The role of glypican-3 in hepatocellular carcinoma: Insights into diagnosis and therapeutic potential.

Glypican-3 (GPC-3) is predominantly found in the placenta and fetal liver, with limited expression in adult tissues. Its re-expression in hepatocellular carcinoma (HCC) and secretion into the serum highlights its potential as a diagnostic marker. GPC-3 is involved in important cellular processes such as proliferation, metastasis, apoptosis, and epithelial-mesenchymal transition through various signaling pathways including Wnt, IGF, YAP, and Hedgehog. To review the structure, biosynthesis, and post-translational modifications of GPC-3, and to elucidate its signaling mechanisms and role as a pro-proliferative protein in HCC, emphasizing its diagnostic and therapeutic potential. A comprehensive literature review was conducted, focusing on the expression of GPC-3 in various tumors, with a special emphasis on HCC. The review synthesized findings from experimental studies and clinical trials, analyzing the overexpression of GPC-3 in HCC, its differentiation from other liver diseases, and its potential as a diagnostic and therapeutic target. GPC-3 overexpression in HCC is linked to aggressive tumor behavior and poor prognosis, including shorter overall and disease-free survival. Additionally, GPC-3 has emerged as a promising therapeutic target. Ongoing investigations, including immunotherapies such as monoclonal antibodies and CAR-T cell therapies, demonstrate potential in inhibiting tumor growth and improving clinical outcomes. The review details the multifaceted roles of GPC-3 in tumorigenesis, including its impact on tumor-associated macrophages, glucose metabolism, and epithelial-mesenchymal transition, all contributing to HCC progression. GPC-3's re-expression in HCC and its involvement in key tumorigenic processes underscore its value as a biomarker for early diagnosis and a target for therapeutic intervention. Further research is warranted to fully exploit GPC-3's diagnostic and therapeutic potential in HCC management.

Impact of gut microbiota on metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma: pathways, diagnostic opportunities and therapeutic advances.

Metabolic dysfunction-associated steatohepatitis (MASH) and progression to hepatocellular carcinoma (HCC) exhibits distinct molecular and immune characteristics. These traits are influenced by multiple factors, including the gut microbiome, which interacts with the liver through the "gut-liver axis". This bidirectional relationship between the gut and its microbiota and the liver plays a key role in driving various liver diseases, with microbial metabolites and immune responses being central to these processes. Our review consolidates the latest research on how gut microbiota contributes to MASH development and its progression to HCC, emphasizing new diagnostic and therapeutic possibilities. We performed a comprehensive literature review across PubMed/MedLine, Scopus, and Web of Science from January 2000 to August 2024, focusing on both preclinical and clinical studies that investigate the gut microbiota's roles in MASH and HCC. This includes research on pathogenesis, as well as diagnostic and therapeutic advancements related to the gut microbiota. This evidence emphasizes the critical role of the gut microbiome in the pathogenesis of MASH and HCC, highlighting the need for further clinical studies and trials. This is to refine diagnostic techniques and develop targeted therapies that exploit the microbiome's capabilities, aiming to enhance patient care in liver diseases.

Whether Present Era Demand Change in Pharmaceutical Promotional Ways to be More Eco- and Doctor-Friendly? An Observational Study.

Aim: Pharmaceutical promotion is the principal aspect of the healthcare system. In this study, we aimed to portray the opinion of doctors and medical representatives (MRs) on conventional pharmaceutical ways (usage of promotional or educational paper materials and physician drug samples) for pharmaceutical promotion. Materials and Methods: In this cross-sectional observational study, data were collected from doctors and MRs across India using self-administered Google forms. Data were analyzed, and results were drawn. Results: A total of 314 doctors and 272 MRs participated in the study. As per 95.5% of doctors, continuing medical education (CME)/books/online information is the most common and convenient method to update medical knowledge, whereas 67.9% of MRs also think the same. Only 5.5% of doctors prefer paper material provided by pharmaceutical companies to update their knowledge. Most doctors say paper materials provided by pharmaceutical companies contribute less than 25% to product information, rather CME, books, and online information contribute significantly. MRs also think similarly. 66.2% of MRs agree that more than 25% of paper material gets wasted due to non-distribution. 73.2% of doctors and 75.4% of MRs agree that the use of paper materials for product promotion is not cost-effective, even if it contributes to deforestation. Only 51% of doctors use more than 50% of medical samples in patient care and only half of doctors and MRs think expired medical samples are disposed of correctly. 56.1% of doctors and 71.4% of MRs think a significant amount of medical samples are wasted and are hazardous to the environment. Conclusions: Both doctors and MRs are of the opinion that the conventional method of paper promotion, that is, paper material and drug samples, is not cost-effective and also not eco-friendly. Hence, need to rethink - is there a need to change with time?

Inhibition of monoamine oxidases and neuroprotective effects: chalcones vs. chromones.

Eighteen compounds derived from two sub-series, (HC1-HC9) and (HF1-HF9), were synthesized and evaluated for their inhibitory activities against monoamine oxidase (MAO). HC (chalcone) series showed higher inhibitory activity against MAO-B than against MAO-A, whereas the HF (chromone) series showed reversed inhibitory activity. Compound HC4 most potently inhibited MAO-B with an IC50 value of 0.040 µM, followed by HC3 (IC50 = 0.049 µM), while compound HF4 most potently inhibited MAO-A (IC50 = 0.046 µM), followed by HF2 (IC50 = 0.075 µM). The selectivity index (SI) values of HC4 and HF4 were 50.40 and 0.59, respectively. Structurally, HC4 (4-OC2H5 in B-ring) showed higher MAO-B inhibition than other derivatives, suggesting that the -OC2H5 substitution of the 4-position in the B-ring contributes to the increase of MAO-B inhibition, especially -OC2H5 (HC4) > -OCH3 (HC3) > -F (HC7) > -CH3 (HC2) > -Br (HC8) > -H (HC1) in order. In MAO-A inhibition, the substituent 4-OC2H5 in the B-ring of HF4 contributed to an increase in inhibitory activity, followed by -CH3 (HF2), -F (HF7), -Br (HF8), -OCH3 (HF3), and-H (HF1). In the enzyme kinetics and reversibility study, the Ki value of HC4 for MAO-B was 0.035 ± 0.005 µM, and that of HF4 for MAO-A was 0.035 ± 0.005 µM, and both were reversible competitive inhibitors. We confirmed that HC4 and HF4 significantly ameliorated rotenone-induced neurotoxicity, as evidenced by the reactive oxygen species and superoxide dismutase assays. This study also supports the significant effect of HC4 and HF4 on mitochondrial membrane potential in rotenone-induced toxicity. A lead molecule was used for molecular docking and dynamic simulation studies. These results show that HC4 is a potent selective MAO-B inhibitor and HF4 is a potent MAO-A inhibitor, suggesting that both compounds can be used as treatment agents for neurological disorders.

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.

Case Report of Primary Synovial Sarcoma of the Thyroid Gland: An Unusual Histology at Atypical Location.

Primary synovial sarcoma of the thyroid gland is extremely rare, aggressive, and has a dismal prognosis. We report the case of a 15-year-old male who presented with a progressively increasing neck mass, which was excised and the histopathological and immunohistochemical study suggested biphasic synovial sarcoma of the thyroid gland which was confirmed by synovial sarcoma translocation. There are 14 cases of primary synovial sarcoma of the thyroid reported in the literature so far. This study aimed to document the occurrence of synovial sarcoma histology at an unusual anatomical location with a review of the literature on this rare entity.

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.

Identification of Kaempferol as Viral Entry Inhibitor and DL-Arginine as Viral Replication Inhibitor from Selected Plants of Indian Traditional Medicine against COVID-19: An in silico Guided in vitro Approach.

BACKGROUND: Indian traditional medicinal plants are known for their great potential in combating viral diseases. Previously, we reported a systematic review approach of seven plausible traditional Indian medicinal plants against SARS-CoV-2. METHODS: Molecular docking was conducted with Biovia Discovery Studio. Three binding domains for spike glycoprotein (PDB IDs: 6LZG, 6M17, 6M0J) and one binding domain of RdRp (PDB ID: 7BTF) were used. Among 100 phytoconstituents listed from seven plants by the IMPPAT database used for virtual screening, the best six compounds were again filtered using Swiss ADME prediction and Lipinski's rule. Additionally, a pseudovirion assay was performed to study the interaction of SARS-CoV-2 S1-protein with the ACE 2 receptor to further confirm the effect. RESULTS: Chebulagic acid (52.06 Kcal/mol) and kaempferol (48.84 Kcal/mol) showed increased interaction energy compared to umifenovir (33.68 Kcal/mol) for the 6LZG binding domain of spike glycoprotein. Epicatechin gallate (36.95 Kcal/mol) and arachidic acid (26.09 Kcal/mol) showed equally comparable interaction energy compared to umifenovir (38.20 Kcal/mol) for the 6M17 binding domain of spike glycoprotein. Trihydroxychalcone (35.23 Kcal/mol) and kaempferol (36.96 Kcal/mol) showed equally comparable interaction energy with umifenovir (36.60 Kcal/mol) for 6M0J binding domain of spike glycoprotein. Upon analyzing the phytoconstituents against RdRp binding domain, DL-arginine (41.78 Kcal/mol) showed comparable results with the positive control remdesivir (47.61 Kcal/mol). ADME analysis performed using Swiss ADME revealed that kaempferol and DL arginine showed drug-like properties with appropriate pharmacokinetic parameters. Further in vitro analysis of kaempferol by pseudovirion assay confirmed an acceptable decrease of the lentiviral particles in transfected HEK293T-hACE2 cells. CONCLUSION: The study highlights that kaempferol and DL-arginine could be the significant molecules to exhibit potent action against SARS-CoV-2 and its variants.

2,4-Dihydroxycinnamic acid as spike ACE2 inhibitor and apigenin as RdRp inhibitor in Nimbamritadi Panchatiktam Kashayam against COVID-19: an in silico and in vitro approach.

Nimbamritadi Panchatiktam Kashayam (NPK) is an ayurvedic formulation composed of ingredients with potent anti-viral activities. We studied the interaction energy of 144 phytoconstituents present in NPK against spike receptor-binding domain (RBD) complexed with ACE2 protein (PDB ID: 6LZG) and RNA-dependent RNA polymerase protein (PDB ID: 7BTF) using Biovia Drug Discovery studio. The result indicated that 2,4-hydroxycinnamic acid exerts more significant binding affinities (28.43 kcal/mol) than Umifenovir (21.24 kcal/mol) against spike ACE2. Apigenin exhibited the highest binding affinities (54.63 kcal/mol) compared with Remdesivir (24.52 kcal/mol) against RdRp. An in vitro analysis showed a reduction in the number of lentiviral particles on transfected HEK293T-hACE2 cells as assessed by pseudovirus inhibition assay. At the same time, the tested compounds showed non-toxic up to 100 µg/ml in normal cells by MTT assay. The study highlights the plausible clinical utility of this traditional medicine against SARS CoV2.

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.