Pancreatic cancer (PC) is a highly aggressive malignancy with limited treatment options and poor prognosis. Dahuang Zhechong Pill, a traditional Chinese medicine, has shown promise in inhibiting inflammation. This study investigates the effects of combining Dahuang Zhechong Pill with TNS4 silencing on PC, focusing on their combined role in suppressing PC progression and exploring potential therapeutic applications. Intellectual property implications related to this combination are also explored. Bioinformatic analysis was used to identify the key role of TNS4 in PC. CFPAC-1 PC cells were cultured and genetically modified using lentiviral transfection to stably knock down TNS4 expression. Cell proliferation was assessed using the CCK-8 assay, while cell migration and invasion capabilities were evaluated through Transwell assays. Colony formation and flow cytometry were performed to analyze clonogenic potential and cell cycle distribution, respectively. Apoptosis was assessed using tunel staining. Subcutaneous and orthotopic tumor models were established in nude mice to investigate the in vivo effects. Mice were treated with Dahuang Zhechong Pill by oral gavage. Immunohistochemistry and immunofluorescence were employed to detect the expression of key proteins involved in the NF-κB/VEGF pathway, including E-cadherin and Vimentin. ELISA was used to measure circulating IL-17 and amylase levels in mouse serum to test inflammation response. TNS4 was upregulated in PC and positively associated with PC progression. TNS4 silencing significantly reduced CFPAC-1 cell proliferation, migration, and invasion in vitro. Flow cytometry demonstrated an increase in G0/G1 phase arrest and apoptosis in the TNS4 silencing group. Subcutaneous models showed the anti-tumor effect of TNS4 silencing. Furthermore, Dahuang Zhechong Pill treatment, when combined with TNS4 knockdown, resulted in a marked decrease in tumor size in orthotopic models. Immunohistochemical analysis revealed reduced expression of NF-κB and VEGF in tumor tissues from the combination treatment group. ELISA results indicated lower levels of serum IL-17, and amylase and higher levels of insulin in combination-treated mice. We proposed an innovative therapeutic approach combining traditional Chinese medicine with targeted gene silencing to inhibit PC progression. By investigating the synergistic effects of TNS4 silencing and Dahuang Zhechong Pill in suppressing the NF-κB/VEGF signaling pathway, our findings highlighted a promising strategy that targets tumor proliferation and modulates the inflammatory microenvironment in PC. Dahuang Zhechong Pill, in combination with TNS4 silencing, effectively inhibits the NF-κB/VEGF pathway and inflammation response, leading to reduced PC progression. These findings suggest a potential therapeutic approach for targeting PC through the combined use of traditional Chinese medicine and gene editing.
BCL-2 was the first gene identified to have antiapoptotic effects, and venetoclax is an oral selective BCL-2 inhibitor, which has great potential in the treatment of patients with acute myeloid leukemia (AML) who are not candidates for intensive therapy. Notably, posaconazole, an oral antifungal drug, is also a strong factor that can affect blood venetoclax concentrations. To the best of our knowledge, the relationship between BCL-2 expression, posaconazole, and venetoclax, as well as their influence on treatment efficacy and the prognosis of patients with AML, has not been reported. In this single-center retrospective study, the relationship between BCL-2 expression and blood venetoclax concentration was analyzed in 35 patients with AML. After that, we explored the differences in curative effect, adverse reactions, and outcomes between patients with different BCL-2 expression levels and patients with different venetoclax concentration levels, respectively. BCL-2 mRNA expression levels were examined by reverse transcription quantitative PCR. Blood venetoclax concentrations were measured using high-performance liquid chromatography- tandem mass spectrometry. The results revealed that among patients with AML, those with lower primary BCL-2 expression had a higher complete remission (CR) rate (p =0.005), overall response (OR) rate (p <0.0001), and progression-free survival time (p =0.04). Posaconazole was revealed to be a strong factor that was able to increase blood venetoclax concentration (p <0.001) and CR rate in the venetoclax plus posaconazole group compared to that in the venetoclax monotherapy group (p =0.002); however, no significant difference was identified in the occurrence of adverse reactions between these groups. Among low and high-blood venetoclax concentration groups, the event-free survival of the former group was significantly higher (p =0.013). Higher levels of BCL-2 expression at initial diagnosis may have adverse effects on the efficacy and prognosis of patients, and higher levels of venetoclax concentration may advance the time of adverse reactions in patients, thus adversely affecting event-free survival (EFS).
Colorectal cancer is a significant global public health challenge, contributing substantially to cancer-related mortality worldwide. Vitexin has been shown to promote the polarization of macrophages towards the M1 phenotype, a process dependent on the Vitamin D receptor. This polarization is crucial in the tumor microenvironment, as it helps mitigate the progression from chronic colitis to colorectal cancer. Despite its potential, the mechanisms of vitexin's action and its impact on colon cancer remain unclear. This study aims to evaluate the inhibitory effects of vitexin on cell proliferation and apoptosis in the Caco-2 colon cancer cell line, with a specific focus on its modulation of antioxidant enzyme activities, pro-apoptotic factors, and key signaling pathways involved in cell survival and proliferation. The IC50 of vitexin against Caco-2 cells was determined. Cell viability and necrosis rates were assessed after 48 hours of incubation with vitexin at concentrations of 19.01, 38.01, and 76.02 μg/mL. Additionally, levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), P53, Bax, TSC2, Sestrin 2, and PUMA, as well as the expression of AMPK, PI3K, Akt, and mTOR genes and proteins, were measured using q-PCR and Western blotting techniques in Caco-2 cells post-incubation. Vitexin exhibited an IC50 of 38.01 ± 0.64 μg/mL against Caco-2 cells. Treatment with vitexin at the specified concentrations for 48 hours resulted in a significant decrease in cell viability by 28.40%, with inhibitory rates reaching 71.6%. Apoptosis rates increased to 93.81%, 171.41%, and 294.12%, respectively, with a corresponding rise in necrosis rates by 194.19%, 400.22%, and 811.44%. Pharmacological analysis revealed that vitexin significantly inhibited SOD and CAT activities while enhancing MDA production. Furthermore, vitexin treatment upregulated the expression of key apoptotic markers (P53, Bax, TSC2, Sestrin 2, and PUMA) and the expression of AMPK, PI3K, and Akt, while downregulating mTOR genes and proteins, implicating various signaling pathways. This study demonstrates that vitexin induces apoptosis in Caco-2 colon cancer cells through multiple mechanisms, including modulation of antioxidant enzymes, upregulation of pro-apoptotic factors, and regulation of key signaling pathways involved in cell survival and proliferation. These findings suggest that vitexin's mechanisms of action involve complex interactions with various cellular pathways, making it a promising candidate for further research and potential therapeutic applications in colorectal cancer.
Cancer drug resistance has emerged as a formidable challenge in the field of clinical oncology, significantly hampering the success of treatment strategies and leading to suboptimal outcomes for patients. In a broad array of therapeutic settings, the emergence of resistance has become a primary source of concern, ranging from conventional chemotherapy to modern immunotherapy and targeted therapies. The complexity of cancer drug resistance is further exacerbated by the involvement of oncoviruses, such as human papillomavirus (HPV), Epstein-Barr virus (EBV), and hepatitis B virus (HBV), which play pivotal roles in the initiation, progression, and response to treatment of various cancers. The intricate interactions between these oncoviruses and cancer cells have been found to significantly influence drug efficacy. These viruses can alter critical cellular pathways, including drug metabolism, DNA repair mechanisms, and the tumor microenvironment, thus promoting drug resistance. A profound understanding of these virus-cancer-drug interactions is crucial for the development of novel treatment approaches that can effectively overcome drug resistance. This review aimed to contribute to a broader awareness of the multifaceted nature of cancer drug resistance, particularly in the context of oncovirus involvement. By highlighting the critical role of oncoviruses in cancer development and treatment response, this review hopes to stimulate further research and the development of novel treatment strategies that can effectively overcome drug resistance and ultimately improve patient outcomes. As we advance toward precision oncology, a more holistic understanding of the complex interplay among cancer, its associated viruses, and therapeutic drugs is crucial for achieving optimal therapeutic responses.
Widespread drug resistance in the treatment of non-small cell lung cancer (NSCLC) seriously restricts clinical efficacy, so the development of new drug delivery systems to overcome drug resistance has become a key area of research. Currently, no systematic study has been conducted on anti-drug resistance drug delivery systems for NSCLC. This study systematically analyzed patent application trends and delivery system types for drug resistance in NSCLC over the past two decades using the WIPO, Espacenet, and Incopat global patent databases. The analysis focused on the evolution of delivery technology and the value and effectiveness of related technologies. The results showed that the number of patent applications has grown continuously, reflecting progressive innovation in this field of technology from basic research and development to breakthrough applications. The main technology types are nano delivery (56.6% of total patents) and coupled delivery (28.3%). Additionally, emerging technologies such as exosomes, vesicles, and siRNA have emerged. There has been a leap in technology evolution from single-carrier development to intelligent, responsive delivery. In recent years, research has focused on the synergistic application of stimuli-responsive nano systems and combination therapy. High-value patents typically offer the combined benefits of various technologies and mechanisms, particularly in terms of overcoming drug resistance, achieving precise delivery, and reducing toxic side effects. This study provides an important theoretical basis and practical guidance for optimizing the research and development (R&D) strategy and patent portfolio for anti-drug-resistance drug delivery technology in NSCLC.
The CUGBP ELAV-like family member 2 (CELF2) gene is irregularly expressed in various types of cancer. However, the role of CELF2 in stomach adenocarcinoma (STAD) remains unclear. This study aims to elucidate its potential role in modulating tumor behavior in STAD, as well as its correlation with tumor-infiltrating immune cells. Bioinformatics analysis methods were employed to investigate the CELF2 expression levels of CELF2 in STAD and its correlation with clinicopathological factors. CELF2 expression was quantified in STAD cells using qRT-PCR and Western blot. Immunohistochemistry confirmed CELF2 expression in STAD versus adjacent normal tissues. The effects of CELF2 expression on cell proliferation were evaluated using CCK-8 and colony formation assays, and migration and invasion assays evaluate cellular motility and invasiveness. Differential expression and protein-protein interaction (PPI) network analysis were conducted to predict the downstream targets of CELF2. Our findings revealed that CELF2 expression was significantly reduced in STAD tissues and was correlated with patient survival outcomes. Moreover, CELF2 overexpression demonstrated a notable inhibitory effect on cell proliferation, migration, and invasion in STAD cells. Importantly, CELF2 appeared to exert its effects through the regulation of the downstream target gene adiponectin (ADIPOQ). The knockdown of ADIPOQ effectively negated the inhibitory effects of CELF2 on cell proliferation and migration. This study underscores CELF2 as a tumor suppressor in STAD, whose downregulation promotes progression and correlates with poor prognosis. The CELF2/ADIPOQ axis represents a new regulatory pathway with therapeutic implications. The lack of deeper mechanistic insights into how CELF2 regulates ADIPOQ also warrants further investigation. CELF2 acts as a tumor suppressor in STAD by inhibiting proliferation, migration, and invasion, partly through regulating ADIPOQ and influencing the immune microenvironment. It represents a promising prognostic biomarker and new therapeutic target, with the CELF2/ADIPOQ axis offering a specific pathway for future drug development.
Hypoxia is a hallmark of aggressive breast cancers, particularly Triple- Negative Breast Cancer (TNBC), where stabilization of Hypoxia-Inducible Factor-1α (HIF-1α) upregulates Carbonic Anhydrase IX (CAIX), thereby enabling tumor pH homeostasis, proliferation, and resistance to therapy. Selective CAIX inhibition, therefore, offers a promising therapeutic strategy. In this study, a thiazolidine derivative was identified as a selective inhibitor of CAIX with the use of integrated computational, in vitro, and in vivo studies to develop targeted therapy against TNBC. A series of thiazolidinone derivatives was subjected to in silico molecular docking against human carbonic anhydrase isoforms. The most active compound, 2-(4-chlorophenyl)-3- (4-ethoxyphenyl)thiazolidin-4-one (BCS12), was tested and analyzed using 200 ns MD simulations to evaluate the stability of the complexes. Pharmacokinetic parameters were predicted using ADME profiling. Cytotoxicity was evaluated in MDA-MB-231 and MDA-MB-468 breast cancer cells, with IC50 values of 15.49 μM and 18.81 μM, compared to 121.6 μM in noncancerous MCF-10A cells (n = 3, p < 0.05). Free Radical generation, mitochondrial membrane depolarization, and expression of apoptosis markers (Bax, Bcl-2, caspase 9, caspase 7, and caspase 3, and PARP) were quantified using mechanistic studies in hypoxia-adapted MDA-MB- 231 cells by RT-qPCR, western blotting, and immunofluorescence. The number of apoptotic cells was also determined by flow cytometry. The in vivo activity was assessed against DMBAinduced breast tumor-bearing rats by histopathology and TUNEL staining. BCS12 showed strong docking affinity as well as stable binding with active-site residues of CAIX in simulations. It preferentially suppressed TNBC cell viability, promoted oxidative stress, impaired the integrity of mitochondria, and activated an intracellular apoptosis pathway. In vivo, BCS12 treatment induces an increase of TUNEL-positive nuclei in a dosedependent manner compared with the control, with significantly higher contrast index values at 20 mg/kg and 40 mg/kg (p < 0.0001). The apoptotic response was strongest in the 40 mg/kg group, and was associated with a marked decrease in tumor burden and restoration of tissue architecture. The lead compound reduced tumor mass, improved histological parameters, and increased TUNEL-positive apoptotic nuclei with an associated decrease in expression of CAIX and activation of pro-apoptotic proteins. Our findings suggest that BCS12 disrupts hypoxia-induced survival pathways through inhibition of CAIX to enhance TNBC cell sensitivity to apoptosis. These data reveal a therapeutic benefit of selective CAIX inhibition to counteract hypoxia-induced therapy resistance and further insights into the mechanism underlying hypoxia-targeted therapies for aggressive breast cancer. BCS12 selectively inhibits CAIX, leading to the effective impairment of hypoxic adaptation and apoptosis in TNBC. The in silico, in vitro, and pre-clinical model data together provide evidence for the candidacy of this compound as a lead candidate for hypoxia-targeted therapy of breast cancer. Due to its unique chemical structure and therapeutic characteristics, BCS12 may be a candidate for patent filing for future translational development.
Leukemia and radiation-induced liver toxicity are significant health challenges requiring effective therapeutic strategies. This study aimed to evaluate the therapeutic efficacy and radiosensitizing effects of Diosgenin-loaded silver nanoparticles (Dio-AgNPs) in ENU-induced leukemic mice, with a focus on their dual role in mitigating leukemia progression and γ-irradiation-induced hepatotoxicity. Dio-AgNPs were synthesized and characterized using TEM, UV-Vis spectroscopy, FT-IR spectroscopy, and encapsulation efficiency analysis. Leukemic mice were treated with Dio-AgNPs (90 mg/kg b.w.) and γ-irradiation (2 Gy). Biological assays assessed hematological parameters, liver function, oxidative stress biomarkers, and gene expression (Nrf2, ABCC1, NQO1). Molecular docking analyzed diosgenin's binding affinities to target proteins. Histological evaluation of liver tissues and in silico ADMET profiling were also performed. Dio-AgNPs exhibited a mean diameter of 51.60 ± 1.54 nm, zeta potential of -19.5 ± 0.2 mV, and high encapsulation efficiency (84.98 ± 0.45%). Treatment significantly improved blood parameters (e.g., 39.4% increase in Hb, 41.5% reduction in WBCs), reduced liver enzymes (40.4% decrease in AST), and lowered oxidative stress (50.1% reduction in MDA). Synergy with γ-irradiation enhanced radiosensitivity (IC50: 24.55 μg/mL vs. 58.35 μg/mL alone). Molecular docking revealed strong binding to Nrf2 (-9.04 kcal/mol), ABCC1 (-10.05 kcal/mol), and NQO1 (-10.71 kcal/mol). Histology confirmed hepatoprotection, with minimal degeneration in combination-treated groups. Dio-AgNPs demonstrated multifaceted benefits, including anti-leukemic, antioxidant, and anti-inflammatory effects, amplified by γ-irradiation. The activation of the Nrf2 pathway and modulation of detoxification genes (ABCC1, NQO1) underpinned their therapeutic mechanism. Limitations include a single timepoint analysis and the need for human-relevant validation. Dio-AgNPs are a promising dual-function therapy for leukemia and radiationinduced liver damage, combining targeted cytotoxicity with organ protection. Future research should optimize dosing and explore clinical translation.
An aberrant increase in cancer incidences has demanded extreme attention globally despite advancements in diagnostic and management strategies. The high mortality rate is concerning, and tumour heterogeneity at the genetic, phenotypic, and pathological levels exacerbates the problem. In this context, lack of early diagnostic techniques and therapeutic resistance to drugs, sole awareness among the public, coupled with the unavailability of these modern technologies in developing and low-income countries, negatively impact cancer management. One of the prime necessities of the world today is the enhancement of early detection of cancers. Several independent studies have shown that screening individuals for cancer can improve patient survival but are bogged down by risk classification and major problems in patient selection. Artificial intelligence (AI) has significantly advanced the field of oncology, addressing various medical challenges, particularly in cancer management. Leveraging extensive medical datasets and innovative computational technologies, AI, especially through deep learning (DL), has found applications across multiple facets of oncology research. These applications range from early cancer detection, diagnosis, classification, and grading, molecular characterization of tumours, prediction of patient outcomes and treatment responses, personalized treatment, and novel anti-cancer drug discovery. Over the past decade, AI/ML has emerged as a valuable tool in cancer prognosis, risk assessment, and treatment selection for cancer patients. Several patents have been and are being filed and granted. Some of those inventions were explored and are being explored in clinical settings as well. In this review, we will discuss the current status, recent advancements, clinical trials, challenges, and opportunities associated with AI/ML applications in cancer detection and management. We are optimistic about the potential of AI/ML in improving outcomes for cancer and the need for further research and development in this field.
This study aims to enhance the understanding of underlying mechanisms and potential therapies of the solute carrier organic anion (SLCO) transporter family in internal environment disorder (IED)-induced hepatocellular carcinoma (HCC). This could lead to new therapeutic strategies and offer new directions for the creation of new patents for HCC treatment products. The orthotopic transplantation (OT), IED and IED-based OT (IED-OT) mouse models were established. Expression patterns of Slco4a1 and Slco1b2 were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting (WB) and immunohistochemistry (IHC) in various tissues, including lung, stomach, liver, spleen, kidney, colon, small intestine, HCC tissues and adjacent non-cancerous tissues. Animals exhibited symptoms, including weight loss, lethargy, chills, dyspnea, altered hair texture, and gastrointestinal disturbances, confirming the successful establishment of the IED model. The analysis demonstrated differential expression and tissue-specific distribution of Slco4a1 and Slco1b2, which are associated with IED-induced changes. These alterations potentially disrupt organ transport functions, thereby promoting the development of HCC. Additionally, they suggest a role in rebalancing the tumor microenvironment and mitigating damage resulting from abnormal substance accumulation. This study reveals that IED promotes HCC progression by altering the expression and distribution of Slco4a1 and Slco1b2, leading to transport dysfunction in affected organs. Furthermore, IED and OT exhibit synergistic effects in HCC development. These findings enhance the understanding of the underlying mechanisms of IED related HCC. Future studies should establish animal models incorporating both internal and external factors, with cellular experiments needed to further validate the mechanisms. Changes in SLCO expression and distribution induced by IED may play pivotal roles in the development of HCC. These findings contribute insights that could inform novel therapeutic strategies against HCC.
Schisandra chinensis has been reported to exhibit antitumor activity; however, its active components and molecular mechanisms in non-small cell lung cancer (NSCLC) remain unclear. Network pharmacology was employed to identify active compounds and potential targets of Schisandra chinensis against NSCLC, followed by protein-protein interaction analysis, GO and KEGG enrichment analyses, and molecular docking. A549 cells were used for experimental validation. Cell viability was assessed by MTT assay, oxidative stress markers (GSH, SOD, MDA) were quantified, and the expression of PTGS2, inflammatory factors, and apoptosis-related genes was examined by qRT-PCR and Western blot. Eight active components of Schisandra chinensis were identified, with seven overlapping targets related to NSCLC. Molecular docking revealed that Gomisin R exhibited the strongest binding affinity to PTGS2, with a docking score of -7.3 kcal/mol. In vitro experiments demonstrated that Gomisin R significantly inhibited A549 cell proliferation in a dose- and time-dependent manner, with a pronounced effect observed at 25 µM (p < 0.01). Gomisin R markedly downregulated PTGS2 expression at both mRNA and protein levels (p < 0.001), accompanied by reduced expression of inflammatory cytokines IL-1β and IL-6, increased antioxidant capacity (elevated GSH and SOD levels and decreased MDA content), and modulation of apoptosis-related genes, characterized by decreased Bcl-2 and increased Caspase 9 expression (p < 0.05-0.001). These effects were partially reversed by the PTGS2 agonist rebamipide. These findings suggest that Gomisin R may modulate PTGS2-associated inflammatory and redox pathways in NSCLC cells. The integration of network pharmacology with experimental validation provides a mechanistic framework for understanding the potential role of Gomisin R in NSCLC-related research, although further in vivo studies are required to confirm its translational relevance. Gomisin R exerts anti-NSCLC effects, in part, by regulating PTGS2 expression, leading to suppression of cell proliferation, attenuation of oxidative stress and inflammatory responses, and induction of apoptosis in A549 cells. This study provides quantitative evidence supporting Gomisin R as a key active component of Schisandra chinensis for the treatment of NSCLC.
Multidrug resistance (MDR) in cancer is a major obstacle to achieving success in clinical chemotherapy. It has been observed that overexpression of ATP-Binding Cassette (ABC) transporters plays a crucial role in MDR. This study aimed to find an effective resistance-reversed agent of ABC transporter. A series of new β-carboline derivatives have been synthesized and are being applied in various invention patents. One of these is B-9-8, a novel harman dimer, which was synthesized to conduct a series of experiments. In this study, we investigated whether B-9-8 could reverse ABCG2-mediated drug resistance by using MTT assay, [3H]-mitoxantrone accumulation/efflux assay, western blot analysis, immunofluorescence analysis, ATPase assay, and molecular modeling assay. The results showed that B-9-8 could significantly increase the sensitivity of mitoxantrone, SN-38, and topotecan and effectively overcame drug resistance at non-toxic concentrations in ABCG2-overexpressing cells. Further studies showed that B-9-8 increased the intracellular accumulation of [3H]-mitoxantrone by suppressing the efflux function of ABCG2 in ABCG2-overexpressing cells. B-9-8 could down-regulate the ABCG2 protein expression but did not change the subcellular localization of ABCG2. ATPase analysis indicated that B-9-8 inhibited the ATPase activity of ABCG2 in a concentration-dependent manner. In the molecular docking analysis, B-9-8 demonstrated a strong interaction with the human ABCG2 transporter protein. Our findings indicated that B-9-8 could reverse ABCG2-mediated MDR as a potential and reversible modulator in combination with conventional chemotherapeutic drugs.
Skull base chordoma is a rare, slow-growing primary tumor. Due to its proximity to the brainstem, blood vessels, and nerves, complete surgical resection is challenging. Therefore, postoperative radiotherapy is required to achieve full disease eradication. Compared to photon therapy, proton therapy offers physical dosimetric advantages, ensuring an adequate target dose while minimizing damage to surrounding tissues. Long-term follow-up has confirmed that proton therapy provides survival benefits and enhanced safety in treating skull base chordoma. Consequently, it is considered the standard radiotherapy approach for this condition. However, due to the low incidence of skull base chordoma and the high cost of proton therapy, only a limited number of prospective studies have evaluated its use in this disorder. To date, there is no consensus on proton therapy dosage, fractionation, or target delineation. In this review, we assess the latest advancements and challenges associated with proton therapy for chordomas located at the skull base, aiming to provide a comprehensive understanding of radiotherapy strategies for this disease.
Immune regulatory genes, such as PLXNB2, play critical roles in the tumor microenvironment, yet their specific functions in Multiple Myeloma [MM] remain largely unclear. Transcriptomic and clinical data for MM were retrieved from the Gene Expression Omnibus (GEO) database and analyzed alongside immune regulation-related genes identified from previous Mendelian randomization analysis. Correlations between these genes and immune functions, clinical risk scores, and survival prognosis were evaluated. Virtual drug sensitivity screening was performed for MM immune-related prognostic risk genes. In vitro experiments, including cell cloning, Transwell assays, scratch tests, and ELISA, were conducted to validate findings. PLXNB2 expression was positively correlated with improved MM prognosis, whereas LMNB1 expression showed a negative correlation. MM cell lines exhibited reduced PLXNB2 and increased LMNB1 expression. Overexpression of PLXNB2 and knockdown of LMNB1 significantly inhibited MM cell proliferation, invasion, and migration. Furthermore, these manipulations decreased PD1 and CTLA-4 expression, enhancing the cytotoxic activity of immune cells against MM cells. Our findings highlight the potential immune regulatory functions of PLXNB2 and LMNB1 in MM progression. The interplay between these genes may influence immune evasion and tumor aggressiveness, providing insights into potential therapeutic targets. Reduced PLXNB2 expression may drive LMNB1 upregulation, suppress immune cell responses, and promote MM progression. These genes represent promising biomarkers and therapeutic targets for improving MM treatment strategies.
The precise function of Tolloid Like 2 (TLL2) remains uncertain within the context of Lung Adenocarcinoma (LUAD). The primary objective of this investigation was to conduct a thorough analysis. To assess its diagnostic utility, data from The Cancer Genome Atlas (TCGA) database were used to assess TLL2 expression in pan-cancer and LUAD. The study has also investigated the correlation between TLL2 expression levels and LUAD symptoms and prognosis. Furthermore, the study has explored possible regulatory networks involving TLL2, including its association with immune infiltration, tumor stemness index (mRNAsi), and drug sensitivity in LUAD. We have explored TLL2 expression in single-cell sequencing of LUAD and the genomic variation and clinical significance of TLL2 in LUAD. The expression of TLL2 has been validated in GSE87340 and cell lines by quantitative Real-time PCR (qRT-PCR). An abnormal expression of TLL2 has been found in pan-cancer and LUAD. In LUAD patients, elevated levels of TLL2 were significantly related to the T stage (p = 0.046) and the pathological stage (p = 0.016). The expression of TLL2 in patients with LUAD was significantly associated with poorer Overall Survival (OS) (p < 0.001). The expression of TLL2 was determined to be an independent predictor of poorer OS (p = 0.042). TLL2 was associated with ribosome, neuroactive ligand-receptor interaction, allograft rejection, ECM receptor interaction, asthma, porphyrin and chlorophyll metabolism, focal adhesion, pentose and glucuronate inter-conversions, and ascorbate and aldarate metabolism. The expression of TLL2 in LUAD was correlated with immune infiltration and mRNAsi. The expression of TLL2 was significantly and negatively correlated with TAK-715, XMD13-2, STF-62247, OSI-930, and EHT-1864 in LUAD. The TLL2 gene was up- -regulated in multiple individual LUAD cells. LUAD patients with altered TLL2 had a shorter PFS as opposed to those with unaltered TLL2. The expression of TLL2 was significantly increased in LUAD cells. For patients with LUAD, TLL2 may serve as an immunotherapeutic target and a useful prognosis biomarker.
This study aimed to investigate the role of ZNF146 in osteosarcoma progression and its potential as a therapeutic target and prognostic biomarker, focusing on its interaction with the HMGB1-NF-κB signaling pathway. ZNF146 expression was analyzed in osteosarcoma tissues versus normal tissues using RNA-seq data from the TARGET database and validated in a cohort of 36 patients via RTqPCR, Western blot, and IHC. Functional assays (Transwell, wound healing, colony formation, CCK-8) and molecular analyses (dual-luciferase reporter, ChIP, Western blot) were conducted in MG63 and U2OS cells with ZNF146 modulation. An MG63 xenograft mouse model was used for in vivo validation. ZNF146 was significantly upregulated in osteosarcoma tissues, correlating with poor patient prognosis (p =0.0307). Functionally, ZNF146 overexpression promoted cell proliferation, migration, and invasion, while its knockdown suppressed these effects. Mechanistically, ZNF146 directly binds to the HMGB1 promoter, thereby enhancing HMGB1 expression and activating the NF-κB pathway, which leads to increased cyclin D1 and MMP9 levels. In vivo, ZNF146 knockdown resulted in reduced tumor growth and Ki-67/PCNA expression. These findings establish ZNF146 as a key oncogenic driver in osteosarcoma via HMGB1-NF-κB signaling. The results align with studies implicating ZNF proteins in tumor progression but highlight a novel mechanism. Limitations include unexplored effects on the tumor microenvironment and the need for validation in larger clinical cohorts. ZNF146 promotes osteosarcoma progression through HMGB1-mediated NF-κB activation, suggesting its potential as both a prognostic biomarker and a therapeutic target. Inhibition of ZNF146 or HMGB1 may offer novel strategies for osteosarcoma treatment.
This study aimed to identify key genes linked to resistance to a combination treatment regimen of bevacizumab and pemetrexed in non-small cell lung cancer (NSCLC) through bioinformatics analysis and analysis of their associated pathways. Expression data from the Gene Expression Omnibus (GEO) database (GSE154286) were analyzed. The differentially expressed genes (DEGs) between tissues sensitive and resistant to combined bevacizumab and pemetrexed treatment in NSCLC were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment was investigated, and protein-protein interaction (PPI) networks, as well as transcription factors (TFs)- DEGs-miRNA networks, were created using the STRING tool. Key genes were identified with the help of the MCODE plugin. Additionally, gene set enrichment analysis (GSEA) was utilized to identify pathways linked to the key genes. A retrospective analysis was conducted on clinical data from 80 NSCLC patients. Patients were categorized into drug-resistant and non-resistant groups based on RECIST1.1 criteria. The expression of the key gene TNFSF4 was analyzed using quantitative real-time PCR (qRT-PCR). In the GSE154286 dataset, 35 downregulated DEGs were discovered. KEGG pathway enrichment analysis revealed that these DEGs were primarily associated with immunity and inflammation-related pathways. The PPI network construction highlighted a significant module and led to the identification of 8 candidate genes: TNFRSF18, TNFSF4, LGALS9, FAS, LAG3, CD86, CD80, and FOXP3. The TFs-DEGs-miRNA network analysis pinpointed TNFSF4 as a key gene, potentially regulated by 7 TFs and interacting with 9 miRNAs. GSEA analysis suggested that TNFSF4 may influence NSCLC's pathological processes through involvement in pathways involved in chemokine, JAK/STAT, NOD-like receptor, T cell receptor, toll-like receptor, and PPAR signaling. qRT-PCR detection displayed significantly lower expression of TNFSF4 in the peripheral blood of the patients in the resistant group relative to the non-resistant group (p < 0.0001). Logistic regression analysis showed that low TNFSF4 levels were independently linked to a raised risk of resistance to bevacizumab combined with pemetrexed therapy in lung adenocarcinoma patients. The identification of key genes, such as TNFSF4, and resistance-related signaling pathways through bioinformatics analysis offers valuable insights into potential mechanisms of chemotherapy resistance in NSCLC when treated with the combination of bevacizumab and pemetrexed. These findings provide a theoretical foundation for advancing clinical research on diagnosis and treatment.
Genistein, a phytoestrogen with multi-target anticancer activity, and chitosan, a biocompatible polymer with versatile drug carrier properties, are increasingly investigated for use in advanced drug delivery systems. Cancer remains a leading cause of mortality globally, with current therapeutic approaches like systemic toxicity, non-specific drug delivery, multidrug resistance, and limited bioavailability of therapeutic compounds. This review synthesized evidence from PubMed, Scopus, Web of Science, Science Direct, and Google Patents. Most of the studies involving genistein, chitosan, nano-formulations, pharmacokinetics, regulatory guidelines, and patents were screened. Some of the recent patents from 2020 to 2025 on drug delivery have been analyzed to map translation development. Moreover, the genistein chitosan systems are positioned as a synergistic co-therapy platform. Composite systems such as nanoparticles, liposomes, hydrogels, and micelles show significant improvements in bioavailability (5-10-fold), tumor retention, and reduced systemic toxicity in preclinical models. The clinical implications of this integrated system are profound. Despite strong preclinical data, regulatory challenges persist, including variability in the molecular weight of genistein and chitosan, limited nanotoxicology standards, and classification inconsistencies for natural products. The regulatory landscapes of the developing and non-developing countries, which evolved across key pharmaceutical jurisdictions including the FDA, EMA, CDSCO, PMDA, AND NMPA. Genistein and chitosan drug delivery systems represent a promising approach for precision oncology, offering improved pharmacokinetics, targeted delivery, and reduced toxicity. This review also critically addresses the regulatory gaps, biocompatibility, and modular delivery systems.
Traditional cancer therapies like chemotherapy and radiotherapy frequently face challenges, such as systemic toxicity, the development of resistance, and poor tolerance among patients. Recently, there has been a growing interest in herbal bioactive compounds because of their wide-ranging anticancer properties and natural sources. Nonetheless, the clinical use of these compounds is restricted by their low solubility in water, limited bioavailability, and rapid metabolic clearance. This review comprehensively assesses studies from 2010 to 2023 that investigate nanoformulation strategies aimed at enhancing the delivery of herbal bioactive agents in cancer treatment. The selection of studies was based on their examination of important nanocarrier systems, such as polymeric nanoparticles, liposomes, and lipid-based delivery platforms. The focus was on advancements in pharmacokinetics, drug targeting, and therapeutic outcomes. Research shows that nanoformulated herbal compounds show improved stability, solubility, and controlled release characteristics. Polymeric and lipid-based nanocarriers significantly enhance drug accumulation in tumor tissues, thereby improving antitumor effectiveness and reducing systemic side effects. Numerous studies also demonstrate increased cellular uptake and extended circulation times with nano-encapsulated phytochemicals. Nanoformulation technologies have effectively tackled numerous pharmacological challenges linked to herbal therapeutics. However, while laboratory and preclinical outcomes are promising, obstacles like obtaining regulatory approval, scaling up production, and ensuring consistent quality control impede clinical application. Additionally, the variability in plantderived compounds requires standardization to ensure reproducibility and safety. Nanoformulations of herbal bioactive compounds mark a significant advance in cancer treatment, providing enhanced solubility, targeted delivery, and lower toxicity. Despite the progress made, additional research is required to refine these formulations, address manufacturing and regulatory challenges, and incorporate these strategies into personalized cancer therapy models.
Lysyl oxidase-like 2 (LOXL2) is a metalloenzyme that catalyzes oxidative deamination ε-amino group of lysine. It has been found that LOXL2 is a promotor for the metastasis and invasion in kinds of tumors. Previous studies show that disulfide bonds are important components in LOXL2, and their bioactivity can be regulated by those bonds. In this way, a small molecule covalently binds to the thiol group of cysteine residue could be an effective way to change the function of LOXL2 by blocking the formation of the disulfide bond. This investigation is aiming to screen covalent inhibitor for LOXL2. Covalent molecule libraries of Life Chemical and Enamine were used. The structures of those molecules were optimized by using LigPrep module of Schrödinger. Then optimized by using the LigPrep module of Schrödinger to generate optimal conformations. For covalent docking, CovDock in Glide module was used for the virtual screening. Finally, wound-healing assays were performed to examine the effects of the potential inhibitors. Eight potential small molecules were selected by covalent docking from the databases (in total 7,908 candidates). ADMET evaluation indicated that all those eight small molecules satisfy the general standard. Furthermore, wound healing experiments showed that the compound (F50972176) significantly inhibits the migration of cancer cells. Through advanced methodologies, namely binding affinity calculations and ADMET prediction, this strategy enables a decrease in time consumption and improves operational efficacy in the rapid screening of LOXL2 covalent inhibitors, which constitutes a crucial research area. Virtual screening and experimental verification methods were used to screen covalent inhibitors of LOXL2 by targeting functional disulfide bonds. The compound (F50972176) effectively inhibited the migration of esophageal squamous cell carcinoma cells.