Induced Cell Apoptosis Research Articles

Therapeutic Scrutiny of Lentinus polychrous with Attention to Its Antioxidant, Antimicrobial, and Anticancer Attributes.

Mushrooms, being a source of therapeutically active compounds, are of great interest to researchers due to their historical usage in traditional therapies and the significant role that natural products have played in the development of contemporary medications. Lentinus polychrous is one underutilized mushroom species collected from the laterites of West Bengal, India. Our study aims toward its taxonomic validation, deciphering the secondary metabolic fingerprint, and testing its efficiency in countering many clinical issues, including oxidative stress, growing microbial drug resistance, and cancer. In vitro investigations have shown that the methanolic extract of the mushroom has a broad spectrum of antioxidant activitieswith effective concentration (EC50) ranging from 403.6 ± 3.8 to 841.2 ± 10.7µg/mL depending on the type of free radicals and is effective in combating human pathogenic bacterial strains where MIC50 varies from as low as 302.2 ± 3.8 to 570.6 ± 1.8µg/mL, mediated likely through inducing the breakdown of the outer coat and inducing increased porosity. The fraction was also shown to possess anticancer properties against A549 cells (LD50 120.9 ± 1.83µg/mL) by triggering apoptosis. The modulation of Bcl-2 family gene expression was found to be the primary factor responsible for the induction of apoptosis in A549 cells during the experimental approaches. The findings revealed that the mushroom exhibits significant antioxidant, antibacterial, and particular cytotoxic effects on lung cancer cells, indicating its potential medical importance. These results provide essential insights into possibilities for the development of new therapeutic medicines derived from this mushroom.

(E)-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1H-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer

Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. Methods: A panel of 29 compounds was synthesized and examined by a preliminary screening in estrogen receptor (ER) and progesterone receptor (PR)-positive MCF-7 breast cancer cells together with cell cycle analysis and tubulin polymerization inhibition. Results: (E)-5-(3-(1H-1,2,4-triazol-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2-methoxyphenol 22b was identified as a potent antiproliferative compound with an IC50 value of 0.39 mM in MCF-7 breast cancer cells, 0.77 mM in triple-negative MDA-MB-231 breast cancer cells, and 0.37 mM in leukemia HL-60 cells. In addition, compound 22b demonstrated potent activity in the sub-micromolar range against the NCI 60 cancer cell line panel including prostate, melanoma, colon, leukemia, and non-small cell lung cancers. G2/M phase cell cycle arrest and the induction of apoptosis in MCF-7 cells together with inhibition of tubulin polymerization were demonstrated. Immunofluorescence studies confirmed that compound 22b targeted tubulin in MCF-7 cells, while computational docking studies predicted binding conformations for 22b in the colchicine binding site of tubulin. Compound 22b also selectively inhibited aromatase. Conclusions: Based on the results obtained, these novel compounds are suitable candidates for further investigation as antiproliferative microtubule-targeting agents for breast cancer.

Cobalt oxide nanoparticles induce cytotoxicity and excessive ROS mediated mitochondrial dysfunction and p53-independent apoptosis in melanoma cells

Nanotherapy has emerged as a promising strategy for the targeted and efficient treatment of melanoma, the most aggressive and lethal form of skin cancer, with minimized systemic toxicity. However, the therapeutic efficacy of cobalt oxide nanoparticles (Co3O4NPs) in melanoma treatment remains unexplored. This study aimed to assess the therapeutic potential of Co3O4NPs in melanoma treatment by evaluating their impact on cell viability, genomic DNA and mitochondrial integrity, reactive oxygen species (ROS) generation and apoptosis induction in melanoma A-375 cells. Our findings demonstrated a concentration-dependent reduction in cell viability upon treatment with five Co3O4NP concentrations (0.2, 2, 20, 200, and 2000 µg/ml), with an IC50 value of 303.80 µg/ml. Treatment with this IC50 concentration significantly increased ROS generation, induced dramatic DNA damage, and disrupted mitochondrial membrane potential integrity. Flow cytometric analysis revealed apoptosis and necrosis induction following Co3O4NP exposure at the IC50 concentration value. Results of qRT-PCR analysis demonstrated remarkable dysregulation of apoptotic and mitochondrial genes, including a significant downregulation of apoptotic p53 and mitochondrial ND3 genes and marked upregulation of the anti-apoptotic gene Bcl2. These findings highlight the novel potential of Co3O4NPs as potent inducers of melanoma A-375 cell death in a concentration-dependent manner through excessive ROS production, genomic instability, mitochondrial dysfunction and dysregulation of apoptotic and mitochondrial gene expression, ultimately promoting apoptosis in A-375 cells. This study thus underscores the potential of Co3O4NPs as a promising nanotherapeutic candidate for melanoma treatment, warranting further exploration to elucidate their full biological and clinical applicability.

Biomaterials-mediated biomineralization for tumor blockade therapy.

Recent advancements in tumor therapy have underscored the potential of biomaterials-mediated biomineralization for tumor blockade. By precisely regulating biomineralization and constructing nanomineralized structures at the cellular level, this therapy achieves multi-dimensional targeted inhibition of tumors. Mineralized precursor molecules are engineered to selectively recognize and bind to proteins on the tumor cell membrane, obstructing signal transduction. Biomineralized materials directly target the tumor cell membrane, disrupting its biological functions and inducing cell apoptosis. Additionally, these materials infiltrate the mitochondria of tumor cells, disrupting energy metabolism through mineralization and significantly impairing tumor viability. This biomaterials-mediated approach enhances treatment precision and efficacy while mitigating side effects, offering a unique approach to tumor therapy.

Discovery of Novel Small-Molecule Inhibitors Disrupting the MTDH-SND1 Protein-Protein Interaction.

MTDH-SND1 protein-protein interaction (PPI) plays an important role in the initiation and development of tumors, and it is a target for the treatment of breast cancer. In this study, we identified and synthesized a series of novel small-molecule inhibitors of MTDH-SND1 PPI. The representative compound C19 showed potent activity against MTDH-SND1 PPI with an IC50 of 487 ± 99 nM and tight binding to the SND1-purified protein with a Kd value of 279 ± 17 nM. Compound C19 significantly degraded SND1 and downregulated downstream at the protein level. Further biological evaluations suggested that compound C19 exhibited potent activity against the proliferation of breast cancer MCF-7 cells with an IC50 value of 626 ± 27 nM, significantly inhibited invasion and migration, and induced cell apoptosis. In addition, compound C19 exhibited promising tumor growth inhibition in the xenograft model. Our study provides a potential candidate targeting MTDH-SND1 PPI for the treatment of breast cancer.

Synthesis and Biological Evaluation of a New Biphenyl-Based Organogold(III) Complex with In Vitro and In Vivo Anticancer Activity.

Despite recent advances in cancer treatment, there is still a need for novel compounds with antineoplastic activity. Among 11 biphenyl-based organogold(III) N-heterocyclic carbene (NHC) (BGC) complexes of general formula [(C^C)Au(NHC-pyr)X], where (C^C) = 4,4'-ditertbutylbiphenyl, X = Cl or phenylacetylide, and (NHC-pyr) is a pyridyl-substituted NHC ligand, the complex BGC4 bearing a 4-CF3-pyridyl substituent and a chloride ligand showed promising antineoplastic activity on the triple negative breast cancer cell line. BGC4 was able to induce cell apoptosis but had no effect on the cell cycle. In vivo, BGC4 reduced the tumor growth rate by increasing the necrosis area and decreasing the mitotic activity. Repeated injections of BGC4 did not induce common side effects. The present investigation shows that BGC4 is a promising antineoplastic candidate. Its potential as a future chemotherapy for the treatment of cancer will be strengthened by evaluating its efficacy in combined treatment with current chemotherapy.

Y2O3NPs induce selective cytotoxicity, genomic instability, oxidative stress and ROS mediated mitochondrial apoptosis in human epidermoid skin A-431 Cancer cells

Yttrium oxide nanoparticles (Y2O3NPs) have emerged as a promising avenue for cancer therapy, primarily due to their distinctive properties that facilitate selective targeting of cancer cells. Despite their potential, the therapeutic effects of Y2O3NPs on human epidermoid skin cancer remain largely unexplored. This study was thus conducted to investigate the impact of Y2O3NPs on both human skin normal and cancer cells, with an emphasis on assessing their cytotoxicity, genotoxicity, and the mechanisms underlying these effects. Cell viability and apoptosis induction were assessed using the Sulforhodamine B and chromatin diffusion assay, respectively. Reactive oxygen species (ROS) level, mitochondrial membrane potential integrity, oxidative stress markers and expression level of apoptotic and mitochondrial genes were also estimated. Our findings highlight the selective and significant cytotoxicity of Y2O3NPs against human epidermoid A-431 cancer cells. Notably, exposure to five Y2O3NPs concentrations (0.1, 1, 10, 100 and 1000 µg/ml) resulted in a high concentration-dependent reduction in cell viability and a corresponding increase in cell death observed 72 h post-treatment specifically in A-431 cancer cells, while normal skin fibroblast (HSF) cells exhibited minimal toxicity. When A-431 cancer cells were treated with the half-maximal inhibitory concentration (IC50) of Y2O3NPs for 72 h, a significant increase in ROS generation was noted. This led to oxidative stress, along with severe damage to genomic DNA and mitochondrial membrane potential, triggering substantial apoptosis. Furthermore, a concurrent significant upregulation of apoptotic p53 and mitochondrial ND3 genes was observed, coupled with a notable decrease in the anti-apoptotic Bcl2 gene expression.Overall, Y2O3NPs demonstrate considerable promise as a therapeutic agent for skin epidermoid cancer due to their ability to selectively target and induce cytotoxic effects in A-431 cancer cells, all while causing minimal harm to normal HSF cells. This selective cytotoxicity appears to be associated with Y2O3NPs’ ability to induce excessive ROS production and subsequent oxidative stress, leading to significant genomic DNA fragmentation, loss of mitochondrial permeability, and alterations in apoptotic and mitochondrial genes’ expression, ultimately promoting apoptosis in A-431 cancer cells. These findings establish a foundation for further research into the utilization of Y2O3NPs in targeted cancer therapies and underscore the necessity for ongoing investigation into their safety and efficacy in clinical applications.

The anti-melanoma roles and mechanisms of tricholoma isoflavone derivative CA028

As a form of skin cancer, melanoma’s incidence rate is continuing to rise globally. Therefore, there is an urgent need to find new agents to improve survival in melanoma patients. Isoflavones, a class of phytoestrogens, are primarily found in soy and other legumes. Cumulating evidence demonstrates that isoflavones exhibits significant anti-tumor properties and is beneficial for the prevention and treatment of melanoma. In the present study, we aim to investigate the anti-melanoma role of tricholoma isoflavone derivative CA028. By using in vitro melanoma cell line models, A375 and A2058 and in vivo xenograft mouse model, our results indicate that melanoma proliferation, migration, and invasion are attenuated following CA028 treatment. In addition, the treatment of CA028 induced cell apoptosis of melanoma. Finally, we addressed the mechanism of CA028 against melanoma by comparative transcriptomic analysis. The results of gene ontology highlighted the involvement of CA028’s targets in the cell proliferation, cell apoptosis, and migration ability of melanoma cells. Furthermore, Ingenuity Pathway Analysis constructed the network involved in the apoptotic roles of CA028 through targeting p53 signaling and death receptor signaling. For the first time, our data suggested the possible use of modified isoflavone for therapeutic applications against melanoma.

KDM4A Silencing Reverses Cisplatin Resistance in Ovarian Cancer Cells by Reducing Mitophagy via SNCA Transcriptional Inactivation.

Ovarian cancer is one of the deadliest gynecologic cancers, with chemotherapy resistance as the greatest clinical challenge. Autophagy occurrence is associated with cisplatin (DDP)-resistant ovarian cancer cells. Herein, the role and mechanism of alpha-synuclein (SNCA), the autophagy-related gene, in DDP resistance of ovarian cancer cells are explored. Differentially expressed genes in DDP resistance of ovarian cancer cells were analyzed by GEO2R tools. DDP-resistant ovarian cancer cells (A2780/DDP) were transfected and treated with 2.5 μg/mL DDP for 72 h, followed by the determination of cell viability, proliferation, apoptosis, and expressions of SNCA, lysine demethylase 4A (KDM4A), histone H3 lysine 9 trimethylation (H3K9me3), and mitophagy-related proteins. The H3K9me3 demethylation of SNCA by KDM4A was confirmed by chromatin immunoprecipitation. SNCA and KDM4A were highly expressed in DDP-resistant ovarian cancer cells and their parental cells. KDM4A knockdown diminished expressions of KDM4A and SNCA and elevated H3K9me3 expression and H3K9me3 enrichment on SNCA promoter in A2780/DDP cells. SNCA or KDM4A knockdown inhibited cell viability, proliferation, and levels of LC3-II/LC3-I and Parkin while inducing cell apoptosis and upregulating Cyt-C expression of A2780/DDP cells with/without DDP treatment; however, SNCA overexpression not only did conversely but also reversed the effects of KDM4A knockdown on DDP-treated A2780/DDP cells and vice versa. Silencing of KDM4A-mediated transcription inactivation of SNCA reduces mitophagy, thus inhibiting the resistance of ovarian cancer cells to cisplatin. KDM4A may be a promising drug target for DDP-resistant ovarian cancer cells.

The Transcription Factor ATF2 Accelerates Clear Cell Renal Cell Carcinoma Progression Through Activating the PLEKHO1/NUS1 Pathway.

Clear cell renal cell carcinoma (ccRCC) is a common malignant cancer with high mortality rate. Activating transcription factor 2 (ATF2) and pleckstrin homology domain containing O1 (PLEKHO1) were reported to participate in numerous cancers. However, their roles and the detailed mechanisms in ccRCC development remain largely unknown. RT-qPCR and western blot were used to measure the levels of PLEKHO1, ATF2, and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1). Cell proliferation, apoptosis, invasion, migration and stemness were evaluated using CCK-8 assay, flow cytometry, transwell invasion assay, wound-healing assay and sphere formation assay, respectively. Dual-luciferase reporter assay was conducted to verify the relationship between ATF2 and PLEKHO1. The interaction between PLEKHO1 and NUS1 was proved by Co-IP assay. Xenograft models were utilized to evaluate the tumorigenic capability of ccRCC cells upon PLEKHO1 knockdown. PLEKHO1, ATF2 and NUS1 expression were significantly elevated in ccRCC, and PLEKHO1 might be a prognosis biomarker for ccRCC. PLEKHO1 depletion significantly inhibited cell proliferation, invasion, migration, stemness, and induced cell apoptosis in ccRCC cells. ATF2 activated PLEKHO1 expression via transcription regulation, and PLEKHO1 overexpression could reverse the suppressive effects of ATF2 knockdown on the malignant behaviors of ccRCC cells. Moreover, PLEKHO1 directly bound to NUS1, and PLEKHO1 depletion markedly restrained ccRCC progression through targeting NUS1 in vitro and in vivo. Our findings suggested that ATF2 transcriptionally activated PLEKHO1 to promote the development of ccRCC via regulating NUS1 expression.

Doxycycline Restores Gemcitabine Sensitivity in Preclinical Models of Multidrug-Resistant Intrahepatic Cholangiocarcinoma

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance (MDR), leaving patients with few alternative therapies. Doxycycline, a tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, and stemness. Based on these properties, we investigated the potential of doxycycline to overcome gemcitabine resistance in iCCA. Methods: We evaluated the efficacy of doxycycline in two MDR iCCA cell lines, MT-CHC01R1.5 and 82.3, assessing cell cycle perturbation, apoptosis induction, and stem cell compartment impairment. We assessed the in vivo efficacy of combining doxycycline and gemcitabine in mouse xenograft models. Results: Treatment with doxycycline in both cell lines resulted in a significant reduction in cell viability (IC50 ~15 µg/mL) and induction of apoptosis. Doxycycline also diminished the cancer stem cell population, as indicated by reduced cholangiosphere formation. In vivo studies showed that while neither doxycycline nor gemcitabine alone significantly reduced tumor growth, their combination led to marked decreases in tumor volume and weight at the study endpoint. Additionally, metabolic analysis revealed that doxycycline reduced glucose uptake in tumors, both as a monotherapy and more effectively in combination with gemcitabine. Conclusions: These findings suggest that doxycycline, especially in combination with gemcitabine, can restore chemotherapy sensitivity in MDR iCCA, providing a promising new strategy for improving outcomes in this challenging disease.

A novel peptide CP29L, selected from the phage displayed cyclic random heptapeptide library, demonstrates its potent inhibitory effects to liver cancer HCCLM3 cells by targeting FOXM1.

FOXM1 is the "Achilles' heel" of cancers and hence the potential therapeutic target for anticancer drug discovery. In this work, we selected high affinity peptides against the protein of human DNA binding domain of FOXM1 (FOXM1-DBD) from the disulfide-constrained, phage displayed random cyclic heptapeptide library Ph.D.-C7C. We obtained a novel peptide, 9R-CP29L, which was identified to be a potent anticancer peptide with IC50 values of 9.0 and 11.1μMat 24h for HCCLM3 and MD-MBA-231cells respectively. Molecular docking, CETSA, ITC and immunoblot assays demonstrated that 9R-CP29L can potentially specifically bind to FOXM1-DBD with a Kd value of 1.25μM and reduced the expression of FOXM1. In addition, Annexin V/PI flow cytometry, AO/EB staining, PI flow cytometry, clone formation and Transwell assays revealed that 9R-CP29L also induced cell apoptosis and cell cycle arrest while inhibited the proliferation and migration of HCCLM3 cells. The findings were further supported by the results of qRT-PCR and immunoblot assays for the associated gene (CMYC, CDC25B, BAX, CASPASE3 and MMP2, etc) expression in HCCLM3 cells. Finally, in vivo experiment showed that 9R-CP29 significantly reduced the tumor growth and downregulated the expression of FOXM1 in HCCLM3 xenograft nude mouse models. Taking together, our work provides a novel FOXM1 targeted peptide which has potential in both anticancer drug development and scientific researches.

Anti-tumor activity of an αPD-L1-PE38 immunotoxin delivered by engineered Nissle 1917.

Although immune checkpoint inhibitors specifically targeting the PD-1/PD-L1 axis have exhibited remarkable clinical success, they are not uniformly effective across all patient cohorts. Immunotoxins, a novel class of cancer therapeutics, offering a promising alternative. PD-L1, which is also present in certain normal tissues, limits its suitability as an ideal target for immunotoxins. The probiotic strain of E. coli Nissle 1917 (EcN) could target and colonize to solid tumors, which positions it as a promising candidate for tumor tissue-specific delivery of anti-tumor proteins. In this study, we constructed a PD-L1-targeted immunotoxin, designated as αPD-L1-PE38, by fusing an anti-PD-L1 nanobody and a clinically validated PE38 toxin. This immunotoxin exhibited potent cytotoxic activity against tumor cells while showed slightly cytotoxic activity against normal cells. To effectively deliver the αPD-L1-PE38 to tumor tissues, we engineered the EcN strain to release the immunotoxin induced by L-arabinose. Upon induction, the immunotoxin was efficiently secreted, and exhibited robust anti-tumor activity mainly by inducing cell apoptosis both in vitro and in vivo. Furthermore, we enhanced the immunotoxin's affinity for PD-L1 by optimizing the linker between the nanobody and PE38 toxin. The engineered EcN expressing the optimized immunotoxin, achieved superior anti-tumor activity. Collectively, our study suggests that the delivery of immunotoxins through live bacteria to improve safety and efficacy is a promising option in cancer therapeutics.

GCRV-II major outer capsid protein VP4 promotes cell apoptosis by VDAC2-mediated calcium pathway facilitation

Grass Carp Reovirus (GCRV) is widely concerned because of its widespread prevalence and high mortality to grass carp (Ctenopharyngodon idellus). Viral protein 4 (VP4) is an important major outer capsid protein of GCRV and is involved in the regulation of cell cycle and cycle of GCRV replication. However, the elaborate function of VP4 remains to be explicated. To understand its function, we screened the transcriptome of Ctenopharyngodon idellus kidney (CIK) cells transfected with VP4 and found that VP4 may be involved in regulation of ion transmembrane transporter activity and calcium signaling pathway. It was observed through transmission electron microscopy and confocal microscopy. VP4 causes endoplasmic reticulum (ER) stress and leads to abnormal Calcium ions (Ca2+) concentration in cells. Also, VP4 promoted the loss of mitochondrial membrane potential, which allowed a large amount of Ca2+ to enter mitochondria and led to mitochondrial damage and apoptosis. In this transcriptome, we found that voltage-dependent anion channel 2 (VDAC2) was significantly upregulated. Moreover, the results also showed that the expression of C.idellus voltage-dependent anion channel 2 (CiVDAC2) and the degree of cell apoptosis were increased along with the increase of VP4 transfection. In contrast, knockdown of CiVDAC2 can reduce the concentration of Ca2+ and the occurrence of apoptosis caused by VP4 transfection. In conclusion, the results demonstrated that VP4 can induce cell apoptosis through VDAC2-mediated calcium pathway facilitation. This study provides some insights for the prevention and treatment of GCRV infection in grass carp.

Polystyrene microplastics disrupt adrenal steroid synthesis in male mice via mitochondrial dysfunction.

Microplastics have gained significant social attention, as they can enter our bodies through food and drinking water. The adrenal gland is essential for the maintenance of metabolic homeostasis and stress responses. Nevertheless, the effects of microplastics on the steroid synthesis in the adrenal cortex was still unclear. In this study, through both in vivo and in vitro models, we found that polystyrene microplastics (PS-MPs) impaired adrenal steroid synthesis, leading to a reduction in corticosterone levels. In vivo, we further observed that chronic exposure to PS-MPs (0.25, 0.5 and 1 mg/d for 4 weeks) could induce abnormal mitochondrial morphology and functional disruptions of adrenal glands in male mice, along with an imbalance in cellular oxidative stress, manifested as increased level of reactive oxygen species, diminished antioxidant activity (glutathione peroxidase and superoxide dismutase). In vitro, these occurrences coincided with an elevated rate of cell apoptosis observed in adrenocortical cells following exposure to PS-MPs. We proposed that mitochondrial dysfunction not only directly influenced the biosynthetic processes of steroid hormones but also induced cell apoptosis through the initiation of cellular oxidative stress. The latter may represent a common mechanism underlying the multi-organ toxicity induced by PS-MPs in the body. Our findings would provide new insights for the development of more effective environmental protection measures and the reduction of plastic pollution.

Investigating the Role of Quercetin, an Active Ingredient in Bazhen Decoction, in Targeting CXCL8 to Inhibit Macrophage M2 Polarization and Reshape the Immunological Microenvironment of Colorectal Cancer.

Bazhen Decoction (Eight Treasures Decoction) has demonstrated efficacy in the treatment of colorectal cancer (CRC), yet the active ingredients in it and the mechanisms underlying their anti-cancer properties are not well understood. Through network pharmacology, the effective components of Bazhen Decoction against CRC and their corresponding key genes were delineated. Molecular docking was executed to identify the active component targeting the key gene CXCL8, which led to the discovery of Quercetin. The cellular thermal shift assay method was then used to verify the binding interaction. CRC cells were treated with incremental concentrations of Quercetin, cell viability was evaluated by the Cell Counting Kit-8 assay to calculate the IC50, and apoptosis rates were determined by flow cytometry. Expression of the apoptosis-related proteins Bcl-2 and Cleaved caspase-3 was measured using western blot. The impact of Quercetin on macrophage polarization was studied by co-culturing the treated CRC cells with macrophages, assessing M1 and M2 macrophage distribution via flow cytometry, and quantifying cytokine levels (IL-6, IL-10, IL-12, and CXCL8) with enzyme-linked immunosorbent assay (ELISA). The active ingredient Quercetin from Bazhen Decoction exhibited a targeted binding affinity with the key gene CXCL8, which enabled it to inhibit the proliferation of CRC cells and induce cell apoptosis. The overexpression of CXCL8 was associated with the promotion of CRC malignancy, yet the presence of Quercetin could lessen the impact of CXCL8 overexpression on CRC cells. Moreover, the treatment with Quercetin leads to a diminished abundance of M2 macrophages and an increase in the levels of cytokines IL-6 and IL-12, while reducing the levels of IL-10 and CXCL8, which indicates that Quercetin has an inhibitory effect on macrophage M2 polarization. Quercetin, the active component in Bazhen Decoction that is known for anti-CRC effects, targets and inhibits CXCL8 to impede the malignant behaviors and the M2 polarization of macrophages. Thus, Quercetin may be utilized as an immunomodulatory agent in CRC treatment.

Revealing 5-(3,5-difluorobenzyl)-1H-indazole as the active pharmacophore of ALK/ROS1 dual inhibitors through theoretical calculations and biological activity evaluations

Anaplastic lymphoma kinase (ALK) and tyrosine protein kinase (ROS1) are recognized as driver genes in lung cancer, with dual inhibition of both targets offering a promising approach to enhance therapeutic outcomes in non-small cell lung cancer (NSCLC). Although numerous ALK/ROS1 inhibitors have received FDA approval, detailed research into the essential active structural motifs within these inhibitors remains limited. Addressing this gap, the current study employed computer-aided drug design (CADD) methodologies, incorporating bioisosteric and conformational similarity principles to design and synthesize 31 dual-target 2-morpholinobenzamide derivatives. These derivatives each include the 5-(3,5-difluorobenzyl)-1H-indazole, 4-benzylmorpholine, and thiophene moieties. Based on docking binding energies, we proposed that 5-(3,5-difluorobenzyl)-1H-indazole may represent a key pharmacophore for ALK/ROS1 activity. Subsequent kinase and cellular assays validated this hypothesis, with compound X4 exhibiting optimal inhibitory activity against both ALK and ROS1 kinases and lung cancer cell lines, achieving IC50 values of 0.512 µM (ALK), 0.766 µM (ROS1), and 0.034 ± 0.002 µM (H2228). In vitro antitumor assays demonstrated dose-dependent induction of apoptosis in H2228 cells by X4. Western blot (WB) analysis further confirmed that X4 effectively suppresses the expression of p-ALK and p-ERK. Importantly, X4 exhibited high specificity in targeting ALK and ROS1 across a range of kinases. In an H2228 xenograft model, X4 achieved a tumor inhibition rate of 54.71 %, underscoring its considerable potential in ALK/ROS1 inhibition.

ICOSL deficiency promotes M1 polarization to alleviate liver fibrosis in Schistosomiasis Mice

The expression of inducible co-stimulator ligand (ICOSL) on macrophage (Mφ) implies their ability to interact with inducible co-stimulator (ICOS)-expressing T cells, thereby modulating immune responses within the liver microenvironment. This study aimed to elucidate the mechanism underlying ICOS/ICOSL signaling in the regulation of Mφ polarization during Schistosomiasis-induced liver fibrosis. To investigate this, ICOSL-knock out (KO) and wildtype (WT) C57BL/6 mice were infected with Schistosoma japonicum (S. japonicum) to examine the dynamic changes in Mφ phenotype and observe the pathology alterations in the liver. There was significantly decreased expression of ICOSL both in monocytes of cirrhosis patients and the liver tissue of mice infected with S. japonicum. Furthermore, ICOSL-KO mice exhibited reduced liver granuloma formation and fibrosis during S. japonicum infection. Simultaneously, Mφ in ICOSL-KO mice polarized towards M1-type and induced apoptosis of hepatic stellate cells (HSCs). Overall, the blockade of ICOSL signaling could promote M1 polarization, induce HSCs apoptosis, and ameliorate hepatic fibrosis, suggesting that ICOSL may serve as a potential biomarker for prognosis and therapeutic target for schistosomiasis-induced hepatic fibrosis.

Synthesis, Anti-proliferation, Apoptosis Induction in Breast Cancer Cells, and Aromatase Inhibition of Coumarin-Triazole Hybrids: In Vitro and In Silico Studies

Synthesis, Anti-proliferation, Apoptosis Induction in Breast Cancer Cells, and Aromatase Inhibition of Coumarin-Triazole Hybrids: In Vitro and In Silico Studies

Plant-derived natural compounds for the treatment of acute lung injury: A systematic review of their anti-inflammatory effects in animal models.

Acute lung injury (ALI) is a complex pulmonary disease characterized by a severe inflammatory response. The management of ALI presents a formidable challenge due to the intricate nature of its inflammatory cascade. Numerous studies have highlighted the potential therapeutic benefits of plant-derived natural compounds (PNCs) in treating inflammatory diseases. Our study aims to provide robust current evidence regarding the anti-inflammatory effects and underlying molecular mechanisms of PNCs for ALI treatment. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol was registered in PROSPERO (CRD42024468401). A comprehensive search was conducted in electronic databases including PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal database (VIP), Wanfang database, and China biomedical literature service system (SinoMed) up until November 2023. Preclinical studies published in both English and Chinese were included. Our research encompassed 81 studies, comprising a total of 71 PNCs, including flavonoids, phenylpropanoids, terpenoids, polyphenols, alkaloids, saponins, glycosides, and miscellaneous compounds. This systematic review demonstrated that PNCs played a beneficial role on ALI by regulating the immune response and reducing the release of inflammatory mediators and cytokines. The molecular mechanisms were partially associated with the regulation of Th17/Treg responses, promotion of the polarization of M1-type macrophages to M2-type macrophages, induction of immune cell apoptosis, reversal of microbial dysbiosis in the lungs and the gut, epigenetic modification, and the modulation of inflammatory pathways, including NF-κB, MAPK, TLR4/MyD88, NLRP3/Caspase-1, TGF-β/Smad, Nrf2/HO-1, Rho/ROCK, TLR7/MyD88, and PI3K/AKT, thereby alleviating inflammatory responses and lung damage. The therapeutic effects of PNCs on ALI are mediated through the modulation of immunity and inflammatory pathways. In light of their potential, PNCs represent a promising pharmacological intervention for the treatment of ALI.