Unveiling the role of the Hedgehog signaling pathway in chronic liver disease: Therapeutic insights and strategies.

The Hedgehog (Hh) signaling plays a crucial role in adult liver repair by promoting the expansion and differentiation of hepatic progenitor cells into mature hepatocytes and cholangiocytes. Elevated Hh signaling is associated with severe chronic liver diseases, making Hh inhibitors a promising therapeutic option. Sonidegib and vismodegib, both FDA-approved Smoothened (Smo) inhibitors for basal cell carcinoma (BCC), have shown potential for application in chronic liver disorders based on clinical evidence. We highlight the vital role of the Hh pathway in metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and hepatocellular carcinoma (HCC). Moreover, therapeutic strategies targeting the Hh pathway in chronic liver diseases have been discussed, providing a basis for improving disease management and outcomes.

Mast cells and the gut-liver Axis: Implications for liver disease progression and therapy.

The role of mast cells, traditionally recognized for their involvement in immediate hypersensitivity reactions, has garnered significant attention in liver diseases. Studies have indicated a notable increase in mast cell counts following hepatic injury, underscoring their potential contribution to liver disorder pathogenesis. Predominantly situated in connective tissue that envelops the hepatic veins, bile ducts, and arteries, mast cells are central to both initiating and perpetuating liver disorders. Additionally, they are crucial for maintaining gastrointestinal barrier function. The gut-liver axis emphasizes the complex, two-way communication between the gut microbiome and the liver. Past research has implicated gut microbiota and their metabolites in the progression of hepatic disorders. This review sheds light on how mast cells are activated in various liver conditions such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), viral hepatitis, hepatic fibrogenesis, and hepatocellular carcinoma. It also briefly explores the connection between the gut microbiome and mast cell activation in these hepatic conditions.

Role of Culinary Indian Spices in the Regulation of TGF-ß Signaling Pathway in Inflammation-Induced Liver Cancer.

SCOPE: Hepatocellular carcinoma (HCC) results from various etiologies, such as Hepatitis B and C, Alcoholic and Non-alcoholic fatty liver disorders, fibrosis, and cirrhosis. About 80 to 90% of HCC cases possess cirrhosis, which is brought on by persistent liver inflammation. TGF-ß is a multifunctional polypeptide molecule that acts as a pro-fibrogenic marker, inflammatory cytokine, immunosuppressive agent, and pro-carcinogenic growth factor during the progression of HCC. The preclinical and clinical evidence illustrates that TGF-ß can induce epithelial-to-mesenchymal transition, promoting progression and hepatocyte immune evasion. Therefore, targeting the TGF-ß pathway can be a promising therapeutic option against HCC. METHODS AND RESULTS: We carry out a systemic analysis of eight potentially selected culinary Indian spices: Turmeric, Black pepper, Ginger, Garlic, Fenugreek, Red pepper, Clove, Cinnamon, and their bioactives in regulation of the TGF-ß pathway against liver cancer. CONCLUSION: Turmeric and its active constituent, curcumin, possess the highest therapeutic potential in treating inflammation-induced HCC and they also have the maximum number of ongoing in-vivo and in-vitro studies.

Remote loading in liposome: a review of current strategies and recent developments.

Liposomes have gained prominence as nanocarriers in drug delivery, and the number of products in the market is increasing steadily, particularly in cancer therapeutics. Remote loading of drugs in liposomes is a significant step in the translation and commercialization of the first liposomal product. Low drug loading and drug leakage from liposomes is a translational hurdle that was effectively circumvented by the remote loading process. Remote loading or active loading could load nearly 100% of the drug, which was not possible with the passive loading procedure. A major drawback of conventional remote loading is that only a very small percentage of the drugs are amenable to this method. Therefore, methods for drug loading are still a problem for several drugs. The loading of multiple drugs in liposomes to improve the efficacy and safety of nanomedicine has gained prominence recently with the introduction of a marketed formulation (Vyxeos) that improves overall survival in acute myeloid leukemia. Different strategies for modifying the remote loading process to overcome the drawbacks of the conventional method are discussed here. The review aims to discuss the latest developments in remote loading technology and its implications in liposomal drug delivery.

An Insight Into the Role of Alpha-Fetoprotein (AFP) in the Development and Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the primary malignancy of hepatocytes and the second most common cause of cancer-related mortality across the globe. Despite significant advancements in screening, diagnosis, and treatment modalities for HCC, the mortality-to-incidence ratio remain unacceptably high. A recent study indicates that a minor population of HCCs are AFP negative or express the normal range of AFP levels. Although it is a gold standard and a more reliable biomarker in the advanced stage of HCC and poorly differentiated tumors, it does not serve as a suitable means for screening HCC. AFP plays a significant role in the development and progression of HCC and understanding its role is crucial. By examining the molecular mechanisms involved in AFP-mediated tumorigenesis, we can better understand HCC pathogenesis and identify potential therapeutic targets. This article details the role of alpha-fetoprotein (AFP) in the carcinogenic transformation of hepatocytes. The article also focuses on information about the structure, biosynthesis, and regulation of AFP at the gene level. Additionally, it discusses the immune evasion, metastasis, and control of gene expression that AFP mediates during HCC.

Tumor-Specific Growth Factor (TSGF): A Futuristic Tumor Biomarker in Early Diagnosis of Cancer.

Despite the significant improvement in the treatment modalities, cancer is one of the fastest-growing chronic disease conditions all over the world. Genetic and Epigenetic alterations in the normal physiology of the cell are the key factor for tumor development. These changes can trigger the production of abnormal protein expressions through stimulation of different signaling pathways and can deeply affect normal cell growth and proliferation. Any altered protein expression, genetic variation, micro-RNA or post-translational protein modifications that indicate tumorigenesis can act as an early signal termed as biomarker. Cancer, being a multistep process with accumulating genetic and epigenetic alterations, could be detected early with suitable biomarkers. There are several proteins such as AFP, CA-125, PSA, troponin, CEA, osteopontin, CA 19-9 that act as biomarkers which help in early detection, prognosis, and monitoring of disease progression, a hunt for newer biomarkers with higher specificity and sensitivity is still ongoing. Tumor-specific growth factor (TSGF) is one such budding and prevailing tumor biomarker used for the early-stage detection of several types of carcinomas. TSGF is a gene that helps in tumor angiogenesis and gets released during the preliminary stages from cancer cells that ensure the vascular proliferation of the same. In this review, the clinical investigations of TSGF in different kinds of malignancy is discussed in detail and suggests the possibility of using TSGF as a biomarker in early diagnosis of cancer.

Modulation of carcinogenesis with selected GRAS nutraceuticals via Keap1-Nrf2 signaling pathway.

Keap1-Nrf2 is a fundamental signaling cascade known to promote or prevent carcinogenesis. Extensive studies identify the key target of modulatory aspects of Keap1-Nrf2 signaling against cancer. Nutraceuticals are those dietary agents with many health benefits that have immense potential for cancer chemoprevention. The nutritional supplements known as nutraceuticals are found to be one of the most promising chemoprevention agents. Upon investigating the dual nature of Nrf2, it became clear that, in addition to shielding normal cells from numerous stresses, Nrf2 may also promote the growth of tumors. In the present review, we performed a systematic analysis of the role of 12 different nutraceuticals like curcumin, sulforaphane, resveratrol, polyunsaturated fatty acids (PUFA) from fish oil, lycopene, soybean, kaempferol, allicin, thymoquinone, quercetin, gingerol, and piperine in modulating the Nrf2/Keap1 signaling mechanism. Among these, 12 Generally Recognized As Safe (GRAS) certified nutraceuticals, sulforaphane is the most extensively studied compound in modulating Keap1-Nrf signaling. Even though there is much evidence at preclinical levels, further high-quality research is still required to validate the potential role of these nutraceuticals in Keap1-Nrf2 modulation.

Decoding Immune Signature to Detect the Risk for Early-Stage HCC Recurrence.

Hepatocellular carcinoma (HCC) is often recognized as an inflammation-linked cancer, which possesses an immunosuppressive tumor microenvironment. Curative treatments such as surgical resection, liver transplantation, and percutaneous ablation are mainly applicable in the early stage and demonstrate significant improvement of survival rate in most patients. However, 70-80% of patients report HCC recurrence within 5 years of curative treatment, representing an important clinical issue. However, there is no effective recurrence marker after surgical and locoregional therapies, thus, tumor size, number, and histological features such as cancer cell differentiation are often considered as risk factors for HCC recurrence. Host immunity plays a critical role in regulating carcinogenesis, and the immune microenvironment characterized by its composition, functional status, and density undergoes significant alterations in each stage of cancer progression. Recent studies reported that analysis of immune contexture could yield valuable information regarding the treatment response, prognosis and recurrence. This review emphasizes the prognostic value of tumors associated with immune factors in HCC recurrence after curative treatment. In particular, we review the immune landscape and immunological factors contributing to early-stage HCC recurrence, and discuss the immunotherapeutic interventions to prevent tumor recurrence following curative treatments.

Kaempferide exhibits an anticancer effect against hepatocellular carcinoma in vitro and in vivo.

CONTEXT: Phytochemicals have been promising candidates for cancer therapy, affecting various cancer initiation and progression stages. Kaempferide is a mono methoxy flavone that shows potent anticancer effects on multiple cancers both in vitro and in vivo. MATERIALS AND METHODS: We evaluated the anticancer activity of kaempferide against HCC using an MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. HepG2, Huh7, and N1S1 were used for preliminary in vitro studies. This is followed by an apoptosis analysis assessed by caspase-3 and 9. The in vivo effects of the compound were studied in the N1S1 orthotopically injected SD (Sprague Dawley) rat model, where the animal was given kaempferide (25 mg/kg thrice a week) and vehicle (Cremophor:ethanol) iv. The expression of caspase-9 and a critical tumor marker, transforming growth factor beta 1 (TGF-ß 1), were assessed in both control and treatment tumor samples. RESULTS: Kaempferide-induced dose-dependent cytotoxicity in three HCC cell lines (HepG2: IC50 = 27.94 ± 2.199 µM; Huh7: IC50 = 25.65 ± 0.956 µM; and N1S1: IC50 = 15.18 ± 3.68 µM). Furthermore, caspase-dependent apoptosis was confirmed in vitro. Kaempferide showed a significant reduction in tumor size and tumor volume in vivo. Histopathological evaluation by hematoxylin and eosin (H&E) staining confirmed that altered cells were significantly demolished in the kaempferide-treated animals, which correlates with tumor reduction compared to the vehicle-treated group. Caspase-9 levels were also found to be increased in the treatment group. TGF-ß 1, a crucial marker in invasion and metastasis of liver cancer, was also downregulated in the treatment group (control = 207.8 ± 22.9 pg/mL and kaempferide-treated = 157.3 ± 13.8 pg/mL). CONCLUSION: We report for the first time the potential of kaempferide as a promising alternative against HCC, which further warrants its clinical validation.

Decoding the Mechanism of Drugs of Heterocyclic Nature against Hepatocellular Carcinoma.

OBJECTIVES: Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and accounts for ~90% of cases, with an approximated incidence of >1 million cases by 2025. Currently, the backbone of HCC therapy is the oral multi-kinase inhibitor, Sorafenib, which consists of a Pyridine heterocycle ring system. This review highlights the introspective characteristics of seven anticancer drugs of heterocyclic nature against HCC along with their structural activity relationships and molecular targets. METHODS: Literature collection was performed using PubMed, Google Scholar, SCOPUS, and Cross ref. Additional information was taken from the official website of the FDA and GLOBOCAN. Key findings/ Results: Based on the available literature, approved heterocyclic compounds show promising results against HCC, including Sorafenib (Pyridine), Regorafenib (Pyridine), Lenvatinib (Quinoline), Cabozantinib (Quinoline), Gemcitabine (Pyrimidine), 5-Fluorouracil (Pyrimidine)and Capecitabine (Pyrimidine), their mechanism of action and key aspects regarding its structural activity were included in the review. CONCLUSION: Heterocyclic compounds represent almost two-thirds of the novel drugs approved by FDA between 2010 and 2020 against Cancer. This review summarizes the clinical relevance, mechanism of action, structural activity relationship, and challenges of the seven available anticancer drugs with heterocyclic ring systems against HCC.

Green Synthesized Nanoparticles as a Plausible Therapeutic Strategy Against Hepatocellular Carcinoma: An Update on its Preclinical and Clinical Relevance.

Green nanotechnology can offer notable advantages over the conventional drug delivery methods in terms of improved drug stability, drug-carrying capacity, site-specificity, and feasibility to apply different routes of administration with less systemic toxicities. Metal nanoparticles bio fabricated with phytoconstituents and microbial extracts have gained significant interest for the treatment of various solid tumors including hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is an aggressive cancer with a very poor prognosis. The current treatments of HCC fails to provide tumor specificity, causing many systemic toxicities and poor overall survival benefits especially for patients in advanced and terminal stages. A novel therapeutic approach with maximal therapeutic effect and minimum adverse effects are urgently required for HCC patients. Green synthesized metal nanoparticles offer significant anticancer effects along with minimal systemic toxicities because of their site-specific delivery into the tumor microenvironment (TME). Green synthesized metal nanoparticles can therefore be a highly beneficial strategy for the treatment of HCC if properly validated with preclinical and clinical studies. This review focuses on the preclinical evidence of the most widely studied green metal nanoparticles such as green synthesized silver nanoparticles, gold nanoparticles and selenium nanoparticles. We have also summarised the clinical studies and the patents approved for nanoparticles against HCC.

Plant Extracts and Phytochemicals, a Promising Strategy Against Oral Lichen Planus: A Review on Clinical Trials.

BACKGROUND: Oral lichen planus (OLP) is an autoimmune disease that distress keratinized cells of the oral epithelium. Topical corticosteroids and other potential therapies like immunosuppressives, hydroxychloroquine, azathioprine, mycophenolate, dapsone, retinoids, biologic agents are used for the management of OLP. However, their effectiveness, best dose, duration of treatment and safety remain mostly unidentified. Moreover, recurrence of disease and dose-related side effects are the other issues. OBJECTIVE: The primary objective of the review is to explore the existing clinical trials for the efficacy of phytochemicals in treating OLP in comparison to corticosteroids. A comprehensive information about their mode of action is also discussed. METHODS: We have discussed different clinical trials conducted on various phytochemicals and plant extracts/formulations like curcumin, lycopene, quercetin, glycyrrhizin, purslane, raspberry, aloe vera gel and aloe vera mouthwash for the treatment of OLP. RESULTS: The current therapy for the management of OLP has numerous adverse effects and requires a long-term treatment. Phytochemicals can be a very good alternative in overcoming these side effects and reducing the course of treatment. CONCLUSION: Herbal extracts and their formulations can be an effective alternative to the current therapy due to their proven therapeutic effects, reduced side effects, long-term applicability, prevention of recurrence as well as progression into cancer.

Embelin: A multifaceted anticancer agent with translational potential in targeting tumor progression and metastasis.

Embelin, a natural para-benzoquinone product, is derived from plants of the Embelia genus, particularly Embelia ribes Burm.f. A staple in traditional medicinal formulations for centuries, Embelin's pharmacological actions are attributed to the hydroxyl benzoquinone present in its structure. Its therapeutic potential is bolstered by unique physical and chemical properties. Recently, Embelin, recognized as a non-peptidic, cell-permeable small inhibitor of the X-linked inhibitor of apoptosis protein (XIAP), has garnered significant attention for its anticancer activity. It demonstrates various anticancer mechanisms, such as apoptosis induction, cell cycle arrest, and autophagy, in different cancer types. Additionally, Embelin modulates several signal transduction pathways, including NF-κB, PI3Kinase/AKT, and STAT3, effectively inhibiting the proliferation of diverse cancer cell lines. This literature review illuminates the anticancer potential of Embelin, detailing its mechanisms of action and prospective clinical applications, based on relevant scientific literature from the past decade sourced from various electronic databases. See also the Graphical abstract(Fig. 1).

Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma.

Transforming growth factor-beta (TGF-ß) is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression. Among different ligands of the TGF-ß family, TGF-ß1 modulates most of its biological outcomes. Despite the abundant expression of TGF-ß1 in the liver, steatosis to hepatocellular carcinoma (HCC) progression triggers elevated TGF-ß1 levels, contributing to poor prognosis and survival. Additionally, elevated TGF-ß1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms. TGF-ß1 has a prime role as a diagnostic and prognostic biomarker in HCC. Moreover, TGF-ß1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors. This review provides clinical relevance and up-to-date information regarding the potential of TGF-ß1 in diagnosis, prognosis, and therapy against HCC.

Corrigendum: Blockade of uttroside B-induced autophagic pro-survival signals augments its chemotherapeutic efficacy against hepatocellular carcinoma.

[This corrects the article DOI: 10.3389/fonc.2022.812598.].

Effect of Hydroaloholic Extract of Rotula Aquatica Lour on Gentamicin-Induced Nephrotoxicity in Wistar Albino Rats: An In Vitro and In Vivo Approach.

One-third of the world population suffer from kidney complications such as acute and chronic renal failure, renal calculi, kidney stones, Fanconi's syndrome and urethritis which doesn't have a proper effective treatment regimen. The current study explores the nephroprotective effect of herbal drug Rotula Aquatica by both In Vitro and In Vivo methods. MTT assay was applied In Vitro to evaluate the nephroprotective effect of R. aquatica leaves extract on HEK 293 cell line. The acute toxicity of the extract was evaluated as per the limit test under the protocol of OECD 423 at a concentration of 2000 mg/kg using 6 female rats. Further, an In Vivo study using the Gentamicin-instigated nephrotoxicity model was carried out for a period of 8 days. Biochemical markers of renal damage, endogenous antioxidants and histopathology were determined to assess the effect of treatment. The In Vitro study using HEK 293 cell line resulted in an EC50 value of 51.50 µg/ml for the extract in comparison to the standard drug Cytsone (12.26 µg/ml). Based on the limit test of OECD 423, doses of 200 and 400 mg/kg were chosen for the study. The results revealed a strong nephroprotective activity at 400 mg/kg in Gentamicin-induced nephrotoxicity against standard drug cystone by restoring the decrement in body weight, renal enzymatic and non-enzymatic antioxidants, creatinine and urea levels in urine and plasma. This indicated that hydroalcoholic extract of Rotula aquatica (HAERA) can prevent the Gentamicin toxicity due to the high content of antioxidant and anti-inflammatory secondary metabolites.

Augmented Efficacy of Uttroside B over Sorafenib in a Murine Model of Human Hepatocellular Carcinoma.

We previously reported the remarkable potency of uttroside B (Utt-B), saponin-isolated and characterized in our lab from Solanum nigrum Linn, against HCC. Recently, the U.S. FDA approved Utt-B as an 'orphan drug' against HCC. The current study validates the superior anti-HCC efficacy of Utt-B over sorafenib, the first-line treatment option against HCC. The therapeutic efficacies of Utt-B vs. sorafenib against HCC were compared in vitro, using various liver cancer cell lines and in vivo, utilizing NOD.CB17-Prkdcscid/J mice bearing human HCC xenografts. Our data indicate that Utt-B holds an augmented anti-HCC efficacy over sorafenib. Our previous report demonstrated the pharmacological safety of Utt-B in Chang Liver, the normal immortalized hepatocytes, and in the acute and chronic toxicity murine models even at elevated Utt-B concentrations. Here, we show that higher concentrations of sorafenib induce severe toxicity, in Chang Liver, as well as in acute and chronic in vivo models, indicating that, apart from the superior therapeutic benefit over sorafenib, Utt-B is a pharmacologically safer molecule, and the drug-induced undesirable effects can, thus, be substantially alleviated in the context of HCC chemotherapy. Clinical studies in HCC patients utilizing Utt-B, is a contiguous key step to promote this drug to the clinic.

Biology, Significance and Immune Signaling of Mucin 1 in Hepatocellular Carcinoma.

Mucin 1 (MUC 1) is a highly glycosylated tumor-associated antigen (TAA) overexpressed in hepatocellular carcinoma (HCC). This protein plays a critical role in various immune-mediated signaling pathways at its transcriptional and post-transcriptional levels, leading to immune evasion and metastasis in HCC. HCC cells maintain an immune-suppressive environment with the help of immunesuppressive tumor-associated antigens, resulting in a metastatic spread of the disease. The development of intense immunotherapeutic strategies to target tumor-associated antigen is critical to overcoming the progression of HCC. MUC 1 remains the most recognized tumor-associated antigen since its discovery over 30 years ago. A few promising immunotherapies targeting MUC 1 are currently under clinical trials, including CAR-T and CAR-pNK-mediated therapies. This review highlights the biosynthesis, significance, and clinical implication of MUC 1 as an immune target in HCC.