Role of p53-miRNAs circuitry in immune surveillance and cancer development: A potential avenue for therapeutic intervention.

The genome's guardian, p53, is a master regulatory transcription factor that occupies sequence-specific response elements in many genes and modulates their expression. The target genes transcribe both coding RNA and non-coding RNA involved in regulating several biological processes such as cell division, differentiation, and cell death. Besides, p53 also regulates tumor immunology via regulating the molecules related to the immune response either directly or via regulating other molecules, including microRNAs (miRNAs). At the post-transcriptional level, the regulations of genes by miRNAs have been an emerging mechanism. Interestingly, p53 and various miRNAs cross-talk at different regulation levels. The cross-talk between p53 and miRNAs creates loops, turns, and networks that can influence cell metabolism, cell fate, cellular homeostasis, and tumor formation. Further, p53-miRNAs circuit has also been insinuated in the regulation of immune surveillance machinery. There are several examples of p53-miRNAs circuitry where p53 regulates immunomodulatory miRNA expression, such as miR-34a and miR-17-92. Similarly, a reverse process occurs in which miRNAs such as miR-125b and miR-let-7 regulate the expression of p53. Thus, the p53-miRNAs circuitry connects the immunomodulatory pathways and may shift the pro-inflammatory balance towards the pro-tumorigenic condition. In this review, we discuss the influence of p53-miRNAs circuitry in modulating the immune response in cancer development. We assume that thorough studies on the p53-miRNAs circuitry in various cancers may prove useful in developing effective new cancer therapeutics for successfully combating this disease.

Unveiling the therapeutic promise of natural products in alleviating drug-induced liver injury: Present advancements and future prospects.

Drug-induced liver injury (DILI) refers to adverse reactions to small chemical compounds, biological agents, and medical products. These reactions can manifest as acute or chronic damage to the liver. From 1997 to 2016, eight drugs, including troglitazone, nefazodone, and lumiracoxib, were removed from the market due to their liver-damaging effects, which can cause diseases. We aimed to review the recent research on natural products and their bioactive components as hepatoprotective agents in mitigating DILI. Recent articles were fetched via searching the PubMed, PMC, Google Scholar, and Web of Science electronic databases from 2010 to January 2023 using relevant keywords such as "natural products," "acetaminophen," "antibiotics," "paracetamol," "DILI," "hepatoprotective," "drug-induced liver injury," "liver failure," and "mitigation." The studies reveal that the antituberculosis drug (acetaminophen) is the most frequent cause of DILI, and natural products have been largely explored in alleviating acetaminophen-induced liver injury. They exert significant hepatoprotective effects by preventing mitochondrial dysfunction and inflammation, inhibiting oxidative/nitrative stress, and macromolecular damage. Due to the bioavailability and dietary nature, using natural products alone or as an adjuvant with existing drugs is promising. To advance DILI management, it is crucial to conduct well-designed randomized clinical trials to evaluate natural products' efficacy and develop new molecules clinically. However, natural products are a promising solution for remedying drug-induced hepatotoxicity and lowering the risk of DILI.

Lupeol, an androgen receptor inhibitor, enhances the chemosensitivity of prostate cancer stem cells to antiandrogen enzalutamide-based therapy.

Enzalutamide is an androgen receptor (AR) antagonist commonly used in the treatment of prostate cancer (CaP). However, due to the potential toxicity and development of resistance associated with Enzalutamide-based therapy, there is a need to explore additional compounds that can enhance its therapeutic effectiveness while minimizing toxicity. Lupeol is a pharmacologically active triterpene having anticancer effects. The objective of this study was to explore Lupeol's potential in enhancing the chemosensitivity of chemoresistant CaP cells to Enzalutamide in vitro and in a mouse model. To test our hypothesis, we performed cell viability and luciferase reporter gene assay, flow cytometry, animal studies, and histopathological analysis. Finally, we analyzed the change in selective metabolites in the prostate tissue by LCMS. Results demonstrated that a combination of Lupeol and Enzalutamide could better (i) suppress the Cancer Stem Cells (CSCs) and chemoresistant cells (PTEN-CaP8 and PC3) viability and migration, (ii) increase cell cycle arrest, (iii) inhibit the transcriptional activity of AR, c-MYC, c-FLIP, and TCF (iv) inhibit tumor growth in a mouse model (v) protect Enzalutamide-induced adverse effects in prostate glands and gut tissue (vi) decrease levels of testosterone and methionine metabolites. In conclusion, Lupeol enhances the pharmacological efficacy of Enzalutamide and reduces the adverse effects. Thus, Lupeol could be a promising adjuvant for improving Enzalutamide-based treatment outcomes and warrant further research.

Flubendiamide induced genetic and cellular damages directly influence the life cycle of the oriental leaf worm, Spodoptera litura.

Indiscriminate uses of insecticide greatly damage the environment as well as non-target organisms. Thus, multiple levels of bioassays can help better management of our environment. Flubendiamide is a phthalic acid diamide insecticide that ceases the function of insect muscle leading to paralysis and death. Here, we aimed to explore the effects of Flubendiamide on the life cycle of Spodoptera litura vis-a-vis the mode of action. Fourth instar larvae of the same age (120 ± 2 h) and size were fed with different concentrations (20-80 µg/mL) of Flubendiamide for 12-72 h. We performed a pharmacokinetics study, different biochemical assays, p450, Ecdysone receptor (EcR) and other genes expression analyses by Real-Time PCR and gross damages by Dye exclusion assay and histopathology. Our results demonstrate that the mean concentration of Flubendiamide after 48 h is 9.907 µg/mL and (i) altered the molting, metamorphosis, and reproduction at 80 µg/mL (24 h) (ii) increases all oxidative stress parameters (ROS/RNS, MDA, 8OHdG), decreases oxidative defense mechanisms (SOD, CAT, GST) at 80 µg/mL (48 h) and p450 in a time and concentration-dependent manner, (iii) activates CncC/Maf apoptotic pathways at 80 µg/mL concentration at 24 h while the expression declined from 48 h onwards, (iii) downregulates the EcR expression in a time and concentration-dependent manner, which might be responsible for disturbed molting, metamorphosis, and reproduction, and (iv) increase the expression of apoptotic genes (Caspase 1, -3, and - 5), in time and concentration-dependent manner causing gross morphological and histological damages. In conclusion, indiscriminate use of this insecticide can affect the ecosystem and have the capacity to cause multiple hazardous effects on experimental organisms. Thus, it warrants further investigations to improve and optimize the integrated pest management packages, including Flubendiamide for better management.

Protective effects of a polyherbal medicine, Majoon Suranjan against bisphenol-A induced genetic, oxidative and tissue damages.

Bisphenol-A (BPA) is a toxic chemical largely produced and used in polycarbonate plastics worldwide. Majoon Suranjan (MS), a polyherbal formulation, is used as an anti-inflammatory medicine against rheumatoid arthritis. The present study aimed to evaluate BPA-induced toxicity and its possible amelioration by MS. To test our hypothesis, we performed gas chromatography-mass spectrometry (GC-MS) analysis, DNA interaction studies, genotoxicity tests, oxidative stress parameters, and histopathological examinations. GC-MS profiling of MS revealed the presence of various anti-oxidant compounds. DNA interaction studies showed that both chemicals intercalate between DNA base pairs. Next, we observed BPA-induced genotoxicity and oxidative damage. The observed effects might be due to BPA-induced reactive oxygen species production. Further, BPA changed the anti-oxidant enzyme activities, increased the malondialdehyde, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels, and caused gross damage to the liver and kidney. Interestingly, these effects were significantly reversed by MS. In conclusion, MS shows protective effects against BPA-induced toxicity and could be a potential alternative medicine against BPA toxicity, especially in third-world countries where BPA uses are not strictly regulated.Highlights:Bisphenol-A (BPA) induces multiple toxic effects.BPA induces genotoxicity, oxidative and tissue damage.Majoon Suranjan (MS) ameliorates the BPA induced toxic effects.GC-MS profiling show various active anti-oxidant compounds in MS.MS is anti-genotoxic, anti-oxidant, and hepato-renal protective.

Apigenin alleviates cancer drug Sorafenib induced multiple toxic effects in Swiss albino mice via anti-oxidative stress.

Sorafenib is an FDA-approved chemotherapeutic drug used as standard therapy for advanced-stage cancers. However, Sorafenib-induced multiple adverse effects are a major limitation that directly impacts patients' physical and physiological well-being. Therefore, it is vital to identify agents that can lessen the associated adverse effects and enhance efficacy. Apigenin, a dietary plant flavone, is a bioactive-compound present in fruits and vegetables having anti-oxidant, anti-inflammatory, and anti-cancer properties. Our study aimed to investigate Sorafenib-induced toxic effects at genomic, cellular, and tissue level and the potential protective effects of Apigenin. To achieve our goal, we treated Swiss albino mice with Apigenin (50 mg/kg bw) alone or in combination with Sorafenib (40 mg/kg bw). Next, we performed DNA interaction, genotoxicity, oxidative damages, anti-oxidant activities, liver enzyme levels, and histopathological studies. We demonstrated that Apigenin and Sorafenib bind DNA via electrostatic interaction. Further, Sorafenib induces genetic, oxidative, and tissue damages characterized by an increase in chromosomal aberrations and micronucleus, reactive oxygen species (ROS) and reactive nitrogen species (RNS), oxidative and DNA damage, lipid peroxidation, and hepato-renal damages, and a decrease in antioxidant-enzymes. Interestingly, the Sorafenib-induced adverse effects were ameliorated by Apigenin. Our findings indicate that Apigenin has protective effects against Sorafenib-induced toxicity and could be combined with Sorafenib to lessen its adverse effects and enhance its efficacy. However, further pre-clinical and clinical studies are required to evaluate Apigenin's effectiveness with Sorafenib.

Emerging role of long non-coding RNAs in cancer chemoresistance: unravelling the multifaceted role and prospective therapeutic targeting.

Chemotherapy is one of the important treatment modules in early as well as advanced stages of cancer. However, the major limitation of chemotherapy is the development of chemoresistance in the transformed cells of cancer patients, which leads to cancer recurrence. Long non-coding RNAs (lncRNA) are the transcripts longer than 200 nucleotides in length, which are reported to associate with the initiation, progression, recurrence, and metastasis of different cancers. Several lncRNAs have been implicated in the prevalence of chemoresistant phenotypes and also in the restoration of drug sensitivity in chemoresistant cells. LncRNAs such as HOTAIR, H19, and a lot more are involved in the chemoresistance of cancer cells. Therefore, targeting the lncRNAs may serve as a novel strategy for treating chemoresistant cancer. This review throws light on the role of lncRNA in chemoresistance along with the perspective of the therapeutic targets for the treatment of multiple cancers.

Apigenin enhances sorafenib anti-tumour efficacy in hepatocellular carcinoma.

BACKGROUND: The "one drug-one target" paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce unexpected off-target effects and accelerate therapeutic efficacy. Sorafenib- an FDA-approved drug for liver cancer, has multiple limitations. Therefore, it is recommended to identify an agent that increases its effectiveness and reduces toxicity. In this regard, Apigenin, a plant flavone, would be an excellent option to explore. METHODS: We used in silico, in vitro, and animal models to explore our hypothesis. For the in vitro study, HepG2 and Huh7 cells were exposed to Apigenin (12-96 µM) and Sorafenib (1-10 µM). For the in vivo study, Diethylnitrosamine (DEN) (25 mg/kg) induced tumor-bearing animals were given Apigenin (50 mg/kg) or Sorafenib (10 mg/kg) alone and combined. Apigenin's bioavailability was checked by UPLC. Tumor nodules were studied macroscopically and by Scanning Electron Microscopy (SEM). Biochemical analysis, histopathology, immunohistochemistry, and qRT-PCR were done. RESULTS: The results revealed Apigenin's good bioavailability. In silico study showed binding affinity of both chemicals with p53, NANOG, ß-Catenin, c-MYC, and TLR4. We consistently observed a better therapeutic efficacy in combination than alone treatment. Combination treatment showed i) better cytotoxicity, apoptosis induction, and cell cycle arrest of tumor cells, ii) tumor growth reduction, iii) increased expression of p53 and decreased Cd10, Nanog, ß-Catenin, c-Myc, Afp, and Tlr4. CONCLUSIONS: In conclusion, Apigenin could enhance the therapeutic efficacy of Sorafenib against liver cancer and may be a promising therapeutic approach for treating HCC. However, further research is imperative to gain more in-depth mechanistic insights.

Role of epigenetic drugs in sensitizing cancers to anticancer therapies: emerging trends and clinical advancements.

Epigenetic changes play a significant role in cancer progression, maintenance and therapy resistance. Generally, epigenetic modifications are reversible, thereby gaining attention for therapeutic interventions. However, limited efficacy and therapy resistance remain the significant limitations of conventional and epigenetic anticancer therapies. Recently, combination therapies with epigenetic drugs (epi-drugs) and conventional anticancer treatment have gained widespread attention. Here, epi-drugs are administered with anticancer therapies to increase their therapeutic efficacy and sensitize cancer cells resistant to therapies. This review summarizes the mechanism of epi-drugs in reversing resistance to anticancer therapies. Further, the challenges faced during developing combination therapies with epi-drugs are discussed. We believe the clinical benefit of combination therapies could be increased by overcoming the challenges faced during epi-drug development.

Epigenetic changes play a significant role in cancer development and progression. Epigenetic drugs (epi-drugs) target enzymes involved in regulating epigenetic changes to maintain normal cell functioning. Epi-drugs include histone deacetylase inhibitors and DNA methyltransferase inhibitors, among others. These drugs have shown potential as standalone treatments for cancer and have also been found to work well in combination with other therapies (chemotherapy, radiotherapy and immunotherapy), helping to overcome treatment resistance. By targeting the epigenetic alterations that contribute to treatment resistance, epi-drugs have the potential to enhance the effectiveness of these therapies. This review article focuses on how epi-drugs overcome resistance to different cancer treatments. Combining epi-drugs with conventional anticancer therapies could provide better management of cancer. However, more preclinical and clinical research is needed to understand the potential benefits and optimize the use of these combinations fully. Overall, epi-drugs offer a promising avenue for improving cancer treatment outcomes and warrant further investigation.

Specific targeting of cancer stem cells by immunotherapy: A possible stratagem to restrain cancer recurrence and metastasis.

Cancer stem cells (CSCs), the tumor-initiating cells playing a crucial role in cancer progression, recurrence, and metastasis, have the intrinsic property of self-renewal and therapy resistance. The tumorigenic properties of these cells include generation of cellular heterogeneity and immuno-suppressive tumor microenvironment (TME), conferring them the capability to resist a variety of anti-cancer therapeutics. Further, CSCs possess several unique immunological properties that help them escape recognition by the innate and adaptive immune system and shape a TME into a pro-tumorigenic and immunosuppressive landscape. In this context, immunotherapy is considered one of the best therapeutic options for eliminating CSCs to halt cancer recurrence and metastasis. In this review, we discuss the various immunomodulatory properties of CSCs and the interaction of CSCs with the immune system enabling immune evasion. In addition, we also highlight the present research update on immunotherapeutic targeting of CSCs and the possible further scope of research on this topic. We believe that a deeper understanding of CSCs' immunological properties and the crosstalk between CSCs and the immune system can develop better innovative immune-therapeutics and enhance the efficacy of current therapy-resistant cancer treatments.

Protective effect of green synthesized Selenium Nanoparticles against Doxorubicin induced multiple adverse effects in Swiss albino mice.

AIMS: Doxorubicin (DOX) is a widely used drug against multiple cancers. However, its clinical Use is often restricted due to multiple adverse effects. Recently, Selenium Nanoparticles (SeNPs) are gaining attention due to their low toxicity and higher biocompatibility, making them attractive nanoparticles (NPs) in medical and pharmaceutical sciences. Therefore, the current study aimed to assess if our biosynthesized SeNP from the endophytic fungus Fusarium oxysporum conjugated with DOX could alleviate the DOX-induced adverse effects. MAIN METHODS: For this purpose, we investigated various genotoxic, biochemical, histopathological, and immunohistochemical parameters and finally analyzed the metabolite profile by LC-MS/MS. KEY FINDINGS: We observed that DOX causes an increase in reactive oxygen and nitrogen species (ROS, RNS), 8-OHdG, and malondialdehyde (MDA), decreases antioxidant defense systems and reduces BCL-2 expression in cardiac tissue. In addition, a significant increase in DNA damage and alteration in the cytoarchitecture of the liver, kidney, and heart tissues was observed by Comet Tail Length and histopathological studies, respectively. Interestingly, the DOX-SeNP conjugate reduced ROS/RNS, 8-OHdG, and MDA levels in the liver, kidney, and heart tissues. It also restored the antioxidant enzymes and cytoarchitectures of the examined tissues, reduced genotoxicity, and increased the BCL-2 levels. Finally, metabolic profiling showed that DOX reduced the number of cardioprotective metabolites, which DOX-SeNP restored. SIGNIFICANCE: Collectively, the present results describe the protective effect of DOX-conjugated SeNP against DOX-induced toxicities. In conclusion, DOX-SeNP conjugate might be better for treating patients receiving DOX alone. However, it warrants further thorough investigation.

Therapeutic implications of probiotics in microbiota dysbiosis: A special reference to the liver and oral cancers.

The microbiota plays an important role in maintaining the body's homeostasis. Imbalance in the microbiota is referred to as microbiota dysbiosis. Microbiota dysbiosis leads to pro-inflammatory immune response and progression of cancer- one of the leading causes of mortality globally. Accumulating evidence suggest the role of microbiota-dysbiosis in the liver and oral carcinogenesis and the therapeutic role of probiotic strains against these diseases. Probiotics are active microbial strains that have recently gained clinical importance due to their beneficial effects on the human body associated with the prevention and treatment of different diseases, including cancer. Multiple researchers have reported the use of probiotic strains in the modulation of microbiota and immune responses for cancer prevention and management. Clinical trials have also highlighted the efficacy of probiotic strains in reducing the side effects of microbiota dysbiosis related to cancer. In this context, the probiotic-mediated modulation to reverse microbiota dysbiosis is now considered one of the possible novel strategies for cancer prevention and management. In this article, we review the association between microbiota dysbiosis and liver/oral cancer. This review highlights the research advances on the anti-cancer activity of probiotic strains and their metabolites in the management of liver and oral cancers.

Revisiting inorganic nanoparticles as promising therapeutic agents: A paradigm shift in oncological theranostics.

Cancer remains a global health problem largely due to a lack of effective therapies. Major cancer management strategies include chemotherapy, surgical resection, and radiation. Unfortunately, these strategies have a number of limitations, such as non-specific side effects, uneven delivery of the drugs, and lack of proper monitoring technology. Inorganic nanoparticles (NPs) are considered promising agents in treating and tracing cancer due to their unique physicochemical properties such as the controlled release of drugs, bioavailability, biocompatibility, stability, and large surface area. Also, they enhance the solubility of hydrophobic drugs, prolong their circulation time, prevent undesired off-targeting and subsequent side effects, making them efficient particles in cancer theranostics. Promising inorganic-NPs include gold, selenium, silica, and oxide NPs. Further, several techniques are used to modify the surface of inorganic-NPs, making them more efficient for the effective transport of therapeutic cargos to overcome cellular barriers. Thus, inorganic-NPs function effectively, surmounting the intrinsic drawbacks of traditional organic NPs. This mini-review summarizes the significant inorganic-NPs, their properties, surface modifications, cellular uptake, and bio-distributions, along with their potential use in cancer theranostics. We also discuss the promises and challenges faced during the inorganic-NPs mediated therapeutic approach for cancer and these particles' status in the clinical setting.