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Abstract: Ganoderic acid DM (GADM) is a triterpenoid isolated from Ganoderma lucidum, a well-known edible medicinal mushroom. In the present study, we found that GADM effectively inhibited cell proliferation and colony formation in MCF-7 human breast cancer cells, which was much stronger than that of MDA-MB-231 breast cancer cells. GADM both concentration- and time-dependently mediated G1 cell cycle arrest and significantly decreased the protein level of CDK2, CDK6, cycle D1, p-Rb and c-Myc in MCF-7 cells. Moreover, GADM obviously induced DNA fragmentation and cleavage of PARP which are the characteristics of apoptosis and decreased the mitochondrial membrane potential in MCF-7 cells. Besides, we also showed that GADM elicited DNA damage as measured by comet assay which is a sensitive method for DNA damage detection. γ-H2AX, a marker of DNA damage, was also slightly up-regulated after treated with GADM for 6h, suggesting that the G1 cell cycle arrest and apoptosis induced by GADM may be partially resulted from GADM-induced DNA damage. These results have advanced our current understandings of the anti-cancer mechanisms of GADM. [Copyright &y& Elsevier]

Abstract: Although inhibition of cyclooxygenase-2 (COX-2) or activation of peroxisome proliferators-activated receptor γ (PPAR-γ) leads to growth inhibition in malignancies, the synergistic anti-tumor effects of combination of COX-2 inhibitor (NS-398) and PPAR-γ agonist (rosiglitazone) on the human pancreatic cancer cells remains unknown. Here, we evaluated the effects of NS-398 and/or rosiglitazone on the cell proliferation and apoptosis in a pancreatic cancer cell line, SW1990. NS-398 and rosiglitazone decreased cell proliferation in a dose- and time-dependent manner. Proliferating cell nuclear antigen (PCNA) labeling index significantly decreased in the cells treated with either NS-398 or rosiglitazone. Both NS-398 and rosiglitazone alone induced apoptotic cell death of SW1990. The combination of NS-398 and rosiglitazone exerted synergistic effects on proliferation inhibition, and apoptosis induction in SW1990 cells, with down-regulation of Bcl-2 and up-regulation of Bax expression. Our results indicate that simultaneous targeting of COX-2 and PPAR-γ inhibits pancreatic cancer development more effectively than targeting each molecule alone. [Copyright &y& Elsevier]

Since the side effects and chemo-resistance of docetaxel (DTX) limit its anticancer performance in treating castration-resistant prostate cancer (CRPC), many studies have attempted to identify novel combination treatment to meet clinical needs. Platycodin D (PD), a natural component from Platycodon grandiflorus(Jacq.) A.DC. appears to inhibit proliferation in many cancers. This study investigated the effect of combining PD and DTX in DU-145 cells and explored its underlying mechanism. Anti-proliferation activity was detected by MTT assay. The combination index (CI) was calculated to elucidate the synergistic effect of PD and DTX. DAPI and Annexin V-FITC/PI staining were used to observe the apoptosis. To monitor autophagy flux, Ad-mCherry-GFP-LC3 was conducted. Flow cytometry was employed to investigate the production of reactive oxygen species (ROS) and the expression levels of proteins were analyzed by western blot. Results showed that PD and DTX combination treatment synergistically inhibited cell growth. Annexin-V/PI staining demonstrated that combination treatment enhanced apoptosis, accompanied with the upregulation of cleaved PARP, cleaved caspase-3/9 and Bax/Bcl-2 ratio. Additionally, PD and DTX together inhibited autophagy with the downregulation of related proteins compared with PD group. Flow cytometry indicated that the combination group promoted ROS production, increased the expression of p-P38 (Thr180/Tyr182), decreased the expression of p-EGFR and suppressed its downstream Akt/mTOR and ERK pathways. Briefly, PD combined with DTX showed significant synergism on DU-145 cells with enhanced apoptosis and alleviated autophagy, suggesting that PD could decrease the dosage and side effects of DTX and optimize its clinical use for prostate cancer. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) is one of the most common health problems in people's lives, which brings a massive burden to clinicians, and the leading cause of LBP is intervertebral disc degeneration (IDD). IDD is mainly caused by factors such as aging, mechanical stress, and lack of nutrition. The pathological mechanism of IDD is very complex, involving inflammatory response, cell metabolism disorder, and so on. Unfortunately, in the current treatment of IDD, only relieving symptoms as the primary means of relieving a patient's pain cannot effectively inhibit or reverse the progression of IDD. Tumor necrosis factor-α (TNF-α) is a multifunctional pro-inflammatory factor involved in many diseases' pathological processes. With the in-depth study of the pathological mechanism of IDD, more and more evidence has shown that TNF-α is an essential activator of IDD, which is related to the metabolic disorder, inflammatory responses, apoptosis, and other pathological processes of extracellular dissociation in the intervertebral disc. Therefore, anti-TNF-α therapy is an effective therapeutic target for alleviating IDD, especially in inhibiting extracellular matrix degradation and reducing inflammatory responses. This article reviews the pathological role of TNF-α in IDD and the latest research progress of TNF-α inhibitors in treating IDD. • Summary of TNF-α and pathological mechanisms of Intervertebral Disc Degeneration and new research. • Discuss the relationship between TNF-α in intervertebral disc degeneration, NP cell apoptosis, pyroptosis and autophagy. • The figures in the article should give scholars who are new to this field a direct understanding of the mechanism. • It may be helpful to treat intervertebral disc degeneration with TNF-α inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Gastrin and cyclooxygenase-2 (COX-2) play important roles in the carcinogenesis and progression of gastric cancer. However, it remains unknown whether the combination of cholecystokinin-2 (CCK-2) receptor antagonist plus COX-2 inhibitor exerts synergistic anti-tumor effects on human gastric cancer. Here, we demonstrated that the combination of AG-041R (a CCK-2 receptor antagonist) plus NS-398 (a selective COX-2 inhibitor) treatment had synergistic effects on proliferation inhibition, apoptosis induction, down-regulation of Bcl-2 and up-regulation of Bax expression in MKN-45 cells. These results indicate that simultaneous targeting of CCK-2 receptor and COX-2 may inhibit gastric cancer development more effectively than targeting either molecule alone. [Copyright &y& Elsevier]

The Jian-Yan-Ling (JYL) capsule is a famous anti-aging Chinese patent medicine. It is applied mainly to delay senescence to improve cognition in aging individuals. However, the action mechanisms of JYL for improving cognition have not been determined. We will evaluate the effect of the JYL capsule at improving the cognition of aging mice by improving oxidative stress in the hippocampus and exploring its action mechanism. A senescence mouse model was developed via intraperitoneal injection of D-galactose. The effect of the JYL capsule at improving the learning and memory abilities of mice was evaluated using the Morris water maze and novel object recognition tests. The apotosis of model mice hippocampus' were determined by TUNEL analysis. The antioxidant capacity of the JYL capsule was evaluated by determining the activities of antioxidant enzymes and expressions of oxidative products. The regulation of the Nrf2/HO-1 signaling pathway of the JYL capsule was evaluated by determining the expressions of related proteins via western blotting analysis. In vitro , H 2 O 2 -treated mouse hippocampal HT22 cells were used to evaluate the antioxidant capacity of JYL-containing rat serum by determining the cell viability, apoptotic level and expressions of related proteins. JYL capsules enhanced the learning and memory abilities of model mice according to behavioral tests. The results of TUNEL analysis showed that the JYL capsule ameliorated hippocampal apoptosis in model mice. JYL capsules also exerted significant antioxidant capacity by increasing the activities of antioxidant enzymes while decreasing the levels of oxidative products both in the hippocampus and serum. The regulation of Nrf2/HO-1 pathway might contribute to the antioxidant function. In vitro , JYL-containing rat serum protected HT22 cells from H 2 O 2 induced oxidative stress. The apoptosis of HT22 cells was also attenuated by regulating the caspase and Nrf2/HO-1 signaling pathways. The amelioration of neuronal oxidative stress of hippocampus might contribute to the D-galactose-induced cognition impairment of senescence mice. These findings provide evidence for the application of JYL capsules to enhance cognition in aging individuals. [Display omitted] [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP) and disability in the elderly, imposing significant public health and economic burden worldwide. Meanwhile, the pathological mechanisms of IDD remain complicated, and treatment strategy to reverse IDD is primarily due to the unclear specific mechanisms of IDD and the lack of particular effective targets. Interleukin-1β (IL-1β), one of the most important members of the IL-1 family, can induce solid pro-inflammatory activity by stimulating the secretion of various pro-inflammatory mediators and is considered the key to IDD mediator. However, in recent years, IL-1β is considered to be able to regulate IVD cell death in many ways, such as apoptosis, pyroptosis, ferroptosis, and so on. At the same time, numerous studies on IL-1β inhibitors suggest that inhibition of IL-1β may be a promising biological therapy for IDD. Many IL-1β inhibitors have been investigated through various pathogenic biological mechanisms, including inhibiting inflammatory processes, regulating ECM degradation, and more. Therefore, anti-IL-1β therapy may have the effect of alleviating disc degeneration. This article mainly reviews the mechanisms and functions of IL-1β in IDD and investigates advances in IL-1β inhibition as a promising biotherapeutic approach for disc degeneration. • The current article reviews the mechanisms and functions of IL-1β in IDD and investigates advances in IL-1β inhibition as a promising biotherapeutic approach for disc degeneration. We demonstrate function of IL-1β from different aspects, such as inflammatory responses, ECM metabolism, cell senescence, cell apoptosis, pyroptosis, and ferroptosis, oxidative stress, angiogenesis and neoinnervation in IDD. It is suitable for the audience of Experimental Gerontology, as IDD is a condition affecting the elderly. • This article could provide a valuable resource for researchers and clinicians seeking to better understand the role of IL-1β in IDD and explore potential therapeutic targets. • We provide a comprehensive review of the involvement of IL-1β in intervertebral disc degeneration (IVDD) and its potential as a therapeutic target. However, the article would benefit from a more detailed discussion on the differences between animal models and human in vivo experiments, as well as the potential limitations and challenges in translating these findings to human subjects. • We have presented several studies that show the promising effects of IL-1β inhibition in vitro and in animal models. However, the safety, reliability, and effectiveness of such treatments in humans remain uncertain. The article would benefit from a discussion of the challenges in conducting clinical trials for these treatments and the need for more extensive clinical studies in the future. • While we acknowledge the difficulty of studying intervertebral disc (IVD) tissue homeostasis, the review would benefit from a more in-depth exploration of the inflammatory process during IDD and its implications for the development of IL-1β-centered therapies. This may include a discussion of the role of inflammation in maintaining homeostasis and the potential risks of completely suppressing IL-1β-induced inflammation. • The article discusses the potential for IL-1β-centered therapy to restore homeostasis in the intervertebral disc. However, it would be beneficial for researchers and clinicians to provide more information on the current state of research in this area, including any promising drug candidates or novel approaches to treatment. [ABSTRACT FROM AUTHOR]

• The development of new therapeutic drug for SS treatment is urgent medical need. • Apoptosis, cycle arrest, intracellular ROS, mitochondria and autophagy were detected to identify effect of DATS on SS. • High-throughput RNA-sequencing analysis was performed to clarify a comprehensive molecular portrait for DATS-induced transcriptional regulation. • Go and KEGG analysis were performed to reveal the related molecular events induced by DATS pharmacological properties. • PPI network was conducted to identify hub genes and protein feature. Synovial sarcoma (SS) is a malignant soft tissue sarcoma and its natural history is a long, indolent clinical course followed by high rate of local recurrence and distant metastasis. Current therapies are still limited in increasing satisfactory of 5-year survival, especially for patients with recurrence and metastasis. Accordingly, finding new therapeutic drug for SS treatment is clinically urgent need. Diallyl trisulfide (DATS), a bioactive compound derived from garlic, is reported as a promising anti-cancer agent for various carcinomas. However, its effect on anti-SS remains unknown. This study investigated the anti-SS effect of DATS in human synovial sarcoma SW982 cells. CCK-8 assay were used to examine the cell viability. High-content Imaging System was used to examine the apoptosis, intracellular ROS and autophagy. Flow cytometry was used to detect cell cycle. qPCR and Western blot were used to examine the expression of related mRNA and protein. High-throughput RNA-sequencing and bio-information analysis were used to investigate the mRNA profiling. The results showed a suppressive effect of DATS on tumor biology of SW982 cells including inducing apoptosis, triggering G2/M cell cycle arrest, elevating intracellular ROS and damaging mitochondria. Further high-throughput RNA-sequencing analysis clarified a comprehensive molecular portrait for DATS-induced transcriptional regulation. Besides, protein–protein interaction (PPI) analysis demonstrated that a network consisted of FOXM1, CCNA2, CCNB1, MYBL2, PLK1 and CDK1 might be response for DATS-induced G2/M cell cycle arrest and increased intracellular ROS. Notably, protein feature analysis revealed structure enrichment in microtubule network like kinesin motors domain, and tubulin domain. Molecular function analysis suggested that DATS-induced dysfunction of microtubule network might be the major cause for its effect on cell cycle arrest and successive apoptosis. Furthermore, 28 hub genes (including KIF2C, PLK1, CDK1, BIRC5, CCNB2, CENPF, TPX2, TOP2A and so on) were determined. Finally, pathway analysis showed that DATS-induced differentially expressed genes were mainly involved in cell cycle. Collectively, our findings for the first time provided the DATS-induced cellular response and transcriptional profiling of SW982 cells, which proposes that suppression of DATS on SS is multi-targeted and represent a therapeutic evidence for SS. [ABSTRACT FROM AUTHOR]

Highlights: [•] We reported IC-4 as a novel irreversible TKI for EGFR. [•] IC-4 inhibited proliferation, induced apoptosis and a G2/M arrest in breast cancer cells. [•] IC-4 exhibited anti-angiogenesis effects in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Abstract: The co-inhibitory molecule B7-H1 has been broadly detectable on human inflammatory renal tubular epithelial cells (TECs) and is proposed to limit tubular damage through down-regulation of tubulointerstitial infiltration T cell activation. Nevertheless, factors that initiate B7-H1 expression on TECs remain unclarified. The terminal complement complex C5b-9, which deposits diffusely on tubules and glomerules of diseased kidneys, is now recognized as a mediator that triggers cellular activation rather than inducing cell death. Whether the up-regulation of B7-H1 on tubules is also induced by C5b-9 is uncertain. Here, after assembling functional sublytic C5b-9 on the membranes of TECs based on purified complement components, we found that B7-H1 gene transcription and protein synthesis was enhanced by C5b-9. Promoter constructs in a luciferase assay, site-directed mutagenesis and laser scanning confocal microscopy assay (LSCM) revealed that the transcription factor NF-κB is primarily responsible for C5b-9-mediated B7-H1 expression. To further detect the physiologic function of B7-H1, triggering B7-H1 with its agonist mAb (clone 5H1) profoundly enhanced Fas expression on C5b-9-treated TECs and thus induced TEC apoptosis. Interestingly, pretreatment of TECs with Fas blocking antibodies prevented this effect. Our results propose that C5b-9 regulates tubular pathogenesis in glomerulonephritis or other renal autoimmune diseases, possibly through enhances cell apoptosis mediated by B7-H1 signals, in addition to it directly promotes tubular damage. [Copyright &y& Elsevier]