The protective effects of protocatechuic acid against natural and chemical toxicants: cellular and molecular mechanisms.

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.

RUTIN, a widely consumed flavonoid, that commonly induces hormetic effects.

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.

Δ9-Tetrahydrocannabinol (THC): A Critical Overview of Recent Clinical Trials and Suggested Guidelines for Future Research.

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.

Taurine induces hormesis in multiple biological models: May have transformative implications for overall societal health.

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.

Flavonoids commonly induce hormetic responses.

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.

Hormesis determines lifespan.

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.

Remdesivir: treatment of COVID-19 in special populations.

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.

Melatonin attenuates liver injury in arsenic-treated rats: The potential role of the Nrf2/HO-1, apoptosis, and miR-34a/Sirt1/autophagy pathways.

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.

An Evaluation of Zebrafish, an Emerging Model Analyzing the Effects of Toxicants on Cognitive and Neuromuscular Function.

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.

Protective effects of natural compounds against paraquat-induced pulmonary toxicity: the role of the Nrf2/ARE signaling pathway.

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.

Quercetin induces its chemoprotective effects via hormesis.

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.

Polyamines and hormesis: Making sense of a dose response dichotomy.

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.

Natural compounds against nonalcoholic fatty liver disease: A review on the involvement of the LKB1/AMPK signaling pathway.

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 ß-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.

Hormesis, biological plasticity, and implications for clinical trial research.

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.

Role of apoptosis and autophagy in mediating tramadol-induced neurodegeneration in the rat hippocampus.

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 1ß (IL-1ß) 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-1ß 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-1ß/JNK/Bcl-2/Beclin1 and Bcl-2/Bax signaling pathways and dysfunction of mitochondrial respiratory chain enzymes.

Probabilistic risk assessment of exposure to multiple mycotoxins in consumers of packaged and unpackaged spices in Iran.

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.

Naringin commonly acts via hormesis.

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.

Oxytocin as neuro-hormone and neuro-regulator exert neuroprotective properties: A mechanistic graphical review.

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.

Mas receptor: a potential strategy in the management of ischemic cardiovascular diseases.

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 3ß (GSK3ß); 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 ß1 (TGF-ß1); Tumor necrosis factor α (TNF-α); Uncoupling protein 1 (UCP1); Ventrolateral medulla (VLM).