Induction of IFIT1/IFIT3 and inhibition of Bcl-2 orchestrate the treatment of myeloma and leukemia via pyroptosis.

Induction of pyroptosis is proposed as a promising strategy for the treatment of hematological malignancies, but little is known. In the present study, we find clioquinol (CLQ), an anti-parasitic drug, induces striking myeloma and leukemia cell pyroptosis on a drug screen. RNA sequencing reveals that the interferon-inducible genes IFIT1 and IFIT3 are markedly upregulated and are essential for CLQ-induced GSDME activation and cell pyroptosis. Specifically, IFIT1 and IFIT3 form a complex with BAX and N-GSDME therefore directing N-GSDME translocalization to mitochondria and increasing mitochondrial membrane permeabilization and triggering pyroptosis. Furthermore, venetoclax, an activator of BAX and an inhibitor of Bcl-2, displays strikingly synergistic effects with CLQ against leukemia and myeloma via pyroptosis. This study thus reveals a novel mechanism for mitochondrial GSDME in pyroptosis and it also illustrates that induction of IFIT1/T3 and inhibition of Bcl-2 orchestrate the treatment of leukemia and myeloma via pyroptosis.

Bruceine B Displays Potent Antimyeloma Activity by Inducing the Degradation of the Transcription Factor c-Maf.

The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), a not-yet-curable malignancy of plasma cells. In the present study, we establish a c-Maf-based luciferase screen system and apply it to screen a homemade library composed of natural products from which bruceine B (BB) is identified to display potent antimyeloma activity. BB is a key ingredient isolated from the Chinese traditional medicinal plant Brucea javanica (L.) Merr. (Simaroubaceae). BB inhibits MM cell proliferation and induces MM cell apoptosis in a caspase-3-dependent manner. The mechanism studies showed that BB inhibits c-Maf transcriptional activity and downregulates the expression of CCND2 and ITGB7, the downstream genes typically modulated by c-Maf. Moreover, BB induces c-Maf degradation via proteasomes by inducing c-Maf for K48-linked polyubiquitination in association with downregulated Otub1 and USP5, two proven deubiquitinases of c-Maf. We also found that c-Maf activates STAT3 and BB suppresses the STAT3 signaling. In the in vivo study, BB displays potent antimyeloma activity and almost suppresses the growth of myeloma xenografts in 7 days but shows no overt toxicity to mice. In conclusion, this study identifies BB as a novel inhibitor of c-Maf by promoting its degradation via the ubiquitin-proteasomal pathway. Given the safety and the successful clinical application of bruceine products in traditional medicine, BB is ensured for further investigation for the treatment of patients with MM.

Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway.

Proteasomes are overexpressed in multiple myeloma (MM) and proteasomal inhibitors (PIs) have been widely used for the treatment of MM. PIs are reported to induce MM cell apoptosis but impair necroptosis. In the present study, we found that PIs MG132 and bortezomib induce MM cell pyroptosis, a novel type of cell death, in a GSDME-dependent manner. Lack of GSDME totally blocks PI-induced pyroptosis. Interestingly, we found that Caspase-3/6/7/9 are all involved in pyroptosis triggered by PIs because the specific inhibitor of each caspase ablates GSDME activation. PIs markedly reduce mitochondrial membrane potential. Moreover, PIs disrupt the interaction of Bcl-2 and BAX, induce cytochrome c release from mitochondria to cytosol and activate GSDME. Furthermore, we found that overexpression of an N-terminal portion of GSDME suffices to release cytochrome c from mitochondria and to activate Caspase-3/9, suggesting N-GSDME might penetrate the mitochondrial membrane. Consistent with Bcl-2 inhibition, BAX can induce MM cell pyroptosis in a GSDME-dependent manner. In accordance with these findings, inhibition of Bcl-2 synergizes with PIs to induce MM cell pyroptosis. Therefore, the present study indicates that PIs trigger MM cell pyroptosis via the mitochondrial BAX/GSDME pathway and provides a rationale for combined treatment of MM with Bcl-2 and proteasome inhibitors to increase therapeutic efficiency via induction of pyroptosis.

Research on Vibration Control Technology of Robot Motion Based on Magnetorheological Elastomer.

The vibration and impact of a humanoid bipedal robot during movements such as walking, running and jumping may cause potential damage to the robot's mechanical joints and electrical systems. In this paper, a composite bidirectional vibration isolator based on magnetorheological elastomer (MRE) is designed for the cushioning and damping of a humanoid bipedal robot under foot contact forces. In addition, the vibration isolation performance of the vibration isolator was tested experimentally, and then, a vibration isolator dynamics model was developed. For the bipedal robot foot impact, based on the vibration isolator model, three vibration reduction control algorithms are simulated, and the results show that the vibration damping effect can reach 85%. Finally, the MRE vibration isolator hardware-in-the-loop-simulation experiment platform based on dSPACE has been built to verify the vibration reduction control effect of the fuzzy PID algorithm. The result shows the vibration amplitude attenuates significantly, and this verifies the effectiveness of the fuzzy PID damping control algorithm.

Targeting the oncogenic transcription factor c-Maf for the treatment of multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy derived from clonal expansion of plasma cells within the bone marrow and it may progress to the extramedullary region in late stage of the disease course. c-Maf, an oncogenic zipper leucine transcription factor, is overexpressed in more than 50% MM cell lines and primary species in association with chromosomal translocation, aberrant signaling transduction and modulation of stability. By triggering the transcription of critical genes including CCND2, ITGB7, CCR1, ARK5, c-Maf promotes MM progress, proliferation, survival and chemoresistance. Notably, c-Maf is usually expressed at the embryonic stage to promote cell differentiation but less expressed in healthy adult cells. c-Maf has long been proposed as a promising therapeutic target of MM and a panel of small molecule compounds have been identified to downregulate c-Maf and display potent anti-myeloma activities. In the current article, we take a concise summary on the advances in c-Maf biology, pathophysiology, and targeted drug discovery in the potential treatment of MM.

Identification of SCRG1 as a Potential Therapeutic Target for Human Synovial Inflammation.

Synovial inflammation of joint tissue is the most important cause of tissue damage, joint destruction, and disability and is associated with higher morbidity or mortality. Therefore, this study aims to identify key genes in osteoarthritis synovitis tissue to increase our understanding of the underlying mechanisms of osteoarthritis and identify new therapeutic targets. Five GEO datasets with a total of 41 normal synovial membrane tissues and 45 osteoarthritis synovial membrane samples were used for analysis, and seven common differential genes were identified. The classification model constructed by LASSO analysis showed that six genes including CDKN1A, FOSB, STMN2, SLC2A3, TAC, and SCRG1 can be used as biomarkers of osteoarthritis, and the SCRG1 gene shows importance in osteoarthritis. Furthermore, drug database enrichment found that these six DEGs may be the drug targets of synovitis in osteoarthritis, and Valproic Acid CTD 00006977 may be a potential targeted therapeutic drug of SCRG1. Spearman correlation analysis was performed on the SCRG1 gene, and 27 genes with consistent expression were obtained. Functional analysis showed that 27 genes were mainly involved in metabolism, complement, antigen presentation, apoptosis, and regulation of immune pathways. The co-regulatory network of TFs-miRNA suggested that the SCRG1 gene may be regulated by hsa-miR-363-3p miRNA. In conclusion, SCRG1, as a diagnostic marker of osteoarthritis, co-regulates immune-related pathways through the interaction of related proteins, playing an important role in the occurrence and development of osteoarthritis, which may be a novel drug target.

miR-877-3p promotes TGF-ß1-induced osteoblast differentiation of MC3T3-E1 cells by targeting Smad7.

MicroRNAs (miRNAs) are emerging as important regulators of various physiological and pathological processes and may serve key roles in the maintenance of bone homeostasis via effects on osteoblast differentiation. The aim of the present study was to define the role of miR-877-3p in osteoblast differentiation using MC3T3-E1 cells, an osteoblast precursor cell line. It was demonstrated using RT-qPCR analysis that miR-877-3p was gradually increased in MC3T3-E1 cells during the osteoblastic differentiation induced by transforming growth factor (TGF)-ß1. Gain-of-function and loss-of-function experiments revealed that the overexpression of miR-877-3p promoted the osteoblastic differentiation of MC3T3-E1 cells, whereas depletion of miR-877-3p inhibited this process in vitro and in vivo. Bioinformatics analysis and validation experiments demonstrated that Smad7, which acts as a negative regulator of osteogenesis, was a target of miR-877-3p. Furthermore, the overexpression of Smad7 partially reversed the osteoblastic differentiation of MC3T3-E1 cells induced by miR-877-3p. In conclusion, the results of the present study suggest that the miR-877-3p/Smad7 axis is associated with the osteoblastic differentiation of MC3T3-E1 cells and may indicate a potential therapeutic approach for osteogenesis disorders.

MicroRNA­223 promotes osteoblast differentiation of MC3T3­E1 cells by targeting histone deacetylase 2.

MicroRNAs (miRNAs) have emerged as pivotal regulators in various physiological and pathological processes at the post­transcriptional level, and may serve important roles in osteogenic differentiation. However, their roles and functions are not fully understood. In the present study, miR­223­5p was identified as a modulator of osteoblastic differentiation in MC3T3­E1 cells. Reverse transcription­quantitative polymerase chain reaction and western blotting demonstrated that miR­223­5p was significantly upregulated in MC3T3­E1 cells following the induction of osteoblast differentiation. Overexpression of miR­223­5p promoted osteogenic differentiation both in vitro and vivo. Expression of histone deacetylase 2 (HDAC2), which acts as a negative regulator of osteogenesis, was regulated by miR­223­5p. Collectively, the results of the present study revealed a novel miR­223­5p/HDAC2 axis that regulates osteoblast differentiation, and may serve as a potential target for enhancing bone formation in vivo.

Anti-inflammatory effect of Mongolian drug Naru-3 on traumatic spinal cord injury and its mechanism of action.

Objective This study was performed to confirm the anti-inflammatory effect of the Mongolian drug Naru-3 on traumatic spinal cord injury (TSCI) and its possible mechanism of action. Methods We prepared a TSCI model using Sprague-Dawley rats. The rats were divided into a Naru-3 group and a methylprednisolone group. Real-time polymerase chain reaction and western blotting were performed to measure the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß. Enzyme-linked immunosorbent assay kits were employed to detect serum inflammatory cytokine levels. The localization and expression of monocyte chemotactic protein-1 (MCP-1) in spinal cord tissue was determined by immunohistochemical analysis. Flow cytometry was performed to analyze the ratio of M1- and M2-phenotype macrophages. The locomotor function recovery was evaluated by the Basso, Beattie, and Bresnahan score. Results Naru-3 significantly inhibited the inflammatory response and reduced the expression of TNF-α, IL-6, and IL-1ß in both spinal cord and blood in a time- and concentration-dependent manner. Immunohistochemical analysis indicated that Naru-3 significantly reduced MCP-1 expression in spinal cord and promoted M2-phenotype macrophage differentiation. Conclusions Naru-3 is an effective treatment for impact-induced TSCI in rats. Naru-3 treatment affects inflammatory cytokine levels and macrophage differentiation, which play a role in TSCI remission.