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Environmental chemicals and drugs can induce cardiotoxicity, mainly by generating free radicals. Reactive oxygen species play a critical role in the pathogenesis of cardiac tissue injury. This highlights a need for prevention of cardiotoxicity by scavenging free radicals. Melatonin has been shown to act as a protector against various conditions in which free radicals cause molecular and tissue injury. Some of the mechanisms by which melatonin operates as a free radical scavenger and antioxidant have been identified. The importance of endogenous melatonin in cardiovascular health and the benefits of melatonin supplementation in different cardiac pathophysiological disorders have been shown in a variety of model systems. Melatonin continues to attract attention for its potential therapeutic value for cardiovascular toxicity. The therapeutic potential of melatonin in treatment of cardiotoxicities caused by various chemicals along with suggested molecular mechanisms of action for melatonin is reviewed. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is an antineoplastic agent obtained from Streptomyces peucetius. It is utilized in treating different kinds of cancers, such as leukemia, lymphoma, and lung, and breast cancers. The main side effect of DOX is cardiotoxicity. Metformin (MET) is an antihyperglycemic drug used for type 2 diabetes treatment. It is proposed that MET has a protective effect against DOX cardiotoxicity. Our review demonstrated that MET has several possible mechanisms of action, which can prevent or at least reduce DOX cardiotoxicity including a decrease of free radical generation and oxidative stress, 5′ adenosine monophosphate-activated protein kinase activation, and ferritin heavy chain expression in cardiomyocytes cells. The combination of MET and DOX has been shown to enhance the anticancer activity of DOX by a number of authors. The literature reviewed in the present report supports the hypothesis that MET can reduce the cardiotoxicity that often occurs with DOX treatment. [ABSTRACT FROM AUTHOR]

Melatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), p-PI3K, Akt, p-Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl-XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin-1 phosphorylation. Beclin-1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP-activated protein kinase (AMPK), Wnt/β-catenin, mitogen-activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways., (© 2024 International Union of Biochemistry and Molecular Biology.)

Protocatechuic acid (PCA) is a water-soluble polyphenol compound that is extracted from certain fruits and plants or obtained from glucose fermentation. Several in vivo and in vitro studies have determined that PCA has protective effects against the toxicity of natural and chemical toxicants. We searched these articles in PubMed, Google Scholar, and Scopus with appropriate keywords from inception up to August 2023. Forty-nine studies were found about protective effects of PCA against drug toxicity, metal toxicity, toxins, chemical toxicants, and some other miscellaneous toxicants. PCA indicates these protective effects by suppression of oxidative stress, inflammation, and apoptosis. PCA reduces reactive oxygen/nitrogen species (RONS) and enhances the level of antioxidant parameters mainly through the activation of the Nrf-2 signaling pathway. PCA also decreases the levels of inflammatory mediators via downregulating the TLR-4-mediated IKBKB/NF-κB and MAPK/Erk signaling pathways. In addition, PCA inhibits apoptosis by lowering the expression of Bax, caspase-3, and caspase-9 along with enhancing the level of the antiapoptotic protein Bcl-2. Further evaluation, especially in humans, is necessary to confirm PCA as a potential therapeutic approach to intervene in such toxicities., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite its popularity along with many proposed therapeutic applications, the safety profile of Aloe vera gel beverages remains unsettled. The putative toxicology concern has focused on the hydroxyanthraquinone derivatives (HADs) found in the latex portion of the Aloe leaf. Despite harvesting and processing designed to eliminate or significantly reduce these compounds, certain HADs, such as aloin, may be present and have been associated with carcinogenicity in non-decolorized whole leaf extract containing approximately 6400 ppm aloin A and 71 ppm aloin-emodin. Sprague Dawley rats had free access to drinking water or a commercially and widely available Aloe vera gel beverage (Forever Living Products) prepared from the inner leaves of Aloe barbadensis Miller containing 3.43 ppm total aloin for 90 days. Under the conditions of the study and based on the toxicological endpoints evaluated, there were no adverse test substance-related findings, including altered thyroid hormones. No histologic differences or histopathological changes were detected in the multiple tissues and organs examined. The Ki-67 proliferation assay demonstrated no increased cell proliferation in the liver, lungs, kidneys, or urinary bladder, which might have been attributed to the dietary administration of the Aloe vera gel beverage via drinking water for 90 days. These data lend increasing confidence regarding the safety of appropriately processed Aloe vera gel beverages, such as the beverage tested in this study., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Aloe Vera Company, Scottsdale, AZ, funded the study, which was conducted at Product Safety Laboratories, Dayton, NJ. Allen W. Singer, and Mark R. Bauter are employees of Stage Bio, Mount Jackson, VA Product Safety Labs, Dayton, NJ 08810, respectively. A. Wallace Hayes, Peter Pressman, and Roger Clemens are members of the Scientific Advisory Board, The Aloe Vera Company and are paid consultants. Although the manuscript has been reviewed by the company, the conclusions and writing of the manuscript are entirely those of the authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The present paper provides the first integrative assessment of the capacity of dietary, endogenous and other agents to induce hormetic dose responses in oocytes, their supportive cells such as granulosa cells, blastocyst formation and early stage embryo development with the goal of improving fertility and reproductive success. The analysis showed that numerous agents enhance oocyte maturation and blastocyst/embryonic development in an hormetic fashion. These findings indicate that numerous agents improve oocyte-related biological functioning under normal conditions as well as enhancing its capacity to prevent damage from numerous chemical toxins and related stressor agents, including heat and age-related processes in pre-post conditioning and concurrent exposures. The present assessment suggests that hormetic-based lifestyles and dietary interventions may offer the potential to enhance healthy reproductive performance with applications to animal husbandry and human biology. The present findings also significantly extend the generality of the hormesis dose response concept to multiple fundamental biological processes (i.e., oocyte maturation, fertilization and blastocyst/embryo development)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Remdesivir (RDV) is the mainstay antiviral therapy for moderate to severe COVID-19. Although remdesivir was the first drug approved for COVID-19, information about its efficacy and safety profile is limited in a significant segment of the population, such as people with underlying diseases, the elderly, children, and pregnant and lactating women. The efficacy and safety profile of RDV in disease progression, renal impairment, liver impairment, immunosuppression, geriatrics, pediatrics, pregnancy, and breastfeeding in COVID-19 patients was evaluated. The databases searched included Embase, Scopus, and PubMed. Only English language studies enrolling specific subpopulations with COVID-19 and treated with RDV were included. Thirty-nine clinical trials, cohorts, cross-sectional studies, and case series/reports were included. Most supported the benefits of RDV therapy for COVID-19 patients, such as lessening the duration of hospitalization, alleviating respiratory complications, and reducing mortality. Adverse effects of RDV, including liver and kidney impairment, were, for the most part, moderate to mild, supporting the safety profile of RDV therapy. RDV therapy was well tolerated, no new safety signals were detected, and liver function test abnormalities were the most common adverse events. Moreover, RDV, for the most part, was effective in managing the complications of COVID-19 and reducing mortality in these patients, except for patients with kidney impairment. Future studies, including RCTs, should include these subpopulations of patients to avoid delays associated with receiving proper medication through compassionate use programs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rutin is a flavonoid present in numerous fruits and vegetables and therefore widely consumed by humans. It is also a popular dietary supplement of 250-500 mg/day. There is considerable consumer interest in rutin due to numerous reports in the biomedical literature of its multi-system chemo-preventive properties. The present paper provides the first assessment of rutin-induced hormetic concentration/dose responses, their quantitative features and mechanistic basis, along with their biological, biomedical, clinical, and public health implications. The findings indicate that rutin-induced hormetic dose responses are widespread, being reported in numerous biological models and cell types for a wide range of endpoints. Of critical importance is that the optimal hormetic findings shown in in vitro systems are currently not achievable for human populations due to low gastrointestinal tract bioavailability. These findings have the potential to strengthen future experimental studies with rutin, particularly concerning study design parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The present paper provides a new perspective of previously published findings by Siwak (Food Chem 141:1227-1241, 2013) which showed that 15 structurally diverse flavonoids reduced toxicity (i.e., enhanced cell viability) from hypochlorite using the MTT assay within a pre-conditioning experimental protocol, with each agent showing a similar biphasic concentration response relationship. We use this Commentary to point out that each of the concentration response relationships are consistent with the hormetic dose response. The paper of Siwak (Food Chem 141:1227-1241, 2013) is unique in that it provides a comparison of a relatively large number of agents using the identical experimental protocol., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This paper represents the first integrative assessment and documentation of taurine-induced hormetic effects in the biological and biomedical areas, their dose response features, mechanistic frameworks, and possible public health, therapeutic and commercial applications. Taurine-induced hormetic effects are documented in a wide range of experimental models, cell types and for numerous biological endpoints, with most of these experimental findings being reported within the past five years. It is suggested that the concept of hormesis may have a transformative effect on taurine research and its public health and therapeutic applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this overview, we seek to appraise recent experimental and observational studies investigating THC and its potential role as adjunctive therapy in various medical illnesses. Recent clinical trials are suggestive of the diverse pharmacologic potentials for THC but suffer from small sample sizes, short study duration, failure to address tolerance, little dose variation, ill-defined outcome measures, and failure to identify and/or evaluate confounds, all of which may constitute significant threats to the validity of most trials. However, the existing work underscores the potential therapeutic value of THC and, at the same time, calls attention to the critical need for better-designed protocols to fully explore and demonstrate safety and efficacy. In the most general sense, the present brief review illuminates some intriguing findings about THC, along with the basic threats to the validity of the research that supports those findings. The intent is to highlight existing generic weaknesses in the existing randomized controlled trial literature and, most importantly, provide guidance for improved clinical research.

Quercetin is a polyphenol present in numerous fruits and vegetables and therefore widely consumed by humans with average daily dietary intakes of 10-20 mg/day. It is also a popular dietary supplement of 250-1000 mg/day. However, despite the widespread consumer interest in quercetin, due to its possible chemopreventive properties, the extensively studied quercetin presents a highly diverse and complex array of biological effects. Consequently, the present paper provides the first assessment of quercetin-induced hormetic concentration/dose responses, their quantitative features and mechanistic foundations, and their biological, biomedical, clinical, and public health implications. The findings indicate that quercetin-induced hormetic dose responses are widespread, being independent of biological model, cell type, and endpoint. These findings have the potential to enlighten future experimental studies with quercetin especially with respect to study design parameters and may also affect the appraisal of possible public health benefits and risks associated with highly diverse consumer consumption practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This paper addresses how long lifespan can be extended via multiple interventions, such as dietary supplements [e.g., curcumin, resveratrol, sulforaphane, complex phytochemical mixtures (e.g., Moringa, Rhodiola)], pharmaceutical agents (e.g., metformin), caloric restriction, intermittent fasting, exercise and other activities. This evaluation was framed within the context of hormesis, a biphasic dose response with specific quantitative features describing the limits of biological/phenotypic plasticity for integrative biological endpoints (e.g., cell proliferation, memory, fecundity, growth, tissue repair, stem cell population expansion/differentiation, longevity). Evaluation of several hundred lifespan extending agents using yeast, nematode (Caenorhabditis elegans), multiple insect and other invertebrate and vertebrate models (e.g., fish, rodents), revealed they responded in a manner [average (mean/median) and maximum lifespans] consistent with the quantitative features [i.e., 30-60% greater at maximum (Hormesis Rule)] of the hormetic dose response. These lifespan extension features were independent of biological model, inducing agent, endpoints measured and mechanism. These findings indicate that hormesis describes the capacity to extend life via numerous agents and activities and that the magnitude of lifespan extension is modest, in the percentage, not fold, range. These findings have important implications for human aging, genetic diseases/environmental stresses and lifespan extension, as well as public health practices and long-term societal resource planning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Arsenic is a toxic metalloid found in the environment in different organic and inorganic forms. Molecular mechanisms implicated in arsenic hepatotoxicity are complex but include oxidative stress, apoptosis, and autophagy. The current study focused on the potential protective capacity of melatonin against arsenic-induced hepatotoxicity. Thirty-six male Wistar rats were allocated into control, arsenic (15 mg/kg; orally), arsenic (15 mg/kg) plus melatonin (10, 20, and 30 mg/kg; intraperitoneally), and melatonin alone (30 mg/kg) groups for 28 days. After the treatment period, the serum sample was separated to measure liver enzymes (AST and ALT). The liver tissue was removed and then histological alterations, oxidative stress markers, antioxidant capacity, the levels of Nrf2 and HO-1, apoptosis (Bcl-2, survivin, Mcl1, Bax, and caspase-3), and autophagy (Sirt1, Beclin-1, and LC3 II/I ratio) proteins, as well as the expression level of miR-34a, were evaluated on this tissue. Arsenic exposure resulted in the enhancement of serum AST, ALT, and substantial histological damage in the liver. Increased levels of malondialdehyde, a lipid peroxidation marker, and decreased levels of physiological antioxidants including glutathione, superoxide dismutase, and catalase were indicators of arsenic-induced oxidative damage. The levels of Nrf2, HO-1, and antiapoptotic proteins diminished, while proapoptotic and autophagy proteins were elevated in the arsenic group concomitant with a low level of hepatic miR-34a. The co-treatment of melatonin and arsenic reversed the changes caused by arsenic. These findings showed that melatonin reduced the hepatic damage induced by arsenic due to its antioxidant and antiapoptotic properties as well as its regulatory effect on the miR-34a/Sirt1/autophagy pathway., (© 2024 Wiley Periodicals LLC.)

Paraquat (PQ) is a toxic herbicide to humans. Once absorbed, it accumulates in the lungs. PQ has been well documented that the generation of reactive oxygen species (ROS) is the main mechanism of its toxicity. Oxidative damage of PQ in lungs is represented as generation of cytotoxic and fibrotic mediators, interruption of epithelial and endothelial barriers, and inflammatory cell infiltration. No effective treatment for PQ toxicity is currently available. Several studies have shown that natural compounds (NCs) have the potential to alleviate PQ-induced pulmonary toxicity, due to their antioxidant and anti-inflammatory effects. NCs function as protective agents through stimulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathways. Elevation of Nrf2 levels leads to the expression of its downstream enzymes such as SOD, CAT, and HO-1. The hypothesized role of the Nrf2/ARE signaling pathway as the protective mechanism of NCs against PQ-induced pulmonary toxicity is reviewed.

An emerging alternative to conventional animal models in toxicology research is the zebrafish. Their accelerated development, regenerative capacity, transparent physical appearance, ability to be genetically manipulated, and ease of housing and care make them feasible and efficient experimental models. Nonetheless, their most esteemed asset is their 70% (+) genetic similarity with the human genome, which allows the model to be used in a variety of clinically relevant studies. With these attributes, we propose the zebrafish is an excellent model for analyzing cognitive and neuromuscular responses when exposed to toxicants. Neurocognition can be readily analyzed using visual discrimination, memory and learning, and social behavior testing. Neuromuscular function can be analyzed using techniques such as the startle response, assessment of activity level, and evaluation of critical swimming speed. Furthermore, selectively mutated zebrafish is another novel application of this species in behavioral and pharmacological studies, which can be exploited in toxicological studies. There is a critical need in biomedical research to discover ethical and cost-effective methods to develop new products, including drugs. Through mutagenesis, zebrafish models have become key in meeting this need by advancing the field in numerous areas of biomedical research., Competing Interests: Declaration of Conflicting InterestsThe authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article.

Although various therapeutic approaches are used to manage nonalcoholic fatty liver disease (NAFLD), the best approach to NAFLD management is unclear. NAFLD is a liver disorder associated with obesity, metabolic syndrome, and diabetes mellitus. NAFLD progression can lead to cirrhosis and end-stage liver disease. Hepatic kinase B1 (LKB1) is an upstream kinase of 5'-adenosine monophosphate-activated protein kinase (AMPK), a crucial regulator in hepatic lipid metabolism. Activation of LKB1/AMPK inhibits fatty acid synthesis, increases mitochondrial β-oxidation, decreases the expression of genes encoding lipogenic enzymes, improves nonalcoholic steatohepatitis, and suppresses NAFLD progression. One potential opening for new and safe chemicals that can tackle the NAFLD pathogenesis through the LKB1-AMPK pathway includes natural bioactive compounds. Accordingly, we summarized in vitro and in vivo studies regarding the effect of natural bioactive compounds such as a few members of the polyphenols, terpenoids, alkaloids, and some natural extracts on NAFLD through the LKB1/AMPK signaling pathway. This manuscript may shed light on the way to finding a new therapeutic agent for NAFLD management., (© 2023 John Wiley & Sons Ltd.)

The diverse biological effects of polyamines (putrescine, spermidine and spermine) were reviewed in the context of hormesis in an integrative manner for the first time. The findings illustrate that each of these polyamines commonly induces hormetic dose responses in a wide range of biological models and types of cells for multiple endpoints in numerous plant species and animal models. Plant research emphasized preconditioning experimental studies in which the respective polyamines conferred some protection against the damaging effects of a broad range of environmental stressors such as drought, salinity, cold/heat, heavy metals and UV-damage in an hormetic manner. Polyamine-based animal hormesis studies emphasized biomedical endpoints such as longevity and neuroprotection. These findings have important biological and biomedical implications and should guide experimental designs of low dose investigations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023 Elsevier B.V. All rights reserved.)

The present paper provides the first integrative assessment of the capacity of naringin and its metabolite, naringenin, to induce hormetic dose responses within a broad range of experimental biomedical models. The findings indicate that these agents commonly induced protective effects that are typically mediated via hormetic mechanisms leading to biphasic dose-response relationships. The maximum protective effects are generally modest, 30-60 % greater than control group values. The range of experimental findings with these agents has been reported for models with various neurodegenerative diseases, nucleus pulpous cells (NPCs) located within intravertebral discs, several types of stem cells (i.e., bone marrow, amniotic fluid, periodontal, endothelial) as well as cardiac cells. These agents also were effective within preconditioning protocols protecting against environmental toxins such as ultraviolet radiation (UV), cadmium, and paraquat. The mechanism(s) by which the hormetic responses mediates these biphasic dose responses is complex but commonly involves the activation of nuclear factor erythroid 2-related factor (Nrf2), an increasingly recognized regulator of cellular resistance to oxidants. Nrf2 appears to play a role in controlling the basal and induced expression of an array of antioxidant response element-dependent genes to regulate oxidant exposure's physiological and pathophysiological outcomes. Hence its importance in the assessment of toxicologic and adaptive potential is likely to be significant., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G. Dhawan is employed by Stantec (ChemRisk), a consulting firm that provides scientific support to the government, corporations, law firms, and various scientific/professional organizations., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Neurodegeneration is progressive cell loss in specific neuronal populations, often resulting in clinical consequences with significant medical, societal, and economic implications. Because of its antioxidant, anti-inflammatory, and anti-apoptotic properties, oxytocin has been proposed as a potential neuroprotective and neurobehavioral therapeutic agent, including modulating mood disturbances and cognitive enchantment., Methods: Literature searches were conducted using the following databases Web of Science, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, and Cochrane from January 2000 to February 2023 for articles dealing with oxytocin neuroprotective properties in preventing or treating neurodegenerative disorders and diseases with a focus on oxidative stress, inflammation, and apoptosis/cell death., Results: The neuroprotective effects of oxytocin appears to be mediated by its anti-inflammatory properties, inhibition of neuro inflammation, activation of several antioxidant enzymes, inhibition of oxidative stress and free radical formation, activation of free radical scavengers, prevent of mitochondrial dysfunction, and inhibition of apoptosis., Conclusion: Oxytocin acts as a neuroprotective agent by preventing neuro-apoptosis, neuro-inflammation, and neuronal oxidative stress, and by restoring mitochondrial function., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Tramadol (TRA) is an analgesic prescribed for treating mild to moderate pains, the abuse of which has increased in recent years. Chronic tramadol consumption produces neurotoxicity, although the mechanisms are unclear. The present study investigated the involvement of apoptosis and autophagy signaling pathways and the mitochondrial system in TRA-induced neurotoxicity., Materials and Methods: Sixty adult male Wistar rats were divided into five groups that received standard saline or TRA in doses of 25, 50, 75, 100, or 150 mg/kg intraperitoneally for 21 days. On the 22nd day, the Open Field Test (OFT) was conducted. Jun N-Terminal Kinase (JNK), B-cell lymphoma-2 (Bcl-2), Beclin1, and Bcl-2-like protein 4 (Bax) proteins and tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) were measured in rat hippocampal tissue., Results: TRA at doses 75, 100, and 150 mg/kg caused locomotor dysfunction in rats and increased total and phosphorylated forms of JNK and Beclin-1, Bax, and Caspase-3. TRA at the three higher doses also increased the phosphorylated (inactive) form of Bcl-2 level while decreasing the unphosphorylated (active) form of Bcl-2. Similarly, the protein levels of TNF-α and IL-1β were increased dose-dependently. The mitochondrial respiratory chain enzymes were reduced at the three higher doses of TRA., Conclusion: TRA activated apoptosis and autophagy via modulation of TNF-α or IL-1β/JNK/Bcl-2/Beclin1 and Bcl-2/Bax signaling pathways and dysfunction of mitochondrial respiratory chain enzymes., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

The present paper identifies a critical factor that leads to false negative results (i.e., failing to indicate efficacy when beneficial results did occur) in randomized human drug trials. The paper demonstrates that human performance can only be enhanced by a maximum of 30-60% as described by the hormetic dose response which defines the limits of biological plasticity. However, human epidemiological/clinical trials typically contain such extensive variability that often requires responses greater than 2-3 times control group responses to show statistical significance. Thus, many potentially beneficial agents may be missed because the clinical trial fails to recognize and take into consideration the limits of biological plasticity. The paper proposes that this hormesis-biological plasticity-clinical trial conundrum can be addressed successfully via the use of a weight-of-evidence methodology similar to that used by regulatory agencies such as EPA in environmental assessment of chemical toxicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. G. Dhawan is employed by Stantec (ChemRisk), a consulting firm that provides scientific support to the government, corporations, law firms, and various scientific/professional organizations., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tramadol (TRA) causes neurotoxicity whereas trimetazidine (TMZ) is neuroprotective. The potential involvement of the PI3K/Akt/mTOR signaling pathway in the neuroprotection of TMZ against TRA-induced neurotoxicity was evaluated. Seventy male Wistar rats were divided into groups. Groups 1 and 2 received saline or TRA (50 mg/kg). Groups 3, 4, and 5 received TRA (50 mg/kg) and TMZ (40, 80, or 160 mg/kg) for 14 days. Group 6 received TMZ (160 mg/kg). Hippocampal neurodegenerative, mitochondrial quadruple complex enzymes, phosphatidylinositol-3-kinases (PI3Ks)/protein kinase B levels, oxidative stress, inflammatory, apoptosis, autophagy, and histopathology were evaluated. TMZ decreased anxiety and depressive-like behavior induced by TRA. TMZ in tramadol-treated animals inhibited lipid peroxidation, GSSG, TNF-α, and IL-1β while increasing GSH, SOD, GPx, GR, and mitochondrial quadruple complex enzymes in the hippocampus. TRA inhibited Glial fibrillary acidic protein expression and increased pyruvate dehydrogenase levels. TMZ reduced these changes. TRA decreased the level of JNK and increased Beclin-1 and Bax. TMZ decreased phosphorylated Bcl-2 while increasing the unphosphorylated form in tramadol-treated rats. TMZ activated phosphorylated PI3Ks, Akt, and mTOR proteins. TMZ inhibited tramadol-induced neurotoxicity by modulating the PI3K/Akt/mTOR signaling pathways and its downstream inflammatory, apoptosis, and autophagy-related cascades.

The current study assessed the risk posed to Iranian consumers by oral exposure to a mixture of ten mycotoxins in 138 packaged and unpackaged spices collected from the Iran market. Concentrations of mycotoxins in samples were quantified by liquid chromatography, tandem mass spectrometry with triple quadrupole, and ion trap. Probabilistic health risks of oral exposure to these mycotoxins for Iranians were assessed under percent tolerable daily intake (TDI) and cancer risk scenarios. Mean concentrations of mycotoxins in both packaged and unpackaged spice samples showed statistically significant variation among different spice samples. Based on a Monte Carlo simulation model, at the 50th, 80th, and 95th centiles, oral consumption of the analyzed samples poses no carcinogenic risk for exposure to aflatoxin. Moreover, in both packaged and unpackaged samples, while the percent TDIs for ochratoxin A, deoxynivalenol, zearalenone, patulin, fumonisin B1, and fumonisin B2 were below 1.0 at the 50th, 80th, and 95th centiles, the value was above 1.0 for aflatoxin B1, aflatoxin B2, aflatoxin G1, and aflatoxin G2 at each of these centiles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Arsenic (As) is a toxic metalloid that is widely distributed in the earth's crust. People are continuously exposed to this toxicant in their food and drinking water. Inorganic arsenic occurs in two oxidation states, arsenite 3 + (iAs 3+ ) and arsenate 5 + (iAs 5+ ). The most toxic form is its trivalent form which interferes with the electron transfer cycle and induces overproduction of reactive oxygen species, leading to depletion of the antioxidant defense system, as well as altering fatty acid levels and mitochondrial action. Since arsenic crosses the blood-brain barrier, it can damage cells in different regions of the brain, causing neurological disorders through the induction of oxidative stress, inflammation, DNA damage, and cell death. Hydroxytyrosol, taurine, alpha-lipoic acid, ellagic acid, and thymoquinone have been shown to effectively alleviate arsenic-induced neurotoxicity. The protective effects are the result of the anti-oxidative and anti-inflammatory properties of the phytochemicals and in particular their anti-apoptotic function via the Nrf2 and PI3/Akt/SIRT1 signaling pathways., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Biomedical and consumer interest in the health-promoting properties of pure single entities of known or unknown chemical constituents and mixtures has never been greater. Since its "rediscovery" in the 1950s, lithium is an example of such a constituent that represents an array of scientific and public health challenges and medical potentials that may now be understood best when seen through the lens of the dose-response paradigm known as hormesis. The present paper represents the first review of the capacity of lithium to induce hormetic dose responses in a broad range of biological models, organ systems, and endpoints. Of significance is that the numerous hormetic findings occur with extensive concentration/dose response evaluations with the optimal dosing being similar across multiple organ systems. The particular focus of these hormetic dose-response findings was targeted to research with a broad spectrum of stem cell types and neuroprotective effects. These findings suggest that lithium may have critically valuable systemic effects with respect to those therapeutically treated with lithium as well as for exposures that may be achieved via dietary intervention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

MasR is a critical element in the RAS accessory pathway that protects the heart against myocardial infarction, ischemia-reperfusion injury, and pathological remodeling by counteracting the effects of AT1R. This receptor is mainly stimulated by Ang 1-7, which is a bioactive metabolite of the angiotensin produced by ACE2. MasR activation attenuates ischemia-related myocardial damage by facilitating vasorelaxation, improving cell metabolism, reducing inflammation and oxidative stress, inhibiting thrombosis, and stabilizing atherosclerotic plaque. It also prevents pathological cardiac remodeling by suppressing hypertrophy- and fibrosis-inducing signals. In addition, the potential of MasR in lowering blood pressure, improving blood glucose and lipid profiles, and weight loss has made it effective in modulating risk factors for coronary artery disease including hypertension, diabetes, dyslipidemia, and obesity. Considering these properties, the administration of MasR agonists offers a promising approach to the prevention and treatment of ischemic heart disease. Abbreviations : Acetylcholine (Ach); AMP-activated protein kinase (AMPK); Angiotensin (Ang); Angiotensin receptor (ATR); Angiotensin receptor blocker (ARB); Angiotensin-converting enzyme (ACE); Angiotensin-converting enzyme inhibitor (ACEI); Anti-PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16); bradykinin (BK); Calcineurin (CaN); cAMP-response element binding protein (CREB); Catalase (CAT); C-C Motif Chemokine Ligand 2 (CCL2); Chloride channel 3 (CIC3); c-Jun N-terminal kinases (JNK); Cluster of differentiation 36 (CD36); Cocaine- and amphetamine-regulated transcript (CART); Connective tissue growth factor (CTGF); Coronary artery disease (CAD); Creatine phosphokinase (CPK); C-X-C motif chemokine ligand 10 (CXCL10); Cystic fibrosis transmembrane conductance regulator (CFTR); Endothelial nitric oxide synthase (eNOS); Extracellular signal-regulated kinase 1/2 (ERK 1/2); Fatty acid transport protein (FATP); Fibroblast growth factor 21 (FGF21); Forkhead box protein O1 (FoxO1); Glucokinase (Gk); Glucose transporter (GLUT); Glycogen synthase kinase 3β (GSK3β); High density lipoprotein (HDL); High sensitive C-reactive protein (hs-CRP); Inositol trisphosphate (IP3); Interleukin (IL); Ischemic heart disease (IHD); Janus kinase (JAK); Kruppel-like factor 4 (KLF4); Lactate dehydrogenase (LDH); Left ventricular end-diastolic pressure (LVEDP); Left ventricular end-systolic pressure (LVESP); Lipoprotein lipase (LPL); L-NG-Nitro arginine methyl ester (L-NAME); Low density lipoprotein (LDL); Mammalian target of rapamycin (mTOR); Mas-related G protein-coupled receptors (Mrgpr); Matrix metalloproteinase (MMP); MAPK phosphatase-1 (MKP-1); Mitogen-activated protein kinase (MAPK); Monocyte chemoattractant protein-1 (MCP-1); NADPH oxidase (NOX); Neuropeptide FF (NPFF); Neutral endopeptidase (NEP); Nitric oxide (NO); Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); Nuclear-factor of activated T-cells (NFAT); Pancreatic and duodenal homeobox 1 (Pdx1); Peroxisome proliferator- activated receptor γ (PPARγ); Phosphoinositide 3-kinases (PI3k); Phospholipase C (PLC); Prepro-orexin (PPO); Prolyl-endopeptidase (PEP); Prostacyclin (PGI2); Protein kinase B (Akt); Reactive oxygen species (ROS); Renin-angiotensin system (RAS); Rho-associated protein kinase (ROCK); Serum amyloid A (SAA); Signal transducer and activator of transcription (STAT); Sirtuin 1 (Sirt1); Slit guidance ligand 3 (Slit3); Smooth muscle 22α (SM22α); Sterol regulatory element-binding protein 1 (SREBP-1c); Stromal-derived factor-1a (SDF); Superoxide dismutase (SOD); Thiobarbituric acid reactive substances (TBARS); Tissue factor (TF); Toll-like receptor 4 (TLR4); Transforming growth factor β1 (TGF-β1); Tumor necrosis factor α (TNF-α); Uncoupling protein 1 (UCP1); Ventrolateral medulla (VLM).

Diabetes mellitus (DM) is a metabolic disease that activates several molecular pathways involved in neurodegenerative disorders. Metformin, an anti-hyperglycemic drug used for treating DM, has the potential to exert a significant neuroprotective role against the detrimental effects of DM. This review discusses recent clinical and laboratory studies investigating the neuroprotective properties of metformin against DM-induced neurodegeneration and the roles of various molecular pathways, including mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and its related cascades. A literature search was conducted from January 2000 to December 2022 using multiple databases including Web of Science, Wiley, Springer, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, Scopus, and the Cochrane Library to collect and evaluate peer-reviewed literature regarding the neuroprotective role of metformin against DM-induced neurodegenerative events. The literature search supports the conclusion that metformin is neuroprotective against DM-induced neuronal cell degeneration in both peripheral and central nervous systems, and this effect is likely mediated via modulation of oxidative stress, inflammation, and cell death pathways., (© 2023. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Chronic arsenic (As) exposure, mainly as a result of drinking contaminated water, is associated with cardiovascular diseases. Mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and autophagy have been suggested as the molecular etiology of As cardiotoxicity. Melatonin (Mel) is a powerful antioxidant. Mel improves diabetic cardiomyopathy, cardiac remodeling, and heart failure. Following pre-treatment with Mel (10, 20, or 30 mg/kg/day i.p.), rats were orally gavaged with As (15 mg/kg/day) for 28 days. Electrocardiographic findings showed that Mel decreased the As-mediated QT interval prolongation. The effects of As on cardiac levels of glutathione (GSH) and malondialdehyde (MDA) were reversed by Mel pretreatment. Mel also modulated the Sirt1 and Nrf2 expressions promoted by As. Mel down-regulated autophagy markers such as Beclin-1 expression and the LC3-II/I ratio. Moreover, the cardiac expression of cleaved-caspase-3 and Bax/Bcl-2 ratio was decreased by Mel pretreatment. Reduced expression of miR-34a and miR-144 by As were reversed by Mel. The histopathological changes of cardiac injury associated with As exposure was moderated by Mel. Mel may improve As-induced cardiac dysfunction through anti-oxidative, anti-apoptotic, and anti-autophagic mechanisms., (© 2023 International Union of Biochemistry and Molecular Biology.)

In recent years, researchers have begun to realize the importance of the role of non-coding RNAs in the treatment of cancer and cardiovascular and neurological diseases. LncRNAs and miRNAs are important non-coding RNAs, which regulate gene expression and activate mRNA translation through binding to diverse target sites. Their involvement in the regulation of protein function and the modulation of physiological and pathological conditions continues to be investigated. Sirtuins, especially Sirt1, have a critical function in regulating a variety of physiological processes such as oxidative stress, inflammation, apoptosis, and autophagy. The lncRNAs/miRNAs/Sirt1 axis may be a novel regulatory mechanism, which is involved in the progression and/or prevention of numerous diseases. This review focuses on recent findings on the crosstalk between non-coding RNAs and Sirt1 in myocardial and cerebral injuries and may provide some insight into the development of novel approaches in the treatment of these disorders. Abbreviation: BMECs, brain microvascular endothelial cells; C2dat1, calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D)-associated transcript 1; EPCs, endothelial progenitor cells; FOXOs, forkhead transcription factors; GAS5, growth arrest-specific 5; HAECs, human aortic endothelial cells; HAND2-AS1, HAND2 Antisense RNA 1; HIF-1α, hypoxia-inducible factor-1α; ILF3-AS1, interleukin enhancer-binding factor 3-antisense RNA 1; KLF3-AS1, KLF3 antisense RNA 1; LncRNA, long noncoding RNA; LUADT1, Lung Adenocarcinoma Associated Transcript 1; MALAT1, Metastasis-associated lung adenocarcinoma transcript 1; miRNA, microRNA; NEAT1, nuclear enriched abundant transcript 1; NF-κB, nuclear factor kappa B; OIP5-AS1, Opa-interacting protein 5-antisense transcript 1; Sirt1-AS, Sirt1 Antisense RNA; SNHG7, small nucleolar RNA host gene 7; SNHG8, small nucleolar RNA host gene 8; SNHG12, small nucleolar RNA host gene 12; SNHG15, small nucleolar RNA host gene 15; STAT3, signal transducers and activators of transcription 3; TUG1, taurine up-regulated gene 1; VSMCs, vascular smooth muscle cells; XIST, X inactive specific transcript; ZFAS1, ZNFX1 Antisense RNA 1.

Aloe has a long history of topical and systemic use with testimonials of countless health benefits and is one of the most popular botanical medicines in the world for the management of a wide variety both of benign and serious ailments including irritable bowel syndromes, osteoarthritis, Type II diabetes mellitus, and viral respiratory illness. The human consumption of Aloe vera extract in beverage form has substantially grown over the last several decades, in no small part, due to the increased consumer interest in alternative approaches to health benefits. The principal aim of the present paper is to characterize the research to date that has explored the genotoxic potential of Aloe vera inner leaf gel extract and decolorized whole leaf extract used in commercially available food-grade drinkable products which contain no more than 10 ppm aloin. Despite prevailing public health opinion, especially in Europe, the consensus of the reviewed studies retrieved from the peer-reviewed literature together with a mutagenic evaluation of an Aloe vera whole leaf decolorized spray-dried powder is that these products are not genotoxic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cisplatin is a highly effective antitumor agent. However, its use is limited due to severe adverse effects, particularly nephrotoxicity, which occurs in approximately 30% of patients. There is a need for novel renoprotective compounds. Sirtuins play a vital role in various physiological and pathological processes such as oxidative stress, apoptosis, inflammation, and mitochondrial bioenergetics. It has been shown that sirtuins can exert a protective effect on cisplatin-induced acute kidney injury by targeting multiple signaling pathways. Besides, sirtuins not only did not reduce the anticancer effect of cisplatin but also increased it. Several natural compounds have been reported to inhibit cisplatin-mediated nephrotoxicity through sirtuin stimulation. These compounds exert their therapeutic effects on cisplatin-induced renal injury by targeting various signaling pathways including Sirt1/p53, Sirt1/NF-κb/p56, AMPK/Sirt1, Sirt1/PGC-1α, and/or by enhancing mitochondrial function., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)