effect, do not include a control/placebo group, or do not evaluate viral viability in an infection model. In the current manuscript, we perform a double-blind, randomized clinical trial where salivary viral load was measured before and after the mouthwash, and where saliva samples were also cultured in an in vitro infection model of SARS-CoV-2 to evaluate the effect of mouthwashes on viral viability. Our data show a 90-99% reduction in SARS-CoV-2 salivary copies with one of the tested mouthwashes, although we show that the remaining viruses are mostly viable. In addition, our data suggest that the active ingredient concentration and the overall excipients' formulation can play an important role; and most importantly, they indicate that the effect is not immediate, being significant at 15 min and having maximum effectiveness after 1 h. Thus, we show that some oral mouthwashes can be useful in reducing viral transmission, although their efficacy must be improved through refined formulations or revised protocols.

Quantitative Susceptibility Mapping MRI in Deep-Brain Nuclei in First-Episode Psychosis.

BACKGROUND: Psychosis is related to neurochemical changes in deep-brain nuclei, particularly suggesting dopamine dysfunctions. We used an magnetic resonance imaging-based technique called quantitative susceptibility mapping (QSM) to study these regions in psychosis. QSM quantifies magnetic susceptibility in the brain, which is associated with iron concentrations. Since iron is a cofactor in dopamine pathways and co-localizes with inhibitory neurons, differences in QSM could reflect changes in these processes. METHODS: We scanned 83 patients with first-episode psychosis and 64 healthy subjects. We reassessed 22 patients and 21 control subjects after 3 months. Mean susceptibility was measured in 6 deep-brain nuclei. Using linear mixed models, we analyzed the effect of case-control differences, region, age, gender, volume, framewise displacement (FD), treatment duration, dose, laterality, session, and psychotic symptoms on QSM. RESULTS: Patients showed a significant susceptibility reduction in the putamen and globus pallidus externa (GPe). Patients also showed a significant R2* reduction in GPe. Age, gender, FD, session, group, and region are significant predictor variables for QSM. Dose, treatment duration, and volume were not predictor variables of QSM. CONCLUSIONS: Reduction in QSM and R2* suggests a decreased iron concentration in the GPe of patients. Susceptibility reduction in putamen cannot be associated with iron changes. Since changes observed in putamen and GPe were not associated with symptoms, dose, and treatment duration, we hypothesize that susceptibility may be a trait marker rather than a state marker, but this must be verified with long-term studies.