A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular carcinoma (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylase (HDAC) activation. However, inhibiting HDACs-an effective treatment for lymphomas-has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 (3) showed a favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53, showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8+ to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Transcriptomic analysis revealed that STR-V-53 primed HCC cells to immunotherapy through HDAC inhibition, impaired glucose-regulated transcription, impaired DNA synthesis, upregulated apoptosis, and stimulated the immune response pathway. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.

Interrogating the Role of Endocytosis Pathway and Organelle Trafficking for Doxorubicin-Based Combination Ionic Nanomedicines.

We have studied the endocytic mechanisms that determine subcellular localization for three carrier-free chemotherapeutic-photothermal (chemo-PTT) combination ionic nanomedicines (INMs) composed of doxorubicin (DOX) and an near-infrared (NIR) dye (ICG, IR820, or IR783). This study aims to understand the cellular basis for previously published enhanced toxicity results of these combination nanomedicines toward MCF-7 breast cancer cells. The active transport mechanism of INMs, unlike free DOX, which is known to employ passive transport, was validated by conducting temperature-dependent cellular uptake of the drug in MCF-7 cells using confocal microscopy. The internalization pathway of these INMs was further probed in the presence and absence of different endocytosis inhibitors. Detailed examination of the mode of entry of the carrier-free INMs in MCF-7 cells revealed that they are primarily internalized through clathrin-mediated endocytosis. In addition, time-dependent subcellular localization studies were also investigated. Examination of time-dependent confocal images indicated that the INMs targeted multiple organelles, in contrast to free DOX that primarily targets the nucleus. Collectively, the high cellular endocytic uptake in cancerous cells (EPR effect) and the multimode targeting ability demonstrated the main reason for the low half-maxima inhibitory concentration (IC50) value (the high cytotoxicity) of these carrier-free INMs as compared to their respective parent chemo and PTT drugs.

Discovery and Folding Dynamics of a Fused Bicyclic Cysteine Knot Undecapeptide from the Marine Sponge Halichondria bowerbanki.

We describe the discovery and structure of an undecapeptide natural product from a marine sponge, termed halichondamide A, that is morphed into a fused bicyclic ring topology via two disulfide bonds. Molecular dynamics simulations allow us to posit that the installation of one disulfide bond biases the intermediate peptide conformation and predisposes the formation of the second disulfide bond. The natural product was found to be mildly cytotoxic against liver and breast cancer cell lines.

Development and validation of a sensitive LC-MS/MS assay of GT-14, a novel Gαi2 inhibitor, in rat plasma, and its application in pharmacokinetic study.

A sensitive and selective LC-MS/MS method was developed and validated for the quantitation of a novel Gαi2 inhibitor, GT-14, in rat plasma using a SCIEX 6500+ triple QUAD LC-MS system equipped with an ExionLC UHPLC unit. GT-14 (m/z 265.2 → 134.1) and griseofulvin (Internal Standard, IS) (m/z 353.1 → 285.1) were detected in a positive mode by electrospray ionization (ESI) using multiple reaction monitoring (MRM). The assay was linear in the concentration range of 0.78-1000 ng/mL in rat plasma. Both accuracy and precision values were within the acceptance criteria of ±15 %, as established by FDA guidance. The matrix effect was negligible from plasma, with signal percentages of 98.5-106.9 %. The mean recovery was 104.5 %, indicating complete extraction of GT-14 from plasma. GT-14 was found to be stable under different experimental conditions. The validated method was successfully applied to evaluate plasma protein binding and in vivo pharmacokinetics of GT-14 in rats.

A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy.

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs, an effective treatment for lymphomas, has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 (3) showed favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib, STR-V-53 showed greater in vivo efficacy. Moreover, STR-V-53 combined with anti-PD1 therapy increased the CD8+ to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Collectively, our data demonstrate that the novel HDACi STR-V-53 is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.

Doxorubicin-Based Ionic Nanomedicines for Combined Chemo-Phototherapy of Cancer.

Synergistic combination therapy approach offers lots of options for delivery of materials with anticancer properties, which is a very promising strategy to treat a variety of malignant lesions with enhanced therapeutic efficacy. The current study involves a detailed investigation of combination ionic nanomedicines where a chemotherapeutic drug is coupled with a photothermal agent to attain dual mechanisms (chemotherapy (chemo) and photothermal therapy (PTT)) to improve the drug's efficacy. An FDA-approved Doxorubicin hydrochloride (DOX·HCl) is electrostatically attached with a near-infrared cyanine dye (ICG, IR783, and IR820), which serves as a PTT drug using ionic liquid chemistry to develop three ionic material (IM)-based chemo-PTT drugs. Carrier-free ionic nanomedicines (INMs) are derived from ionic materials (IMs). The photophysical properties of the developed combination IMs and their INMs were studied in depth. The phototherapeutic efficiency of the combination drugs was evaluated by measuring the photothermal conversion efficiency and singlet-oxygen quantum yield. The improved photophysical properties of the combination nanomedicines in comparison to their parent compounds significantly enhanced INMs' photothermal efficiency. Cellular uptake, dark and light toxicity studies, and cell death mechanisms of the chemo-PTT nanoparticles were also studied in vitro. The combination INMs exhibited enhanced cytotoxicity compared to their respective parent compounds. Moreover, the apoptosis cell death mechanism was almost doubled for combination nanomedicine than the free DOX, which is attributed to enhanced cellular uptake. Examination of the combination index and improved in vitro cytotoxicity results revealed a great synergy between chemo and PTT drugs in the developed combination nanomedicines.

Gαi2 Protein Inhibition Blocks Chemotherapy- and Anti-Androgen-Induced Prostate Cancer Cell Migration.

We have previously shown that heterotrimeric G-protein subunit alphai2 (Gαi2) is essential for cell migration and invasion in prostate, ovarian and breast cancer cells, and novel small molecule inhibitors targeting Gαi2 block its effects on migratory and invasive behavior. In this study, we have identified potent, metabolically stable, second generation Gαi2 inhibitors which inhibit cell migration in prostate cancer cells. Recent studies have shown that chemotherapy can induce the cancer cells to migrate to distant sites to form metastases. In the present study, we determined the effects of taxanes (docetaxel), anti-androgens (enzalutamide and bicalutamide) and histone deacetylase (HDAC) inhibitors (SAHA and SBI-I-19) on cell migration in prostate cancer cells. All treatments induced cell migration, and simultaneous treatments with new Gαi2 inhibitors blocked their effects on cell migration. We concluded that a combination treatment of Gαi2 inhibitors and chemotherapy could blunt the capability of cancer cells to migrate and form metastases.

Cationic Porphyrin-Based Ionic Nanomedicines for Improved Photodynamic Therapy.

This study presents the synthesis and characterization of monosubstituted cationic porphyrin as a photodynamic therapeutic agent. Cationic porphyrin was converted into ionic materials by using a single-step ion exchange reaction. The small iodide counteranion was replaced with bulky BETI and IR783 anions to reduce aggregation and enhance the photodynamic effect of porphyrin. Carrier-free ionic nanomedicines were then prepared by using the reprecipitation method. The photophysical characterization of parent porphyrin, ionic materials, and ionic nanomaterials, including absorbance, fluorescence and phosphorescence emission, quantum yield, radiative and nonradiative rate, and lifetimes, was performed. The results revealed that the counteranion significantly affects the photophysical properties of porphyrin. The ionic nanomaterials exhibited an increase in the reactive oxygen yield and enhanced cytotoxicity toward the MCF-7 cancer cell line. Examination of results revealed that the ionic materials exhibited an enhanced photodynamic therapeutic activity with a low IC50 value (nanomolar) in cancerous cells. These nanomedicines were mainly localized in the mitochondria. The improved light cytotoxicity is attributed to the enhanced photophysical properties and positive surface charge of the ionic nanomedicines that facilitate efficient cellular uptake. These results demonstrate that ionic material-based nanodrugs are promising photosensitizers for photodynamic therapy.

Aflatoxin B1-induced dysfunction in male rats' reproductive indices were abated by Sorghum bicolor (L.Moench) hydrophobic fraction.

The burden of infertility distresses millions of families worldwide. The harmful effects of aflatoxin B1 (AFB1) on the reproductive system involve oxidative stress, culminating in inflammation and cellular apoptosis. The phytochemical in Sorghum bicolor is rich in antioxidants and anti-inflammatory activities. The effect of Sorghum bicolor (L.) Moench (SBE-HP) extract -hydrophobic fraction- enriched in Apigenin (API) was investigated in rats chronically dosed with AFB1 and the likely mechanism (s) of SBE-HP to protect against AFB1-induced reproductive toxicity. Adult Wistar male rats (twenty-four) were selected randomly and allocated into four groups. Cohort 1 was administered 0.05 % carboxymethyl cellulose (CMC); cohort 2 received AFB1 (50 µg/kg) alone; while cohorts 3 and 4 received 5 & 10 mg/kg of (SBE-HP) respectively, along with 50 µg/kg of AFB1. After 28 days, AFB1 induced remarkable reproductive toxicity as evidenced by increased sperm abnormalities, lowered sperm quality and motility, altered serum hormonal levels and testicular enzyme activities, decreased anti-oxidants, increased pro-oxidants, apoptotic and inflammatory biomarkers, as well as altered histoarchitectural structure of the testis, epididymis, and hypothalamus of rats. API-enriched extract of S. bicolor reduced AFB1-induced oxidative, inflammatory, apoptotic, and histological derangement by improving sperm function parameters, testicular enzymes, and reproductive hormones. Anti-oxidant levels and anti-inflammatory mediators were increased while decreases in the activities and levels of pro-oxidants, pro-inflammatory molecules and caspase-9 occurred in the rats' testes, epididymis, and hypothalamus. API-enriched S. bicolor protected the testes, epididymis, and hypothalamus of male rats exposed to AFB1 by modulating oxidative stress, inflammation, and apoptosis.

The Hydrophobic Extract of Sorghum bicolor (L. Moench) Enriched in Apigenin-Protected Rats against Aflatoxin B1-Associated Hepatorenal Derangement.

Aflatoxin B1 (AFB1) is a recalcitrant metabolite produced by fungi species, and due to its intoxications in animals and humans, it has been classified as a Group 1 carcinogen in humans. Preserving food products with Sorghum bicolor sheath can minimise the contamination of agricultural products and avert ill health occasioned by exposure to AFB1. The current study investigated the ameliorating effect of Sorghum bicolor sheath hydrophobic extract (SBE-HP) enriched in Apigenin (API) on the hepatorenal tissues of rats exposed to AFB1. The SBE-HP was characterised using TLC and LC-MS and was found to be enriched in Apigenin and its methylated analogues. The study used adult male rats divided into four experimental cohorts co-treated with AFB1 (50 µg/kg) and SBE-HP (5 and 10 mg/kg) for 28 days. Biochemical, enzyme-linked immunosorbent assays (ELISA) and histological staining were used to examine biomarkers of hepatorenal function, oxidative status, inflammation and apoptosis, and hepatorenal tissue histo-architectural alterations. Data were analysed using GraphPad Prism 8.3.0, an independent t-test, and a one-way analysis of variance. Co-treatment with SBE-HP ameliorated an upsurge in the biomarkers of hepatorenal functionality in the sera of rats, reduced the alterations in redox balance, resolved inflammation, inhibited apoptosis, and preserved the histological features of the liver and kidney of rats exposed to AFB1. SBE-HP-containing API is an excellent antioxidant regiment. It can amply prevent the induction of oxidative stress, inflammation, and apoptosis in the hepatorenal system of rats. Therefore, supplementing animal feeds and human foods with SBE-HP enriched in Apigenin may reduce the burden of AFB1 intoxication in developing countries with a shortage of effective antifungal agents.

Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC).

BACKGROUND: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). METHODS: Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. RESULTS: While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR+ CRPC cells but not AR- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR+ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. CONCLUSION: These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.

The protective effect of 3-indolepropanoic acid on aflatoxin B1-induced systemic perturbation of the liver and kidney function in rats.

Aflatoxin B1 (AFB1) is known to derange the hepatorenal system by redox, DNA adduct formation and apoptotic networks. Endogenous 3-indole propionic acid (3-IPA) is a metabolite of tryptophan metabolism by gut microbiota that can protect against redox imbalance, inflammation and cellular lipid damage. We investigated the beneficial effect of 3-IPA against AFB1-mediated organ toxicity in male rats post 28 days of consecutive treatment. The 3-IPA (25 and 50 mg/kg) was orally administered alongside AFB1 (50 µg/kg) treatment. Biochemical and enzyme-linked immunosorbent assays were utilised to examine biomarkers of hepatorenal function, oxidative status and inflammation. DNA damage and apoptosis were also assessed, and histological staining techniques were used to investigate hepatorenal tissues for pathological indicators. The 3-IPA supplementation abated AFB1-mediated increases in biomarkers of hepatic and renal dysfunction in rat serum. Co-administration of 3-IPA further reduced AFB1-induced redox imbalance (by upregulating antioxidant mediators and enzymes [GSH, TSH, Trx, Trx-R, SOD, CAT, GPx and GST]; reducing reactive oxygen species, lipid peroxidation and DNA adduct [RONS, LPO and 8-OH-dG] formation; suppressing pro-inflammatory and apoptotic mediators [XO, MPO, NO, IL-1ß and Casp -9 and -3]; and upregulating the level of interleukin 10 (IL-10). Moreover, treatment with 3-IPA lessened hepatorenal tissue injuries. These findings suggest that augmenting 3-IPA endogenously from tryptophan metabolism may provide a novel strategy to forestall xenobiotics-mediated hepatorenal toxicity, including AFB1.

Apigeninidin-enriched Sorghum bicolor (L. Moench) extracts alleviate Aflatoxin B1-induced dysregulation of male rat hypothalamic-reproductive axis.

We examined the protective effect of the apigeninidin (API)-enriched fraction from Sorghum bicolor sheaths extracts (SBE-05, SBE-06, and SBE-07) against aflatoxin B1 (AFB1)-induced dysregulation of male rat's reproductive system that may trigger infertility. Male rats (160 ± 12 g) were treated with AFB1 (50 µg/kg) along with 5 or 10 mg/kg of SBE-05, SBE-06, and SBE-07 for 28 days. Subsequently, we assessed the reproductive hormone-prolactin, FSH, LH, testosterone levels, and testicular function enzymes. Moreover, we examined rats' testes, epididymis, and hypothalamus for oxidative and inflammatory stress biomarkers, caspase-9 activity and tissues pathology. We observed that comparative to AFB1 alone treated rats, API co-treatment significantly (p < 0.05) abated the AFB1-mediated decrease in prolactin and antioxidant defenses and lessened lipid peroxidation (LPO) and reactive oxygen and nitrogen species levels in the examined organs-testes, epididymis, and hypothalamus. API abated AFB1-induced hormone decreases-testosterone, FSH, and LH; and caused improvement in sperm quantity and quality. API lessened AFB1-mediated increase in pro-inflammatory cytokine, increased interleukin-10 level, an anti-inflammatory cytokine and reduced caspase-9 activities. In addition, API reduced alterations in the examined tissue histology. Our findings suggest that S. bicolor API-enrich extracts have active antioxidative, antiapoptotic, and anti-inflammatory activities, which can protect against AFB1-induced dysfunction of the hypothalamic-pituitary-gonadal axis.

Apigeninidin-rich Sorghum bicolor (L. Moench) extracts suppress A549 cells proliferation and ameliorate toxicity of aflatoxin B1-mediated liver and kidney derangement in rats.

Sorghum bicolor plant has a high abundance of 3-deoxyanthocyanins, flavonoids and other polyphenol compounds that have been shown to offer numerous health benefits. Epidemiological studies have linked increased intake of S. bicolor to reduced risk of certain cancer types, including lung adenocarcinoma. S. bicolor extracts have shown beneficial effects in managing hepatorenal injuries. This study investigated the cytotoxic potential of three apigeninidin-rich extracts of S. bicolor (SBE-05, SBE-06 and SBE-07) against selected cancer cell lines and their ameliorative effect on aflatoxin B1 (AFB1)-mediated hepatorenal derangements in rats. We observed that, among the three potent extracts, SBE-06 more potently and selectively suppressed the growth of lung adenocarcinoma cell line (A549) (IC50 = 6.5 µg/mL). SBE-06 suppressed the expression of STAT3 but increased the expression of caspase 3. In addition, SBE-05, SBE-06 and SBE-07 inhibited oxidative and nitrosative stress, inflammation, and apoptosis and preserved the histoarchitectural networks of the liver and kidney of rats treated with AFB1. These in vitro and in vivo studies indicate the potential of these cheap and readily accessible extracts for cancer therapy and as chemo-preventive agents in preventing aflatoxin-related health issues.

Caffeic acid mitigates aflatoxin B1-mediated toxicity in the male rat reproductive system by modulating inflammatory and apoptotic responses, testicular function, and the redox-regulatory systems.

Aflatoxin B1 (AFB1 ) is a toxic metabolite of public health concern. The present study investigates the protective effects of caffeic acid (CA) against AFB1 -induced oxidative stress, inflammation, and apoptosis in the hypothalamus, epididymis, and testis of male rats. Five experimental rat cohorts (n = 6) were treated per os for 28 consecutive days as follows: Control (Corn oil 2 ml/kg body weight), AFB1 alone (50µg/kg), CA alone (40 mg/kg) and the co-treated rat cohorts (AFB1 : 50µg/kg + CA1: 20 or 40 mg/kg). Following sacrifice, the biomarkers of hypothalamic, epididymal, and testicular toxicities, antioxidant enzyme activities, myeloperoxidase (MPO) activity, as well as levels of nitric oxide (NO), reactive oxygen and nitrogen (RONS) species and lipid peroxidation (LPO) were analysed spectrophotometrically. Besides, the concentration of tumour necrosis factor-alpha (TNF-α), Bcl-2 and Bax proteins were assessed using ELISA. Results showed that the AFB1 -induced decrease in biomarkers of testicular, epididymal and hypothalamic toxicity was significantly (p < .05) alleviated in rats coexposed to CA. Moreover, the reduction of antioxidant status and the increase in RONS and LPO were lessened (p < .05) in rats co-treated with CA. AFB1 mediated increase in TNF-α, Bax, NO and MPO activity were reduced (p< .05) in the hypothalamus, epididymis, and testis of rats coexposed to CA. In addition, Bcl-2 levels were reduced in rats treated with CA dose-dependently. Light microscopic examination showed that histopathological lesions severity induced by AFB1 were alleviated in rats coexposed to CA. Taken together, the amelioration of AFB1 -induced neuronal and reproductive toxicities by CA involves anti-inflammatory, antioxidant, antiapoptotic mechanisms in rats. PRACTICAL APPLICATIONS: The beneficial antioxidant effects of caffeic acid (CA) are attributed to CA delocalized aromatic rings and free electrons, easily donated to stabilize reactive oxygen species. We report in vivo findings on CA and AfB1 mediated oxidative stress and reproductive dysfunction in rats. CA conjugated esters including chlorogenic acids are widely distributed in plants, and they act as a dietary source of natural defense against infections. CA can chelate heavy metals and reduce production of damaging free radicals to cellular macromolecules. Along these lines, CA can stabilize aflatoxin B1-epoxide as well and avert deleterious conjugates from forming with deoxyribonucleic acids. Hence CA, as a dietary phytochemical can protect against the damaging effects of toxins including aflatoxin B1 that contaminate food. CA dose-dependently abated oxidative, inflammatory, and apoptotic stimuli, improved functional characteristics of spermatozoa and reproductive hormone levels, and prevented histological alterations in experimental rats' hypothalamus and reproductive organs brought about by AFB1 toxicity.

Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges.

Uncontrolled inflammation is a salient factor in multiple chronic inflammatory diseases and cancers. In this review, we provided an in-depth analysis of the relationships and distinctions between uncontrolled inflammation, fibrosis and cancers, while emphasizing the challenges and opportunities of developing novel therapies for the treatment and/or management of these diseases. We described how drug delivery systems, combination therapy and the integration of tissue-targeted and/or pathways selective strategies could overcome the challenges of current agents for managing and/or treating chronic inflammatory diseases and cancers. We also recognized the value of the re-evaluation of the disease-specific roles of multiple pathways implicated in the pathophysiology of chronic inflammatory diseases and cancers-as well as the application of data from single-cell RNA sequencing in the success of future drug discovery endeavors.

Synthetic methodology-enabled discovery of a tunable indole template for COX-1 inhibition and anti-cancer activity.

Establishing structure-activity relationships (SAR) for privileged pharmacophores, such as the indole scaffold, is a key step in the early stages of drug discovery. Herein, we report the synthesis and preliminary SAR studies on substituted 6-hydroxyindole-7-carboxylates as a tunable framework for COX inhibition and anti-cancer activity. To facilitate the SAR discovery, a modular synthetic methodology was employed which enabled the synthesis of the substituted indoles. From the synthesized compounds, five displayed COX-1 inhibition activity in a colorimetric assay with their intracellular activity further confirmed by a cell-based target validation assay. Following molecular docking analyses, key interactions between the active compounds and the COX enzymes were elucidated. In addition to the identified COX inhibitors, two compounds showed selective cytotoxicity against Hep-G2, MCF-7, and LnCaP. The mechanism of cell death was investigated and found to include induction of Caspase-3 activation and cleavage, down-regulation of anti-apoptotic proteins Bcl-xL and Bcl-2, and upregulation of Bax. Finally, two representative compounds were confirmed to induce cell cycle arrest at the G1/G0 stage. In summary, the 6-hydroxyindole-7-carboxylate framework shows promising versatility as a template for the discovery of anti-inflammation or anti-cancer agents, given the evidence of its COX inhibitory and anti-cancer activities herein presented.

Caffeic acid protects against DNA damage, oxidative and inflammatory mediated toxicities, and upregulated caspases activation in the hepatorenal system of rats treated with aflatoxin B1.

Aflatoxicosis can induce largescale toxicities in predisposed populations. Food fortification with adequate antioxidant sources may reduce the toxic burden from aflatoxicosis. We examined the individual and combined effect of Caffeic acid (CA) on the aflatoxin B1 (AFB1)-induced hepatic and renal injury in male rats. Five experimental rat cohort (n = 6) consisting of the control (2 mL/kg corn oil), AFB1 alone (50 µg/kg), CA alone (40 mg/kg), AFB1+CA1 (50 µg/kg + 20 mg/kg) and AFB1+CA2 (50 µg/kg + 40 mg/kg) were so treated for 28 consecutive days. Upon sacrifices, diagnostic markers of hepatorenal functions, oxidative stress, inflammation, oxidative deoxyribonucleic acid -DNA-damage and apoptosis were analysed. Our results showed that CA reduced AFB1-induced toxicities in rats' liver and kidneys by significantly increasing (p < 0.05) endogenous antioxidant and the anti-inflammatory IL-10 level. Caffeic acid simultaneously reduced hepatic and renal dysfunction biomarkers in the serum, oxidative stress, and lipid peroxidation levels. Besides, CA diminished reactive oxygen and nitrogen species, inflammatory nitric oxide levels, interleukin-1 ß and the activities of xanthine oxidase and myeloperoxidase. Additionally, CA reduced DNA damage and caspase-mediated apoptotic responses and preserved the cytoarchitecture of rats' liver and kidneys treated with AFB1. These data suggest that CA can be used as a food additive to mitigate AFB1-induced toxicity in the examined organs.

Indole-3-propionic acid mitigates chlorpyrifos-mediated neurotoxicity by modulating cholinergic and redox-regulatory systems, inflammatory stress, apoptotic responses and DNA damage in rats.

This study probed the neuroprotective influence of indole-3-propionic acid (IPA) in rats exposed to chlorpyrifos (CPF) alone at 5 mg/kg body weight or co-administered with IPA at 12.5 and 25 mg/kg for 14 days. Behavioral data indicated that IPA significantly (p < 0.05) abated CPF-mediated anxiogenic-like behaviors with concomitant improvement in the locomotor and exploratory behaviors as substantiated by track plots and heat maps data. Also, IPA mitigated CPF-mediated diminution in cholinergic and antioxidant defense systems whereas it markedly improved thioredoxin level and thioredoxin reductase activity in cerebral and cerebellar tissues of the animals. Co-administration of IPA significantly enhanced anti-inflammatory cytokine, interleukin-10 but suppressed oxidative and inflammatory stress, caspase-9 and caspase-3 activation with concomitant reduction in 8-hydroxy-2'-deoxyguanosine (8-OHdG) level and histological damage. Collectively, IPA-mediated neuroprotection involves modulation of cholinergic and redox-regulatory systems, inflammatory stress, apoptotic responses and DNA damage in cerebrum and cerebellum of rats.

Protocatechuic acid protects against hepatorenal toxicities in rats exposed to Furan.

Furan formed in processed food is hepatotoxic and likely carcinogenic in humans. We investigated protocatechuic acid (PCA) protective role in rats' hepatorenal function treated with furan. Rats were grouped and treated as follows: Control, PCA (50 mg/kg), furan alone (8 mg/kg), furan + PCA1 (25 + 8 mg/kg), and furan + PCA2 (50 + 8 mg/kg). Upon sacrifice, evaluation of hepatorenal function, oxidative stress status, reactive oxygen and nitrogen species (RONS), lipid peroxidation (LPO), myeloperoxidase (MPO) activity, among nitric oxide (NO) levels were performed. Cytokine levels (IL-10, IL-1ß, TNF-alpha), Caspase 3 and 9 activities, and histopathological examination were also assessed. We found that the final body and relative liver weights changed significantly (p < 0.05) in treated groups. Hepatic transaminases, urea, and creatinine increased (p < 0.05) in furan only treated group, and reduced in PCA co-treated groups. The furan-induced decrease in antioxidant status increased RONS, and LPO levels were alleviated (p < 0.05) by PCA co-treatment. Furthermore, furan-mediated increase in NO, IL-1ß, TNF-alpha levels, MPO, Cas-3, and 9 activities and suppressed IL-10 levels was reversed accordingly in rats' kidney and liver co-treated with PCA. The extent of furan-mediated hepatorenal lesions was lessened in PCA co-treated rats. Our findings suggest that PCA protects against oxido-inflammatory pathways, enhanced caspases 3 and 9 activations induced by furan in rat hepatorenal system.