Corrigendum: Cytokinin and abiotic stress tolerance -What has been accomplished and the way forward?

[This corrects the article DOI: 10.3389/fgene.2022.943025.].

Effect of Lauric acid against ethanol-induced hepatotoxicity by modulating oxidative stress/apoptosis signalling and HNF4α in Wistar albino rats.

Ethanol (EtOH) is most widely used in alcoholic beverages to prepare alcohol. As EtOH is mainly metabolised in the liver, the excessive consumption of EtOH forms a primary toxic metabolic product called acetaldehyde, as the gradual increase in acetaldehyde leads to liver injury, as reported. Lauric acid (LA) is rich in antioxidant, antifungal, antibacterial, anticancer, and antiviral properties. LA is an edible component highly present in coconut oil. However, no report on LA protective effects against the EtOH-instigated hepatotoxicity exists. Therefore, the experiment is carried out to investigate the potency effects of LA on EtOH-instigated hepatotoxicity in thirty male albino rats. Rats were divided into five groups (n-6): control DMSO alone, EtOH -intoxicated, EtOH + LA 180 mg/kg, EtOH + LA 360 mg/kg, and LA alone were administered orally using oral gavage. The study measured body weight every weekend in all rat groups. The rats were sacrificed and assessed for serum markers (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase), antioxidant activity (superoxide dismutase, reduced glutathione, glutathione peroxidase), lipid peroxidation (malondialdehyde), histopathological, cytokine levels (TNF-α, IL-1ß and IL-6), protein expression (caspase 3 and caspase 8 and Bcl-2 and HNF4α) were evaluated after the 56-days study period. The impact of EtOH intoxication reduces the rat's body weight by 90 g, upregulates the liver enzyme markers, depletes the antioxidant levels, produces malondialdehyde, changes the histoarchitecture (periportal inflammation and hepatocyte damage), downregulates the Bcl-2 expressions and HNF4α, and elevates the expression of cytokines and apoptotic markers. LA alleviated EtOH-induced liver toxicity by significant (p < 0.05) modulation of biochemical levels, caspase-8/3 signalling, reducing pro-inflammatory cytokines, and restoring the normal histoarchitecture, upregulating the Bcl-2 and HNF4α Expressions. In conclusion, LA treatment can protect the liver against EtOH-induced hepatotoxicity, evidenced by alleviating Oxidative stress, lipid peroxidation, inflammation, apoptosis, and upregulation of HNF4α.

HPV-associated cancers: insights into the mechanistic scenario and latest updates.

Cancer and related diseases are the second leading cause of death worldwide. The human papillomavirus (HPV) is an infectious agent that can be spread mainly through sexual contact and has been linked to several malignancies in both sexes. HPV is linked to almost all cases of cervical cancer. It is also linked to many head and neck cancer (HNC) cases, especially oropharyngeal cancer. Also, some HPV-related cancers, like vaginal, vulvar, penile, and anal cancers, are related to the anogenital area. Over the past few decades, testing for and preventing cervical cancer has improved, but anogenital cancers are still harder to confirm. HPV16 and HPV18 have been extensively researched due to their significant carcinogenic potential. The products of two early viral genes, E6 and E7, have been identified as playing crucial roles in cellular transformation, as emphasized by biological investigations. The complete characterization of numerous mechanisms employed by E6 and E7 in undermining the regulation of essential cellular processes has significantly contributed to our comprehension of HPV-induced cancer progression. This review focuses on the various types of cancers caused by HPV infection and also sheds light on the signaling cascades involved in the same.

The interplay of arsenic, silymarin, and NF-ĸB pathway in male reproductive toxicity: A review.

Arsenic toxicity is one of the most trending reasons for several malfunctions, particularly reproductive toxicity. The exact mechanism of arsenic poisoning is a big question mark. Exposure to arsenic reduces sperm count, impairs fertilization, and causes inflammation and genotoxicity through interfering with autophagy, epigenetics, ROS generation, downregulation of essential protein expression, metabolite changes, and hampering several signaling cascades, particularly by the alteration of NF-ĸB pathway. This work tries to give a clear idea about the different aspects of arsenic resulting in male reproductive complications, often leading to infertility. The first part of this article explains the implications of arsenic poisoning and the crosstalk of the NF-ĸB pathway in male reproductive toxicity. Silymarin is a bioactive compound that exerts anti-cancer and anti-inflammatory properties and has demonstrated hopeful outcomes in several cancers, including colon cancer, breast cancer, and skin cancer, by downregulating the hyperactive NF-ĸB pathway. The next half of this article thus sheds light on silymarin's therapeutic potential in inhibiting the NF-ĸB signaling cascade, thus offering protection against arsenic-induced male reproductive toxicity.

The pathophysiological and immunological background of the monkeypox virus infection: An update.

In addition to the COVID-19 waves, the globe is facing global monkeypox (MPX) outbreak. MPX is an uncommon zoonotic infection characterized by symptoms similar to smallpox. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus that belongs to the genus Orthopoxvirus (OPXV). MPXV, which causes human disease, has been confined to Africa for many years, with only a few isolated cases in other areas. Outside of Africa, the continuing MPXV outbreak in multiple countries in 2022 is the greatest in recorded history. The current outbreak, with over 10 000 confirmed cases in over 50 countries between May and July 2022, demonstrates that MPXV may travel rapidly among humans and pose a danger to human health worldwide. The rapid spread of such outbreaks in recent times has elevated MPX to the status of a rising zoonotic disease with significant epidemic potential. While the MPXV is not as deadly or contagious as the variola virus that causes smallpox, it poses a threat because it could evolve into a more potent human pathogen. This review assesses the potential threat to the human population and provides a brief overview of what is currently known about this reemerging virus. By analyzing the biological effects of MPXV on human health, its shifting epidemiological footprint, and currently available therapeutic options, this review has presented the most recent insights into the biology of the virus. This study also clarifies the key potential causes that could be to blame for the present MPX outbreak and draw attention to major research questions and promising new avenues for combating the current MPX epidemic.

miRNA in Parkinson's disease: From pathogenesis to theranostic approaches.

Parkinson's disease (PD) is an age associated neurological disorder which is specified by cardinal motor symptoms such as tremor, stiffness, bradykinesia, postural instability, and non-motor symptoms. Dopaminergic neurons degradation in substantia nigra region and aggregation of αSyn are the classic signs of molecular defects noticed in PD pathogenesis. The discovery of microRNAs (miRNA) predicted to have a pivotal part in various processes regarding regularizing the cellular functions. Studies on dysregulation of miRNA in PD pathogenesis has recently gained the concern where our review unravels the role of miRNA expression in PD and its necessity in clinical validation for therapeutic development in PD. Here, we discussed how miRNA associated with ageing process in PD through molecular mechanistic approach of miRNAs on sirtuins, tumor necrosis factor-alpha and interleukin-6, dopamine loss, oxidative stress and autophagic dysregulation. Further we have also conferred the expression of miRNAs affected by SNCA gene expression, neuronal differentiation and its therapeutic potential with PD. In conclusion, we suggest more rigorous studies should be conducted on understanding the mechanisms and functions of miRNA in PD which will eventually lead to discovery of novel and promising therapeutics for PD.

Advances in the Lung Cancer Immunotherapy Approaches.

Despite the progress in the comprehension of LC progression, risk, immunologic control, and treatment choices, it is still the primary cause of cancer-related death. LC cells possess a very low and heterogeneous antigenicity, which allows them to passively evade the anticancer defense of the immune system by educating cytotoxic lymphocytes (CTLs), tumor-infiltrating lymphocytes (TILs), regulatory T cells (Treg), immune checkpoint inhibitors (ICIs), and myeloid-derived suppressor cells (MDSCs). Though ICIs are an important candidate in first-line therapy, consolidation therapy, adjuvant therapy, and other combination therapies involving traditional therapies, the need for new predictive immunotherapy biomarkers remains. Furthermore, ICI-induced resistance after an initial response makes it vital to seek and exploit new targets to benefit greatly from immunotherapy. As ICIs, tumor mutation burden (TMB), and microsatellite instability (MSI) are not ideal LC predictive markers, a multi-parameter analysis of the immune system considering tumor, stroma, and beyond can be the future-oriented predictive marker. The optimal patient selection with a proper adjuvant agent in immunotherapy approaches needs to be still revised. Here, we summarize advances in LC immunotherapy approaches with their clinical and preclinical trials considering cancer models and vaccines and the potential of employing immunology to predict immunotherapy effectiveness in cancer patients and address the viewpoints on future directions. We conclude that the field of lung cancer therapeutics can benefit from the use of combination strategies but with comprehension of their limitations and improvements.

Metabolomic Signatures in Doxorubicin-Induced Metabolites Characterization, Metabolic Inhibition, and Signaling Pathway Mechanisms in Colon Cancer HCT116 Cells.

Doxorubicin (DOX) is a chemotherapeutic agent is used for various cancer cells. To characterize the chemical structural components and metabolic inhibition, we applied a DOX to HCT116 colon cancer cells using an independent metabolites profiling approach. Chemical metabolomics has been involved in the new drug delivery systems. Metabolomics profiling of DOX-applied HCT116 colon cancer cellular metabolisms is rare. We used 1H nuclear magnetic resonance (NMR) spectroscopy in this study to clarify how DOX exposure affected HCT116 colon cancer cells. Metabolomics profiling in HCT116 cells detects 50 metabolites. Tracking metabolites can reveal pathway activities. HCT116 colon cancer cells were evenly treated with different concentrations of DOX for 24 h. The endogenous metabolites were identified by comparison with healthy cells. We found that acetate, glucose, glutamate, glutamine, sn-glycero-3-phosphocholine, valine, methionine, and isoleucine were increased. Metabolic expression of alanine, choline, fumarate, taurine, o-phosphocholine, inosine, lysine, and phenylalanine was decreased in HCT116 cancer cells. The metabolic phenotypic expression is markedly altered during a high dose of DOX. It is the first time that there is a metabolite pool and phenotypic expression in colon cancer cells. Targeting the DOX-metabolite axis may be a novel strategy for improving the curative effect of DOX-based therapy for colon cancer cells. These methods facilitate the routine metabolomic analysis of cancer cells.

Hesperidin and hesperetin against heavy metal toxicity: Insight on the molecular mechanism of mitigation.

Toxic heavy metals (THMs) are non-essential hazardous environmental pollutants with intractable health challenges in humans and animals. Exposure to lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), nickel (Ni), and chromium (Cr) are ubiquitous and unavoidable due to food contamination, mining, and industrial mobilization. They are triggers of tissue impairment and aberrant signaling pathways that cascade into several toxicities and pathologies. Each of Pb, Cd, Hg, As, Ni, and Cr aggravate oxidative inflammation, protein dysregulation, apoptotic induction, DNA damage, endocrine deficits, and mitochondrial dysfunction contributing to the pathophysiology of diseases. Hesperidin (HSD) and hesperetin (HST) are flavonoids from citrus fruits, and systematic investigations suggest their potential to combat the molecular alterations and toxicities induced by THMs. They mitigate heavy metal toxicity via antioxidant, anti-inflammatory, and anti-apoptotic effects via scavenging free radicals and modulation of ATPases, cell cycle proteins, and various cellular signaling pathways, including Nrf2/HO-1/ARE, PI3K/mTOR/Akt, MAPK/caspase-3/Bax/Bcl-2, iNOS/NF-κB/TNF-α/COX-2. This review summarized the mechanistic effects of heavy metal toxicity and the insights on molecular mechanisms underlying mitigation of heavy metal toxicity by HSD and HST. Hesperidin and hesperetin are potential flavonoids for the modulation of pathological signaling networks associated with THMs. Therefore, HSD and HST can be suggested as natural dietary agents and blockers of harmful effects of THMs.

The crosstalk of the human microbiome in breast and colon cancer: A metabolomics analysis.

The human microbiome's role in colon and breast cancer is described in this review. Understanding how the human microbiome and metabolomics interact with breast and colon cancer is the chief area of this study. First, the role of the gut and distal microbiome in breast and colon cancer is investigated, and the direct relationship between microbial dysbiosis and breast and colon cancer is highlighted. This work also focuses on the many metabolomic techniques used to locate prospective biomarkers, make an accurate diagnosis, and research new therapeutic targets for cancer treatment. This review clarifies the influence of anti-tumor medications on the microbiota and the proactive measures that can be taken to treat cancer using a variety of therapies, including radiotherapy, chemotherapy, next-generation biotherapeutics, gene-based therapy, integrated omics technology, and machine learning.

Repurposing FDA-approved drugs against the toxicity of platinum-based anticancer drugs.

Platinum-based anticancer drugs (PADs), mainly cisplatin, carboplatin, and oxaliplatin, are widely used efficacious long-standing anticancer agents for treating several cancer types. However, clinicians worry about PAD chemotherapy and its induction of severe non-targeted organ toxicity. Compelling evidence has shown that toxicity of PAD on delicate body organs is associated with free radical generation, DNA impairment, endocrine and mitochondrial dysfunctions, oxidative inflammation, apoptosis, endoplasmic reticulum stress, and activation of regulator signaling proteins, cell cycle arrest, apoptosis, and pathways. The emerging trend is the repurposing of FDA-approved non-anticancer drugs (FNDs) for combating the side effects toxicity of PADs. Thus, this review chronicled the mechanistic preventive and therapeutic effects of FNDs against PAD organ toxicity in preclinical studies. FNDs are potential clinical drugs for the modulation of toxicity complications associated with PAD chemotherapy. Therefore, FNDs may be suggested as non-natural agent inhibitors of unpalatable side effects of PADs.

Genotypic-Phenotypic Analysis, Metabolic Profiling and Clinical Correlations in Parkinson's Disease Patients from Tamil Nadu Population, India.

Parkinson's disease (PD) is an ageing disorder caused by dopaminergic neuron depletion with age. Growing research in the field of metabolomics is expected to play a major role in PD diagnosis, prognosis and therapeutic development. In this study, we looked at how SNCA and GBA1 gene mutations, as well as metabolomic abnormalities of kynurenine and cholesterol metabolites, were linked to alpha-synuclein (α-syn) and clinical characteristics in three different PD age groups. In all three age groups, a metabolomics analysis revealed an increased amount of 27-hydroxycholesterol (27-OHC) and a lower level of kynurenic acid (KYNA). The effect of 27-OHC on SNCA and GBA1 modifications was shown to be significant (P < 0.05) only in the A53T variant of the SNCA gene in late-onset and early-onset PD groups, whereas GBA1 variants were not. Based on the findings, we observed that the increase in 27-OHC would have elevated α-syn expression, which triggered the changes in the SNCA gene but not in the GBA1 gene. Missense variations in the SNCA and GBA1 genes were investigated using the sequencing technique. SNCA mutation A53T has been linked to increased PD symptoms, but there is no phenotypic link between GBA1 and PD. As a result of the data, we hypothesise that cholesterol and kynurenine metabolites play an important role in PD, with the metabolite 27-OHC potentially serving as a PD biomarker. These findings will aid in the investigation of pathogenic causes as well as the development of therapeutic and preventative measures for PD.

Elimination of microplastics from the aquatic milieu: A dream to achieve.

Microplastics (MPs) have become a significant source of concern as they have emerged as a widespread pollutant that harms the aquatic environment. It has become an enormous challenge, having the capacity to biomagnify and eventually affect human health, biodiversity, aquatic animals, and the environment. This review provides in-depth knowledge of how MPs interact with different toxic organic chemicals, antibiotics, and heavy metals in the aquatic environment and its consequences. Membrane technologies like ultrafiltration (UF), nanofiltration (NF), microfiltration (MF), and dynamic membranes can be highly effective techniques for the removal of MPs. Also, hybrid membrane techniques like advanced oxidation processes (AOPs), membrane fouling, electrochemical processes, and adsorption processes can be incorporated for superior efficiency. The review also focuses on the reactor design and performance of several membrane-based filters and bioreactors to develop practical, feasible, and sustainable membrane technologies. The main aim of this work is to throw light on the alarming scenario of microplastic pollution in the aquatic milieu and strategies that can be adopted to tackle it.

Mechanism of chromium-induced toxicity in lungs, liver, and kidney and their ameliorative agents.

Heavy metal Chromium (Cr), can adversely affect humans and their health if accumulated in organs of the body, such as the lungs, liver, and kidneys. Cr (VI) is highly toxic and has a higher solubility in water than Cr (III). One of the most common routes for Cr exposure is through inhalation and is associated with liver, lung, kidney damage, widespread dermatitis, GI tract damage, human lung cancer, cardiomyopathies, and cardiovascular disease. The increase in ROS production has been attributed to most of the damage caused by Cr toxicity. Cr-induced ROS-mediated oxidative stress has been seen to cause a redox imbalance affecting the antioxidant system balance in the body. The Nrf2 pathway dysregulation has been implicated in the same. Deregulation of histone acetylation and methylation has been observed, together with gene methylation in genes such as p16, MGMT, APC, hMLH1, and also miR-143 repression. Several ultra-structural changes have been observed following Cr (VI)-toxicity, including rough ER dilation, alteration in the mitochondrial membrane and nuclear membrane, pycnotic nuclei formation, and cytoplasm vacuolization. A significant change was observed in the metabolism of lipid, glucose, and the metabolism of protein after exposure to Cr. Cr-toxicity also leads to immune system dysregulations with changes seen in the expression of IL-8, IL-4, IgM, lymphocytes, and leukocytes among others. P53, as well as pro-and anti-apoptotic proteins, are involved in apoptosis. These Cr-induced damages can be alleviated via agents that restore antioxidant balance, regulate Nrf-2 levels, or increase anti-apoptotic proteins while decreasing pro-apoptotic proteins.

Omicron variant infection and the associated immunological scenario.

The million-dollar question that has been the talk of the day is how effective the COVID 19 vaccines are against the Omicron variant. Still, there is no clear-cut answer to this question but several studies have concluded that this Variant of Concern (VOC) successfully weakens the neutralizing capability of the antibodies acquired from the COVID 19 vaccines and prior infections, which indicates that Omicron can easily bypass an individual's humoral immune response. However, the most significant confusion revolves around cell-mediated immunity tackling the Omicron variant. This paper aims to provide a clear idea about the status of the body's immune surveillance concerning the infection caused by the Omicron variant by producing the effectivity of the humoral and cell-mediated immunity in handling the same. This work also provides complete detail of the various characteristics of the Omicron variant and how it may be a blessing in disguise. The effectiveness of the current vaccines, the transmissibility rate of the variant compared to the other variants, and the importance of administering a booster dose to prevent the spread of this variant are also discussed. Finally, this work aims to bridge the gap between the past and the current status of the Omicron infection and sheds light on the hypothetical idea that herd immunity developed from the SARS-COV2 infection may help tackle other dangerous variants.

Mixed Contaminants: Occurrence, Interactions, Toxicity, Detection, and Remediation.

The ever-increasing rate of pollution has attracted considerable interest in research. Several anthropogenic activities have diminished soil, air, and water quality and have led to complex chemical pollutants. This review aims to provide a clear idea about the latest and most prevalent pollutants such as heavy metals, PAHs, pesticides, hydrocarbons, and pharmaceuticals-their occurrence in various complex mixtures and how several environmental factors influence their interaction. The mechanism adopted by these contaminants to form the complex mixtures leading to the rise of a new class of contaminants, and thus resulting in severe threats to human health and the environment, has also been exhibited. Additionally, this review provides an in-depth idea of various in vivo, in vitro, and trending biomarkers used for risk assessment and identifies the occurrence of mixed contaminants even at very minute concentrations. Much importance has been given to remediation technologies to understand our current position in handling these contaminants and how the technologies can be improved. This paper aims to create awareness among readers about the most ubiquitous contaminants and how simple ways can be adopted to tackle the same.

Phytomedicinal therapeutics for male infertility: critical insights and scientific updates.

Infertility is a significant cause of anxiety, depression, and social stigma among couples and families. In such cases, male reproductive factors contribute widely to the extent of 20-70%. Male infertility is a multifactorial disease with several complications contributing to its diagnosis. Although its management encompasses both modern and traditional medicine arenas, the first line of treatment, adopted by most males, focuses on the reasonably successful medicinal plant-based conventional therapies. Phyto-therapeutics, which relies on active ingredients from traditionally known herbs, influences sexual behavior and male fertility factors. The potency of these phyto-actives depends on their preparation methods and forms of consumption, including decoctions, extracts, semi-purified compounds, etc., as inferred from in vitro and in vivo (laboratory animal models and human) studies. The mechanisms of action therein involve the testosterone pathway for stimulation of spermatogenesis, reduction of oxidative stress, inhibition of inflammation, activation of signaling pathways in the testes [extracellular-regulated kinase (ERK)/protein kinase B(PKB)/transformation of growth factor-beta 1(TGF-ß1)/nuclear factor kappa-light-chain-enhancer of activated B cells NF-kB signaling pathways] and mediation of sexual behavior. This review critically focuses on the medicinal plants and their potent actives, along with the biochemical and molecular mechanisms that modulate vital pathways associated with the successful management of male infertility. Such intrinsic knowledge will significantly further studies on medicinal plants that improve male reproductive health.

An anxious relationship between Autism Spectrum Disorder and Gut Microbiota: A tangled chemistry?

Autism spectrum disorder (ASD) is a serious multifactorial neurodevelopmental disorder often accompanied by strained social communication, repetitive behaviour, immune dysregulation, and gastrointestinal (GI) issues. Recent studies have recorded a link between dysbiosis in the gut microbiota (gm) and the primary stages of ASD. A bidirectional connection (also called microbiota-gut-brain-axis) exchanges information between the gut bacteria and central nervous system. When the homeostasis of the microenvironment of the gut is dysregulated, it causes oxidative stress, affecting neuronal cells and neurotransmitters, thereby causing neurodevelopmental disorders. Studies have confirmed a difference in the constitution of gut bacteria among ASD cases and their controls. Numerous studies on animal models of ASD have shown altered gm and its association with abnormal metabolite profile and altered behaviour phenotype. This process happens due to an abnormal metabolite production in gm, leading to changes in the immune system, especially in ASD. Hence, this review aims to question the current knowledge on gm dysbiosis and its related GI discomforts and ASD behavioural symptoms and shed light on the possible therapeutic approaches available to deal with this situation. Thereby, though it is understood that more research might be needed to prove an association or causal relationship between gm and ASD, therapy with the microbiome may also be considered as an effective strategy to combat this issue.