Search Results (10,066)

Diabetes-related ulcers and slow-healing wounds pose a significant health risk to individuals due to their uncertain causes. Mortality rates for diabetes foot ulcers (DFUs) range from 10% after 16 months to 24% after five years. The use of bioactive phytochemicals can play a key role in healing wounds in a predictable time. Recent literature has demonstrated that various natural substances, including flavonoids, saponins, phenolic compounds, and polysaccharides, play key roles at different stages of the wound-healing process through diverse mechanisms. These studies have categorized the compounds according to their characteristics, bioactivities, and modes of action. In this study, we evaluated the role of natural compounds derived from plant sources that have been shown to play a crucial role in immunomodulation. Macrophages are closely involved in immunomodulation within the wound microenvironment and are key players in efferocytosis, inflammation resolution, and tissue regeneration, all of which contribute to successful wound healing. Phytochemicals and their derivatives have shown capabilities in immune regulation, including macrophage migration, nitric oxide synthase inhibition, lymphocyte and T-cell stimulation, cytokine activation, natural killer cell enhancement, and the regulation of NF-κβ, TNF-α, and apoptosis. In this review, we have studied the role of phytochemicals in immunomodulation for the resolution of diabetic wound inflammation. Full article

Mdmx (Mdm4) is established as an oncogene mainly through repression of the p53 tumour suppressor. On the other hand, anti-oncogenic functions for Mdmx have also been proposed, but the underlying regulatory pathways remain unknown. Investigations into the effect of inhibitors for the NEDD8 pathway in p53 activation, human cell morphology, and in cell motility during gastrulation in Xenopus embryos revealed an anti-invasive function of Mdmx. Through stabilisation and activation of the RhoA GTPase, Mdmx is required for the anti-invasive effects of NEDDylation inhibitors. Mechanistically, through its Zn finger domain, Mdmx preferentially interacts with the inactive GDP-form of RhoA. This protects RhoA from degradation and allows for RhoA targeting to the plasma membrane for its subsequent activation. The effect is transient, as prolonged NEDDylation inhibition targets Mdmx for degradation, which subsequently leads to RhoA destabilisation. Surprisingly, Mdmx degradation requires non-NEDDylated (inactive) Culin4A and the Mdm2 E3-ligase. This study reveals that Mdmx can control cell invasion through RhoA stabilisation/activation, which is potentially linked to the reported anti-oncogenic functions of Mdmx. As inhibitors of the NEDD8 pathway are in clinical trials, the status of Mdmx may be a critical determinant for the anti-tumour effects of these inhibitors. Full article

Most patients with metastatic prostate cancer eventually develop resistance to primary androgen deprivation therapy. To identify predictive biomarker for Abiraterone acetate/prednisone resistance, we screened alternative splice variants between responders and non-responders from the PROMOTE clinical study and pinned down the most significant variant, CENPK–delta8. Through preclinical patient-derived mouse xenograft (PDX) and 3D organoids obtained from responders and non-responders, as well as in vitro models, aberrant CENPK–delta8 expression was determined to link to drug resistance via enhanced migration and proliferation. The FLNA and FLOT1 were observed to specifically bind to CENK–delta8 rather than wild-type CENPK, underscoring the role of CENPK–delta8 in cytoskeleton organization and cell migration. Our study, leveraging data from the PROMOTE study, TCGA, and TCGA SpliceReq databases, highlights the important function of alternative splice variants in drug response and their potential to be prognostic biomarkers for improving individual therapeutic outcomes in precision medicine. Full article

Bufotalin (BT), a major active constituent of Chansu, has been found to possess multiple pharmacological activities. Although previous studies have shown that BT could inhibit the growth of glioblastoma (GBM), the safety of BT in vivo and the potential mechanism are still unclear. We conducted a systematic assessment to investigate the impact of BT on GBM cell viability, migration, invasion, and colony formation. Furthermore, in vivo results were obtained to evaluate the effect of BT on tumor growth. The preliminary findings of our study demonstrate the effective inhibition of GBM cell growth and subcutaneous tumor development in mice by BT, with tolerable levels of tolerance observed. Mechanistically, BT treatment induced mitochondrial dysfunction, bursts of reactive oxygen species (ROS), and subsequent cell apoptosis. More importantly, proteomic-based differentially expressed proteins analysis revealed a significant downregulation of integrin β4 (ITGB4) following BT treatment. Furthermore, our evidence suggested that the ITGB4/focal adhesion kinase (FAK)/extracellular signal-related kinase (ERK) pathway involved BT-induced apoptosis. Overall, our study demonstrates the anti-GBM effects of BT and elucidates the underlying mechanism, highlighting BT as a potential therapeutic option for GBM. Full article

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising chemotherapeutic agent because of its selective apoptotic action on cancer cells. However, resistance to TRAIL-induced apoptosis remains a challenge in many cancers. The gintonin-enriched Panax ginseng extract fraction (GEF) has diverse pharmacological benefits. We explored the combined efficacy of GEF and TRAIL in inducing apoptosis in human renal cell carcinoma (RCC) cells. The effect of GEF treatment on the viability, clonogenic potential, wound healing, and TRAIL-induced apoptotic signaling of RCC cells was studied in vitro. Our investigation revealed that GEF pre-treatment sensitized RCC cells to TRAIL-induced apoptosis, as evidenced by DNA fragmentation and cell proliferation, colony formation, and migration inhibition. This sensitization was linked to the upregulation of death receptors 4 and 5 and alterations in apoptotic protein expression, notably, the decreased expression of the Mu-2-related death-inducing gene, a novel anti-apoptotic protein. Our findings underscore the necessity of caspase activation for GEF/TRAIL-induced apoptosis using the pan-caspase inhibitor Z-VAD-FMK. This study demonstrates that GEF sensitizes human RCC cells to TRAIL-induced apoptosis by upregulating DR4/5 and modulating apoptotic protein expression. These findings suggest a promising strategy for overcoming TRAIL resistance in cancer therapy and highlight the potential of GEF as a valuable adjunct to TRAIL-based treatments. Full article

Early detection and surgical excision of tumors have helped improve the survival rate of patients with breast cancer. However, patients with metastatic cancer typically have a poor prognosis. In this study, we propose that ANKRD1 promotes metastasis of breast cancer. ANKRD1 was found to be highly expressed in the MDA-MB-231 and MDA-LM-2 highly metastatic breast cancer cell lines compared to the non-metastatic breast cancer cell lines (MCF-7, ZR-75-30, T47D) and normal breast cancer cells (MCF-10A). Furthermore, high-grade tumors showed increased levels of ANKRD1 compared to low-grade tumors. Both in vitro and in vivo functional studies demonstrated the essential role of ANKRD1 in cancer cell migration and invasion. The previous studies have suggested a significant role of NF-κB and MAGE-A6 in breast cancer metastasis, but the upstream regulators of this axis are not well characterized. Our study suggests that ANKRD1 promotes metastasis of breast cancer by activating NF-κB as well as MAGE-A6 signaling. Our findings show that ANKRD1 is a potential therapeutic target and a diagnostic marker for breast cancer metastasis. Full article

Background/Objectives: Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes. Methods: Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays. Results: Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells. Conclusions: GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia. Full article

Idiosyncratic drug-induced liver injury (iDILI) by flucloxacillin presents as both cholestatic and hepatocellular injury. Its mechanistic steps are explored in the present analysis as limited data exist on the cascade of events leading to iDILI in patients with an established diagnosis assessed for causality by the Roussel Uclaf Causality Assessment Method (RUCAM). Studies with human liver microsomes showed that flucloxacillin is a substrate of cytochrome P450 (CYP) with ist preferred isoforms CYP 3A4/3A7 that toxified flucloxacillin toward 5′-hydroxymethylflucloxacillin, which was cytotoxic to human biliary epithelial cell cultures, simulating human cholestatic injury. This provided evidence for a restricted role of the metabolic CYP-dependent hypothesis. In contrast, 5′-hydroxymethylflucloxacillin generated metabolically via CYP 3A4/3A7 was not cytotoxic to human hepatocytes due to missing genetic host features and a lack of non-parenchymal cells, including immune cells, which commonly surround the hepatocytes in the intact liver in abundance. This indicated a mechanistic gap regarding the clinical hepatocellular iDILI, now closed by additional studies and clinical evidence based on HLA B*57:01-positive patients with iDILI by flucloxacillin and a verified diagnosis by the RUCAM. Naïve T-cells from volunteers expressing HLA B*57:01 activated by flucloxacillin when the drug antigen was presented by dendritic cells provided the immunological basis for hepatocellular iDILI caused by flucloxacillin. HLA B*57:01-restricted activation of drug-specific T-cells caused covalent binding of flucloxacillin to albumin acting as a hapten. Following drug stimulation, T-cell clones expressing CCR4 and CCR9 migrated toward CCL17 and CCL25 and secreted interferon-γ and cytokines. In conclusion, cholestatic injury can be explained metabolically, while hepatocellular injury requires both metabolic and immune activation. Full article

Human-induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) represent a promising and renewable cell source for therapeutic applications. A systematic evaluation of the immunological properties and engraftment potential of iMSCs generated from urine-derived iPSCs is lacking, which has impeded their broader application. In this study, we differentiated urine-derived iPSCs into iMSCs and assessed their fundamental MSC characteristics, immunogenicity, immunomodulatory capacity and in vivo engraftment. Compared to umbilical cord-derived MSCs (UCMSCs), iMSCs demonstrated an enhanced proliferative capacity, a higher level of regenerative gene expression, and lower immunogenicity, strengthening resistance to apoptosis induced by allogeneic peripheral blood mononuclear cells (PBMCs) and the NK-92 cell line. In addition, iMSCs exhibited a diminished ability to inhibit T cell proliferation and activation compared with UCMSCs. Transcriptomic analyses further revealed the decreased expression of immune regulatory factors in iMSCs. After transfusion into mouse models, iMSCs engrafted in the lungs, liver, and spleen and exhibited the ability to migrate to tumor tissues. Our results indicated that iMSCs generated from urine-derived iPSCs have a significant replicative capacity, low immunogenicity and unique immunomodulatory properties, and hence offer obvious advantages in immune privilege and allogenic therapeutic application prospects. Full article

Background: This study aimed to analyze the immunostimulatory activity of gamisoyosan (GSS) on the activation of macrophages in RAW 264.7 cells and its underlying mechanisms. Methods: The effects of GSS on the secretion of nitric oxide (NO), immunomodulatory mediators, cytokines and mRNAs, and related proteins were assessed using the Griess assay, Western blotting, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and H₂DCFDA, respectively. The level of phagocytosis was determined by the neutral red method while the immune function of GSS was determined using adhesion and wound-healing assays. Results: GSS-treated macrophages significantly increased the production of NO, immunomodulatory enzymes, cytokines, and intracellular reactive oxygen species without causing cytotoxicity. GSS effectively improved macrophage immune function by increasing their phagocytic level, adhesion function, and migration activity. Mechanistic studies via Western blotting revealed that GSS notably induced the activation of the Toll-like receptor (TLR) 4-mediated mitogen-activated protein kinase, nuclear factor-κB, and protein kinase B signaling pathways. Conclusions: Overall, our results indicated that GSS could activate macrophages through the secretion of immune-mediated transporters via TLR4-dependent signaling pathways. Thus, GSS has potential value as an immunity-enhancing agent. Full article

Background: Oral squamous cell carcinoma (OSCC) is an aggressive cancer with limited treatment options. Parishin A, a natural compound derived from Gastrodia elata, possesses multiple therapeutic properties. However, its effects on OSCC remain unexplored. Purpose: This study explores the anti-cancer potential of Parishin A on OSCC and its mechanisms. Methods: OSCC cell lines YD-10B and Ca9-22 were treated with varying Parishin A concentrations. Cell viability was detected using the CCK-8 assay, and colony formation was evaluated in agarose gel. Migration and invasion ability were assessed through wound healing and Matrigel invasion assays. The protein expression levels involved in the PI3K/AKT/mTOR signaling pathway and epithelial–mesenchymal transition (EMT) markers were examined via Western blotting. Results: Parishin A inhibited OSCC cell viability in both dose- and time-dependent manners, with significant reductions at 20, 40, 60, and 80 μM, without affecting normal human gingival fibroblasts. Colony formation decreased substantially at ≥40 μM higher Parishin A concentrations in a dose-dependent manner. Also, migration and invasion assays showed significant suppression by Parishin A treatment concentration ≥40 μM in a dose-dependent manner, as evidenced by decreased wound closure and invasion. Western blot analyses revealed increased E-cadherin levels and decreased N-cadherin and vimentin levels, suggesting EMT inhibition. Parishin A also decreased the phosphorylation levels of PI3K, AKT, and mTOR. Conclusion: Collectively, these findings support the potential of Parishin A as an anti-OSCC agent. Full article

Background: Glioblastoma multiforme (GBM) is among the most aggressive and challenging brain tumors, with limited treatment options. Cimicifuga foetida, a traditional Chinese medicine, has shown promise due to its bioactive components. This study investigates the anti-glioma effects of a methanolic extract of C. foetida (CF-ME) in GBM cell lines. Methods: The effects of CF-ME and its index compounds (caffeic acid, cimifugin, ferulic acid, and isoferulic acid) on GBM cell viability were assessed using MTT assays on U87 MG, A172, and T98G cell lines. The ability of CF-ME to induce cell cycle arrest, apoptosis, and autophagy and inhibit metastasis was evaluated using flow cytometry, Western blotting, and functional assays. Additionally, the synergistic potential of CF-ME with temozolomide (TMZ) was explored. Results: CF-ME significantly reduced GBM cell viability in a dose- and time-dependent manner, induced G1 phase cell cycle arrest, promoted apoptosis via caspase activation, and triggered autophagy. CF-ME also inhibited GBM cell invasion, migration, and adhesion, likely by modulating epithelial–mesenchymal transition (EMT) markers. Combined with TMZ, CF-ME further enhanced reduced GBM cell viability, suggesting a potential synergistic effect. However, the individual index compounds of CF-ME exhibited only modest inhibitory effects, indicating that the full anti-glioma activity may result from the synergistic interactions among its components. Conclusions: CF-ME exhibited potent anti-glioma activity through multiple mechanisms, including cell cycle arrest, apoptosis, autophagy, and the inhibition of metastasis. Combining CF-ME with TMZ further enhanced its therapeutic potential, making it a promising candidate for adjuvant therapy in glioblastoma treatment. Full article

Albumin-coated gold nanoparticles display potential biomedical applications, including cancer research, infection treatment, and wound healing; however, elucidating their interaction with normal cells remains an area with limited exploration. In this study, gold nanorods (GNR) were prepared and coated with bovine serum albumin (BSA) to produce GNR-BSA. The functionalized nanoparticles were characterized based on their optical absorption spectra, morphology, surface charge, and quantity of attached protein. The interaction between GNR-BSA and BSA with normal cells was investigated using human dermal fibroblasts. The cytotoxicity test indicated cell viability between ~63–95% for GNR-BSA over concentrations from 30.0 to 0.47 μg/mL and ~85–98% for BSA over concentrations from 4.0 to 0.0625 mg/mL. The impact of the GNR-BSA and BSA on cell migration potential and wound healing was assessed using scratch assay, and the modulation of cytokine release was explored by quantifying a panel of cytokines using Multiplex technology. The results indicated that GNR-BSA, at 10 μg/mL, delayed the cell migration and wound healing 24 h post-treatment compared to the BSA or the control group with an average wound closure percentage of 6% and 16% at 6 and 24 h post-treatment, respectively. Multiplex analysis revealed that while GNR-BSA reduced the release of the pro-inflammatory marker IL-12 from the activated fibroblasts 24 h post-treatment, they significantly reduced the release of IL-8 (p < 0.001), and CCL2 (p < 0.01), which are crucial for the inflammation response, cell adhesion, proliferation, migration, and angiogenesis. Although GNR-BSA exhibited relatively high cell viability towards human dermal fibroblasts and promising therapeutic applications, toxicity aspects related to cell motility and migration must be considered. Full article

Background/Objectives: Alterations in the actin cytoskeleton correlates to tumor progression and affect critical cellular processes such as adhesion, migration and invasion. Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), important regulators of the actin cytoskeleton, are frequently overexpressed in various malignancies. The aim of this study was therefore to identify the key structural features of ROCK1/ROCK2 inhibitors using computer-aided drug design (CADD) approaches. In addition, new developed ROCK inhibitors provided a significant framework for the development of multitarget therapeutics—ROCK/HDAC (histone deacetylases) multitarget inhibitors. Methods: 3D-QSAR (Quantitative structure-activity relationship study) and molecular docking study were employed in order to identify key structural features that positively correlate with ROCK inhibition. MDA-MB-231, HCC1937, Panc-1 and Mia PaCa-2 cells were used for evaluation of anticancer properties of synthesized compounds. Results: C-19 showed potent anti-cancer properties, especially enhancement of apoptosis and cell cycle modulation in pancreatic cancer cell lines. In addition, C-19 and C-22 showed potent anti-migratory and anti-invasive effects comparable to the well-known ROCK inhibitor fasudil. Conclusions: In light of the results of this study, we propose a novel multi-target approach focusing on developing dual HDAC/ROCK inhibitors based on the structure of both C-19 and C-22, exploiting the synergistic potential of these two signaling pathways to improve therapeutic efficacy in metastatic tumors. Our results emphasize the potential of multi-target ROCK inhibitors as a basis for future cancer therapies. Full article

Background: Colorectal cancer is one of the leading and most lethal neoplasms. Standard chemotherapy is ineffective, especially in metastatic cancer, and does not target cancer stem cells. A promising approach to improve cancer treatment is the combination therapy of standard cytostatic drugs with natural compounds. Several plant-derived compounds have been proven to possess anticancer properties, including the induction of apoptosis and inhibition of cancer invasion. This study was focused on investigating in vitro the combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic (LOVO) and stem-like (LOVO/DX) colon cancer cells. Methods: The genotoxic effects that drive cancer cells into death-inducing pathways and the ability to inhibit the migratory properties of cancer cells were evaluated. The γH2AX+ assay and Fast-Halo Assay (FHA) were used to evaluate genotoxic effects, the annexin-V apoptosis assay to rate the level of apoptosis, and the scratch test to assess antimigratory capacity. Results: The results showed that both combinations CPT-CEL and CPT-RSV improve general genotoxicity of CPT alone on metastatic cells and CSCs. However, the assessment of specific double-stranded breaks (DSBs) indicated a better efficacy of the CPT-CEL combination on LOVO cells and CPT-RSV in LOVO/DX cells. Interestingly, the combinations CPT-CEL and CPT-RSV did not improve the pro-apoptotic effect of CPT alone, with both LOVO and LOVO/DX cells suggesting activation of different cell death mechanisms. Furthermore, it was found that the combinations of CPT-CEL and CPT-RSV improve the inhibitory effect of camptothecin on cell migration. Conclusions: These findings suggest the potential utility of combining camptothecin with celastrol or resveratrol in the treatment of colon cancer, including more aggressive forms of the disease. So far, no studies evaluating the effects of combinations of these compounds have been published in the available medical databases. Full article