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Background: Anlotinib, a highly selective inhibitor of VEGFR2, has demonstrated significant anti-tumor effects in various cancers. However, its potential synergistic effects with DDP (cisplatin) in breast cancer (BRCA) remain to be fully elucidated. This study aims to discover the therapeutic efficacy of anlotinib on BRCA, specifically the synergistic effects with DDP, and to elucidate the underlying molecular mechanisms. Methods: BRCA cells were treated with anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, cell cycle distribution, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by flow cytometry technique and Hoechst33342 fluorescence staining. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR, immunofuorescence and western blot. The anti-breast cancer efficacy of anlotinib was evaluated in vivo using a xenograft tumor model. Results: Our findings reveal that increased VEGFA expression in BRCA patients is associated with poorer prognosis, underscoring the need for targeted therapeutic strategies. We also demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion, while their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident through the induction of apoptosis and autophagy in BRCA cells. Mechanistically, anlotinib's effectiveness is linked to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. In vivo study further support these results, showing that anlotinib markedly inhibits tumor growth in xenografted mice. Conclusion: This study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib's effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) significantly impacts the quality of life due to its prolonged duration and lack of effective treatment. Recent findings suggest that targeting neuroinflammation is a promising approach for treating NP. G protein‐coupled receptor 55 (GPR55), a member of the GPCR family, plays an important role in neuroinflammatory regulation. CID16020046, a GPR55 agonist, possesses promising anti‐neuroinflammatory effects. Herein, the therapeutic effect of CID16020046 on NP was investigated in an NP rat model. The NP model was established using the unilateral sciatic nerve chronic constriction injury (CCI) assay. Both sham and CCI rats were intraperitoneally administered with 20 mg/kg CID16020046. NP was assessed using paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). First, we showed that GPR55 was downregulated in the spinal dorsal horn of CCI rats. After CCI rats were treated with CID16020046, the values of PWT and PWL were increased, indicating their effect on pain relief. The treated rats had attenuated release of inflammatory cytokines in the spinal cord, decreased spinal malondialdehyde (MDA) levels, and increased spinal glutathione peroxidase (GSH‐PX) activity. Additionally, the increased levels of phosphorylated nuclear factor (NF)‐κB p65 in CCI rats were significantly alleviated by CID16020046 treatment. Mechanistically, we showed that CID16020046 significantly suppressed the activation of the Janus kinase (JAK2)/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the spinal cord of CCI‐treated rats. However, Colivelin TFA (a STAT3 agonist) abolished the effect of CID16020046 on JAK2/STAT3 activation. In conclusion, our data demonstrate that the activation of GPR55 by CID16020046 alleviates NP and neuroinflammation in CCI rats by mediating the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Recent studies showed that patients with iron overload had increased risk of insulin resistance or diabetes. Ferroptosis is a new type of cell death mainly caused by iron-dependent oxidative damage. In the present study, we investigated potential mechanisms of iron overload induced hepatic ferroptosis and insulin resistance through in vivo and in vitro experiments. In vivo, the mice models of iron overload were established by intraperitoneal injection of iron dextran. The changes of body weight, serum ferritin and blood glucose were measured. Hematoxylin-eosin (HE) and Perl's stainings were used to observe the pathological changes and iron deposition in the liver of mice. In vitro, HepG2 cells were treated with ferric ammonium citrate (FAC, 9 mmol/L, 24 h) to establish the cell models of iron overload. The labile iron pool, cell viability, glucose consumption and glycogen contents were measured. The ultrastructure of mitochondria was observed by transmission electron microscope (TEM). The malondialdehyde (MDA) and glutathione (GSH) kits were used to detect lipid peroxidation in liver tissues of mice and HepG2 cells. RT-PCR and Western blot were used to detect the mRNA and protein expression levels of ferroptosis factors and JAK2/STAT3 signaling pathway. In this study, we used the iron chelator deferasirox in mice and HepG2 cells. Iron overload caused weight loss, elevated serum ferritin, fasting blood glucose, fasting insulin, HOMA-IR, impaired glucose tolerance, and decreased insulin sensitivity in mice. HE staining and Perls staining showed clumps of iron deposition in the liver of iron overload mice. Iron overload could reduce the glucose consumption, increase MDA contents of HepG2 cells, while reduce glycogen and GSH contents in liver tissues of mice and HepG2 cells. TEM showed deletion of mitochondrial ridge and rupture of outer membrane in HepG2 cells with iron overload. Iron chelator deferasirox could significantly improve the above indicators, which might be related to the activation of JAK2/STAT3/SLC7A11 signaling pathway and hepatic ferroptosis. Iron overload could induce hepatic ferroptosis and insulin resistance by inhibiting the JAK2/STAT3/SLC7A11 signaling pathway, and the iron chelator deferasirox might improve hepatic insulin resistance induced by iron overload. [ABSTRACT FROM AUTHOR]

BACKGROUND In the hypothalamic paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHRs), the expression of the testis-specific protein, Y-encoded-like 2 (TSPYL2) and the phosphorylation level of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) are higher comparing with the normotensive Wistar Kyoto rats (WKY). But how they are involved in hypertension remains unclear. TSPYL2 may interact with JAK2/STAT3 in PVN to sustain high blood pressure during hypertension. METHODS Knockdown of TSPYL2 via adeno-associated virus (AAV) carrying shRNA was conducted through bilateral microinjection into the PVN of SHR and WKY rats. JAK2/STAT3 inhibition was achieved by intraperitoneally or PVN injection of AG490 into the SHRs. Blood pressure (BP), plasma norepinephrine (NE), PVN inflammatory response, and PVN oxidative stress were measured. RESULTS TSPYL2 knock-down in the PVN of SHRs but not WKYs led to reduced BP and plasma NE, deactivation of JAK2/STAT3, decreased expression of pro-inflammatory cytokine IL-1β, and increased expression of anti-inflammatory cytokine IL-10 in the PVN. Meanwhile, AG490 administrated in both ways reduced the BP in the SHRs and deactivated JAK2/STAT3 but failed to change the expression of TSPYL2 in PVN. AG490 also downregulated expression of IL-1β and upregulated expression of IL-10. Both knockdown of TSPYL2 and inhibition of JAK2/STAT3 can reduce the oxidative stress in the PVN of SHRs. CONCLUSION JAK2/STAT3 is regulated by TSPYL2 in the PVN of SHRs, and PVN TSPYL2/JAK2/STAT3 is essential for maintaining high BP in hypertensive rats, making it a potential therapeutic target for hypertension. [ABSTRACT FROM AUTHOR]

This study explored the effect of Eupatilin on postmenopausal osteoporosis and explored the mechanisms associated with miR-211-5p. First, the rats were given intragastric administration of Eupatilin every day and subcutaneously injected once a week with oligonucleotides or plasmids that interfered with the expression of miR-211-5p or Janus kinase 2 (JAK2). After 4 weeks, a rat model of osteoporosis was established. Then, serum alkaline phosphatase, calcium and phosphorus levels were detected, as well as femur bone mineral density and biomechanical parameters. HE staining and Masson staining were applied for detecting the pathological condition of femur while immunohistochemical staining was for detecting the positive expression of osteocalcin. In addition, MC3T3-E1 cells were transfected with plasmid vectors interfering with miR-211-5p or JAK2, and cell viability, lactate dehydrogenase cytotoxicity, and cell mineralization were subsequently examined. The relationship between miR-211-5p and JAK2/Signal transducer and activator of transcription 3 (STAT3) pathway was analyzed, and the targeting of miR-211-5p and JAK2 was also verified. The experimental results found that Eupatilin improved the pathological conditions of osteoporotic rats by promoting the proliferation and mineralization of osteoblasts. miR-211-5p was down-regulated and JAK2/STAT3 were up-regulated in osteoporotic rats. Upregulation of miR-211-5p further improved the pathological conditions of osteoporotic rats based on Eupatilin treatment. MiR-211-5p inhibited the JAK2/STAT3 pathway. Upregulation of JAK2 reversed the effects of elevated miR-211-5p on osteoporotic rats. Overall, Eupatilin attenuates postmenopausal osteoporosis through elevating miR-211-5p and repressing JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men, respectively, worldwide. Although the antitumor activity of chalcones has been extensively studied, the molecular mechanisms of isoliquiritigenin analog 2', 4', 4-trihydroxychalcone (metochalcone; TEC) against carcinomas remain less well understood. In this study, we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner. TEC induced cell cycle arrest in the S-phase, cell migration inhibition in vitro, and reduced tumor growth in vivo. Moreover, transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways. TEC triggered the senescence-associated secretory phenotype (SASP) by repressing the JAK2/STAT3 axis. The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway, highlighting the potential of chalcone in senescence-inducing therapy against carcinomas. [ABSTRACT FROM AUTHOR]

Abstract Background Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC. Methods We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments. Results BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO2. Additionally, BIC inhibited SiO2-mediated secretion of the inflammatory cytokines IL-1β, IL-6, TNF-α, and TGF-β1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-β1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process. Conclusion The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-β1, and consequently inhibits FMT and EMT via TGF-β1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent.

Rosa sterilis (RS) is a characteristic fruit in southwestern China that has numerous health benefits; however, its pharmacological effect needs further clarification, especially with respect to the exploration of its potential anti-breast-cancer effect, as there are still knowledge gaps in this regard. This study was designed to investigate the protective effects of Rosa sterilis juice (RSJ) on breast cancer (BC) through in vitro cellular experiments and by establishing mouse 4T1 breast xenograft tumors. This study also had the aim of elucidating RSJ's underlying mechanisms. RSJ can inhibit cell proliferation, affect cell morphology, and impact the clone formation ability of BC; furthermore, it can promote apoptosis by triggering the mitochondrial apoptosis pathway. In mouse 4T1 breast xenograft tumors, RSJ markedly inhibited tumor growth, relieved the pathological lesions, lowered the expression of Ki67, and regulated the expression of the apoptosis-associated protein. Moreover, we observed that RSJ can inhibit the Jak2/Stat3 signaling pathway both in vivo and in vitro. Overall, our research reveals that RSJ can alleviate BC by triggering the mitochondrial apoptosis pathway and suppressing the Jak2/Stat3 pathway, providing new dietary intervention strategies for BC. [ABSTRACT FROM AUTHOR]

• AG490 ameliorated EAE severity and attenuated its typical symptoms. • The neuroprotective effect of AG490 is related to the regulation of JAK2/STAT3 pathway and autophagy. • AG490 may be a potential therapeutic in multiple sclerosis. Multiple sclerosis (MS) is an autoimmune inflammatory condition affecting the central nervous system, and experimental autoimmune encephalomyelitis (EAE) animal models have been extensively used to study it. T-helper 17 cells, which produce interleukin-17(IL-17), play crucial roles in MS pathogenesis, and the JAK2/STAT3 pathway has an essential function in their differentiation from naive CD4 + T cells. This study investigated the effects of the JAK2/STAT3 pathway inhibitor AG490 on EAE in vivo and in vitro , as well as the underlying mechanisms. AG490 ameliorated EAE severity and attenuated its typical symptoms by downregulating proteins associated with the JAK2/STAT3 pathway. Furthermore, it decreased T-helper 17 cell differentiation from naive CD4 + T cells by inactivating STAT3. In addition, it conferred protective effects against EAE by restoring autophagy. These findings indicate the potential of AG490 as a candidate anti-MS therapeutic. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between the therapeutic effect of Fu Yuan Sheng Bai Fang (FYSBF) on acute myeloid leukemia (AML) and the JAK/STAT signaling pathway and its mechanism. Methods: AML HL-60 cells were divided into control group, FYSBF group, IL-6 group (IL-6 is the activator of JAK/STAT signaling pathway) and FYSBF+IL-6 group. HL-60 cells in control group were cultured in normal RPMI 1640 medium, HL-60 cells in FYSBF group were cultured in medium which was added with a final concentration of 200 μg/m L FYSBF, and HL-60 cells in IL-6 group were cultured in medium which was added with a final concentration of 100 ng/mL IL-6. HL-60 cells in FYSBF+IL-6 group were cultured in medium which were added with final concentration of 200 μg/m L FYSBF and 100 ng/mL IL-6. The cell proliferation was detected by CCK-8 assay and clonal formation assay, cell cycle distribution and apoptosis were detected by flow cytometry, cell invasion and migration were detected by Transwell assay, and protein expression levels were analyzed by Western blot assay. Results: Compared with the control group, the relative vitality, number of clones, number of migration and invasion cells and proportion of S-phase cells in FYSBF group were decreased (P＜0.05), and the protein expressions of CDK2, cyclin E, N-cadherin and Vimentin were decreased (P＜0.05), the phosphorylation levels of JAK2 and STAT3proteins were decreased (P＜0.05), the cells proportion of G0/G1 phase and apoptosis rate were increased (P＜0.05), and the protein expression of p21 and E-cadherin were increased (P＜0.05) . Compared with the control group, the relative vitality, number of clones, number of migration and invasion cells and proportion of S-phase cells in IL-6 group were increased (P＜0.05), and the protein expressions of CDK2, cyclin E, N-cadherin and Vimentin were increased (P＜0.05), the phosphorylation levels of JAK2 and STAT3proteins were increased (P＜0.05), the cells proportion of G0/G1 phase and apoptosis rate were decreased (P＜0.05), and the protein expression of p21 and E-cadherin were decreased (P＜0.05) . Compared with the IL-6 group, the relative vitality, number of clones, number of migration and invasion cells and proportion of S-phase cells in FYSBF+IL-6 group were decreased (P＜0.05), and the protein expressions of CDK2, cyclin E, N-cadherin and Vimentin were decreased (P＜0.05), the phosphorylation levels of JAK2 and STAT3proteins were decreased (P＜0.05), the cells proportion of G0/G1 phase and apoptosis rate were increased (P＜0.05), and the protein expression of p21 and E-cadherin were increased (P＜0.05) . Conclusion: FYSBF can inhibit the proliferation, migration, invasion and epithelial-mesenchymal transformation of acute myeloid leukemia cells, and promote cell apoptosis and cell cycle arrest, which may be related to inhibiting the activation of JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

The spleen has an essential role in immune responses regulation and is considered the biggest peripheral immune organ. Citicoline is used for various brain disorders management. This study aimed to examine the using possibility of citicoline to treat γ-radiation-induced splenic inflammation in rats. Eighteen male albino rats were classified into: Group 1 (control) animals were kept as control. Group 2 (γ-radiation) animals were total-body γ-irradiated with 6 Gy. Group 3 (γ-radiation + citicoline) rats were γ-irradiated with 6 Gy, then injected intraperitoneally with citicoline (300 mg/kg/d) 5 min after irradiation for one week. Levels of TNF-α, IL-1β, iNOS, NF-κB, JAK2, and STAT3 were determined in spleen tissue, along with histopathological examination. Rats exposure to gamma-radiation led to elevation in splenic TNF-α, IL-1β, NF-κB, iNOS, JAK2, and STAT3 levels significantly. Treatment with citicoline after gamma-radiation exposure improved this elevation, and modulated gamma-radiation-induced histopathological alterations. This data showed that citicoline inhibited γ-radiation-induced splenic inflammation via suppressing NF-κB and JAK2/STAT3 signaling pathways in spleen tissue. [ABSTRACT FROM AUTHOR]

Skin cutaneous melanoma (SKCM) is the skin malignancy with the highest mortality rate, and its morbidity rate is on the rise worldwide. Smoking is an independent marker of poor prognosis in melanoma. The α5-nicotinic acetylcholine receptor (α5-nAChR), one of the receptors for nicotine, is involved in the proliferation, migration and invasion of SKCM cells. Nicotine has been reported to promote the expression of a disintegrin and metalloproteinase 10 (ADAM10), which is the key gene involved in melanoma progression. Here, we explored the link between α5-nAChR and ADAM10 in nicotine-associated cutaneous melanoma. α5-nAChR expression was correlated with ADAM10 expression and lower survival in SKCM. α5-nAChR mediated nicotine-induced ADAM10 expression via STAT3. The α5-nAChR/ADAM10 signaling axis was involved in the stemness and migration of SKCM cells. Furthermore, α5-nAChR expression was associated with ADAM10 expression, EMT marker expression and stemness marker expression in nicotine-related mice homograft tissues. These results suggest the role of the α5-nAChR/ADAM10 signaling pathway in nicotine-induced melanoma progression. [ABSTRACT FROM AUTHOR]

Radiation resistance is a crucial factor influencing therapeutic outcomes in colorectal cancer (CRC). Baicalein (BE), primarily derived from Scutellaria baicalensis, has demonstrated anti‐CRC properties. However, the impact of BE on the radiosensitivity of CRC remains unclear. This study aimed to evaluate the radiosensitization effects of BE and elucidate its mechanism in CRC radiotherapy. We established an in vitro radioresistant cell model (CT26‐R) using parental CRC cells (CT26) subjected to ionizing radiation (IR). CT26‐R cells were pretreated with or without BE, followed by transfection with pcDNA‐NC and pcDNA‐JAK2. The proliferation of CT26‐R cells treated with BE and IR was assessed using a colony formation assay. A CRC animal model was developed in BALB/c mice via CT26‐R cell transplantation. The radiosensitizing effect of BE on CRC was evaluated in vivo. TUNEL assay was conducted to detect apoptosis in tumor tissue. The expression levels of p‐STAT3, JAK2, PD‐L1, and SOCS3 in vitro and in vivo were measured by western blotting. Our results demonstrated that BE significantly increased radiosensitivity in vitro and in vivo and enhanced apoptosis in tumor tissues. Additionally, BE significantly downregulated the expression of p‐STAT3, JAK2, and PD‐L1, and significantly upregulated SOCS3 expression. These in vivo effects were reversed by pcDNA‐JAK2. In summary, our data suggest that BE enhances CRC radiosensitivity by inhibiting the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the potential therapeutic applications of (+)-catechin in the treatment of neuropathic pain. In vivo study, 32 SD rats were randomly divided into four groups: sham group, chronic constriction injury (CCI) group, CCI + ibuprofen group and CCI+ (+)-catechin group. They were subjected to behavioural tests, ELISA, immunohistochemistry and Western blotting. The mechanisms involved were investigated using specific inhibitors in cell experiments. Results of in vivo experiments showed that (+)-catechin could reduce the cold sensitivity pain in a rat model of CCI; ELISA and immunohistochemistry results showed that (+)-catechin could decrease the levels of IL-8, IL-6, TNF-α, CCL2 and CCL5 in serum and the expression levels of nNOS, COX2, IL6, TNF-α, IBA-1 and CSF1R in DRG of CCI rats. Finally, western blot confirmed that (+)-catechin could diminish the levels of IL-34/CSF1R/JAK2/STAT3 signalling pathway in DRG of CCI rats. In vitro studies showed that (+)-catechin reduced IL-34 secretion in LPS-induced RSC96 cells. Meanwhile, (+)-catechin administration in LPS-induced Schwann cell–conditioned medium (L-CM) significantly inhibited the proliferation and migration of RAW264.7 cells; in addition, L-CM+(+)-catechin reduced the activation of the CSF1R/JAK2/STAT3 signalling pathway. (+)-Catechin attenuated the Schwann cell-macrophage cascade response in the DRG by modulating the IL34/CSFIR axis and inhibiting activation of the JAK2/STAT3 pathway, thereby attenuating CCI-induced neuropathic pain in rats. [ABSTRACT FROM AUTHOR]

Background: Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC. Methods: We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments. Results: BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO2. Additionally, BIC inhibited SiO2-mediated secretion of the inflammatory cytokines IL-1β, IL-6, TNF-α, and TGF-β1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-β1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process. Conclusion: The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-β1, and consequently inhibits FMT and EMT via TGF-β1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent. [ABSTRACT FROM AUTHOR]

Erythroleukemia, a subtype of acute myeloid leukemia (AML), is a life-threatening malignancy that affects the blood and bone marrow. Despite the availability of clinical treatments, the complex pathogenesis of the disease and the severe side effects of chemotherapy continue to impede therapeutic progress in leukemia. In this study, we investigated the antitumor activity of L76, an acylphloroglucinol compound derived from Callistemon salignus DC., against erythroleukemia, along with its underlying mechanisms. MTT assays were performed to evaluate the inhibitory effects of L76 on cancer cell viability, while flow cytometry was used to analyze apoptosis and cell cycle arrest in HEL cells. The molecular mechanisms of L76 were further explored using Western blotting, microscopic analysis, and cellular thermal shift assays (CETSA). Our in vitro experiments demonstrated that L76 inhibits proliferation, induces G1/S cell cycle arrest, and promotes apoptosis in human leukemia cells. Mechanistically, L76 exerts its effects by targeting STAT3 and p38-MAPK, and by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, this study highlights the potential of L76 as an anti-erythroleukemia agent, demonstrating its ability to target STAT3 and p38-MAPK, and to inhibit the PI3K/AKT/mTOR signaling pathway. These findings suggest that L76 could be a promising candidate for the treatment of erythroleukemia.

BackgroundAnlotinib, a highly selective inhibitor of VEGFR2, has demonstrated significant anti-tumor effects in various cancers. However, its potential synergistic effects with DDP (cisplatin) in breast cancer (BRCA) remain to be fully elucidated. This study aims to discover the therapeutic efficacy of anlotinib on BRCA, specifically the synergistic effects with DDP, and to elucidate the underlying molecular mechanisms.MethodsBRCA cells were treated with anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, cell cycle distribution, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by flow cytometry technique and Hoechst33342 fluorescence staining. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR, immunofuorescence and western blot. The anti-breast cancer efficacy of anlotinib was evaluated in vivo using a xenograft tumor model.ResultsOur findings reveal that increased VEGFA expression in BRCA patients is associated with poorer prognosis, underscoring the need for targeted therapeutic strategies. We also demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion, while their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident through the induction of apoptosis and autophagy in BRCA cells. Mechanistically, anlotinib’s effectiveness is linked to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. In vivo study further support these results, showing that anlotinib markedly inhibits tumor growth in xenografted mice.ConclusionThis study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib’s effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway.

Accumulating evidence suggests that M2-polarized tumor-associated macrophages (TAMs) play a crucial role in cancer progression, making them a promising target for therapy. This study explored the molecular mechanisms by which Platycodon grandiflorum regulates M2 polarization of TAMs to exert anti-tumor effects. UPLC-MS identified the chemical composition and blood-absorbed components. Immunohistochemistry and Western blot detected TAM infiltration and proliferation pathways, while q-RT-PCR measured M2 macrophage marker expression. Our findings showed that PR reduces melanoma weight, inhibits the mTOR pathway, and suppresses M2-polarized macrophages. PR downregulates JAK2 and p-STAT3, promotes JAK2 degradation, and enhances ubiquitination. Molecular docking indicated strong affinities between Platycodin D components and JAK2/STAT3, highlighting PR’s potential in regulating TAMs and offering new clinical insights.

Abstract Increased production of reactive oxygen species (ROS) leads to oxidative stress, with its damaging effect extending to the mitochondria and plasma membrane. Further, prolonged inflammation can result in chronic disease development. The marine microdiatom Odontella aurita is recognized for its potential in food and pharmaceutical development. Moreover, it contains antioxidant and anti-inflammatory properties. However, studies regarding the efficacy of their varying extract forms and their underlying mechanisms remain scarce. Therefore, this study aims to explore the antioxidant and anti-inflammatory effects of Odontella aurita extracts obtained using various extraction methods (hot water, 70% ethanol, and chloroform:methanol (CM)). Among the three Odontella aurita extracts, the CM extract demonstrated superior efficacy in protecting RAW 264.7 cells from H2O2-induced cytotoxicity. It significantly lowered the levels of ROS and enhanced the expression of superoxide dismutase and glutathione peroxidase. Furthermore, the CM extract outperformed other extracts in inhibiting LPS-induced nitric oxide production, reducing mRNA levels in nitric oxide synthase, cyclooxygenase, and the proinflammatory cytokines interleukin IL-1β, IL-6, TNFα. Additionally, CM extract effectively suppressed the activation of NF-κB/IκBα and JAK2-STAT3 in LPS-induced RAW 264.7 cells. HPLC–UV analysis revealed a remarkable 33-fold higher fucoxanthin content in CM compared to the ethanol extract. GC–MS analysis identified elevated levels of cholest-5-en-3-ol, phytol, eicosapentaenoic acid methyl ester, methyl palmitate, palmitoleic acid methyl ester, and neophytadiene in the CM extract. These findings suggest that Odontella aurita CM extract is a promising antioxidant candidate for preventing or treating inflammatory diseases, consequently emphasizing its potential for further development. Graphical Abstract

Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti‐inflammatory activities and our study aimed to identify its effect on TNBS‐induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS‐induced colitis, which may provide novel strategies for CD treatment. [ABSTRACT FROM AUTHOR]

Introduction: Although LncRNA JPX has been linked to a number of malignancies, it is yet unknown how it relates to endometrial carcinoma (EC). Investigating the expression, functional activities, and underlying molecular processes of lncRNA JPX in EC was the goal of this work. Methods: RT-qPCR was used to examine the differences in lncRNA/microRNA (miRNA, miR)/mRNA expression between normal cervical and EC tissues or cells. Cell Counting Kit-8, flow cytometry, and transwell were used to evaluate the association between lncRNA JPX/miR-140-3p/phosphoinositide-3-kinase catalytic subunit α (PIK3CA) in Ishikawa and JEC cell lines. The impact of JPX on the downstream janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway was investigated using Western blot analysis. Results: When comparing EC tissues to nearby normal tissues, JPX expression is markedly increased in EC tissues, with greater expression in advanced-stage EC. Furthermore, compared to normal epithelial cells, EC cell lines have higher levels of JPX expression. In Ishikawa and JEC endometrial cancer cell lines, we used siRNA-mediated suppression of JPX to find lower cell viability, increased apoptosis, cell cycle arrest, and reduced migration and invasion. We next verified that miR-140-3p binds to downstream target cells to impede the transcription and translation of PIK3CA, which in turn prevents the growth of Ishikawa and JEC cells. JPX functions as a ceRNA to adsorb miR-140-3p. This procedure required controlling JAK2/STAT3, a downstream signal. Conclusion: JPX enhances the development of Ishikawa and JEC cells and activates downstream JAK2/STAT3 signal transduction via the miR-140-3p/PIK3CA axis, offering a possible therapeutic target for the treatment of EC. [ABSTRACT FROM AUTHOR]

Increased production of reactive oxygen species (ROS) leads to oxidative stress, with its damaging effect extending to the mitochondria and plasma membrane. Further, prolonged inflammation can result in chronic disease development. The marine microdiatom Odontella aurita is recognized for its potential in food and pharmaceutical development. Moreover, it contains antioxidant and anti-inflammatory properties. However, studies regarding the efficacy of their varying extract forms and their underlying mechanisms remain scarce. Therefore, this study aims to explore the antioxidant and anti-inflammatory effects of Odontella aurita extracts obtained using various extraction methods (hot water, 70% ethanol, and chloroform:methanol (CM)). Among the three Odontella aurita extracts, the CM extract demonstrated superior efficacy in protecting RAW 264.7 cells from H2O2-induced cytotoxicity. It significantly lowered the levels of ROS and enhanced the expression of superoxide dismutase and glutathione peroxidase. Furthermore, the CM extract outperformed other extracts in inhibiting LPS-induced nitric oxide production, reducing mRNA levels in nitric oxide synthase, cyclooxygenase, and the proinflammatory cytokines interleukin IL-1β, IL-6, TNFα. Additionally, CM extract effectively suppressed the activation of NF-κB/IκBα and JAK2-STAT3 in LPS-induced RAW 264.7 cells. HPLC–UV analysis revealed a remarkable 33-fold higher fucoxanthin content in CM compared to the ethanol extract. GC–MS analysis identified elevated levels of cholest-5-en-3-ol, phytol, eicosapentaenoic acid methyl ester, methyl palmitate, palmitoleic acid methyl ester, and neophytadiene in the CM extract. These findings suggest that Odontella aurita CM extract is a promising antioxidant candidate for preventing or treating inflammatory diseases, consequently emphasizing its potential for further development. [ABSTRACT FROM AUTHOR]

Cryptotanshinone (CPT), which is an important active ingredient of herbs, has shown great value for research. In particular, CPT exerts antitumor effects on various types of cancer; however, there are relatively few studies of CPT on gastric cancer cells. The objectives of this study were to investigate how CPT affects apoptosis in 5-fluorouracil-resistant SGC-7901 gastric cancer cells (SGC-7901/5-FU cells) and the molecular mechanism underlying its action. In this study, SGC-7901/5-FU cells were treated with 5-fluorouracil (5-FU) and CPT and the viability of the cells was assessed by CCK8 assay. Additionally, cellular apoptosis rates were evaluated using immunofluorescence and flow cytometry. Related gene expression was evaluated using Quantitative Real-time PCR methods and Western Blot, respectively. CPT inhibited SGC-7901/5-FU cell growth. The immunofluorescence results showed that CPT caused nuclear shrinkage in the cells. Quantitative Real-time PCR and Western Blot results also showed CPT decreased the expression of Mcl-1, Bcl-xl and Bcl-2 levels, and increased the expression of Bax. We demonstrated that CPT can inhibit the growth of SGC-7901/5-FU cells, and the mechanism may be related to the inhibition of the JAK2/STAT3 pathway. Additionally, CPT increased the inhibitory effect of 5-fluorouracil on SGC-7901/5-FU cells, an effect that correlated with changes in cellular resistance. [ABSTRACT FROM AUTHOR]

The role of KIAA0040 role in glioma development is not yet understood despite its connection to nervous system diseases. In this study, KIAA0040 expression levels were evaluated using qRT‐PCR, WB and IHC, and functional assays were conducted to assess its impact on glioma progression, along with animal experiments. Moreover, WB was used to examine the impact of KIAA0040 on the JAK2/STAT3 signalling pathway. Our study found that KIAA0040 was increased in glioma and linked to tumour grade and poor clinical outcomes, serving as an independent prognostic factor. Functional assays showed that KIAA0040 enhances glioma growth, migration and invasion by activating the JAK2/STAT3 pathway. Of course, KIAA0040 enhances glioma growth by preventing tumour cell death and promoting cell cycle advancement. Our findings suggest that targeting KIAA0040 could be an effective treatment for glioma due to its role in promoting aggressive tumour behaviour and poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Keloid represents a benign skin tumor with many cancer‐like features. Extracellular vesicles (EVs) derived from human adipose‐derived stem cells (hADSCs) play a role in cell migration of multiple diseases. Aims: This study aimed to investigate the impact of hADSC‐EVs on human keloid fibroblasts (HKFs). Methods: hADSCs were cultured to the 3rd generation, and subsequently assessed for their osteogenic, adipogenic, and chondrogenic differentiative abilities using flow cytometry, alizarin red, oil red O, and alcian blue staining techniques. hADSC‐EVs were isolated through ultracentrifugation and subsequently identified. HKFs at the 3rd generation were subjected to treatment with hADSC‐EVs to observe their endocytosis of EVs by immunofluorescence. CCK‐8, wound healing, and Transwell assays were performed to test HKF proliferation and migration. The levels of autophagy proteins, collagens, and Janus kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) were determined through Western blot analysis. Suppressor of cytokine signaling 1 (SOCS1) expression was determined by RT‐qPCR and Western blot. Results: hADSC‐EVs were successfully isolated from hADSCs. PKH67‐labeled hADSC‐EVs were observed to be endocytosed by HKFs, resulting the inhibition of HKF proliferation, migration, as well as a reduction in collagen deposition. hADSC‐EVs carried SOCS1 into HKFs to suppress HKF autophagy. SOCS1 downregulation in hADSC‐EVs partially nullified the inhibitory effect of hADSC‐EVs on HKFs. hADSC‐EV‐carried SOCS1 inhibited the activation of the JAK2/STAT3 pathway. JAK2/STAT3 pathway activation partially abrogated the suppression of hADSC‐EVs on the proliferation, migration, and collagen deposition of HKF. Conclusion: hADSC‐EVs carried SOCS1 into HKFs and suppressed HKF autophagy, proliferation, migration, and collagen deposition by inactivating the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Postmenopausal osteoporosis (PMOP) poses a significant threat to women's health worldwide. Eupatilin is a key bioactive component of the Chinese herbal medicine Artemisia asiatica Nakai. Recent research reports have proved the inhibitory function of Eupatilin in many diseases. MicroRNAs (miRNAs) are 21–23 nucleotide‐long, single‐stranded, noncoding RNA molecules generated endogenously, and many studies have indicated that miRNAs are involved in the development of osteoporosis. This study explored the role and potential mechanism of Eupatilin underlying PMOP. First, rats were given intragastric administration of Eupatilin every day and subcutaneous injections of oligonucleotides or plasmids that interfered with miR‐211‐5p or janus kinase 2 (JAK2) once a week. After 4 weeks, the PMOP rat model was established. Then, serum alkaline phosphatase, calcium, and phosphorus levels, as well as femur bone mineral density and biomechanical parameters, were detected. Hematoxylin–eosin staining and Masson staining were applied for detecting the pathological condition of femur, and immunohistochemical staining was for detecting osteocalcin. MC3T3‐E1 cells were transfected with plasmid vectors interfering with miR‐211‐5p or JAK2; and cell viability, lactate dehydrogenase cytotoxicity, and cell mineralization were subsequently examined. The relationship between miR‐211‐5p and JAK2/signal transducer and activator of transcription 3 (STAT3) pathway was analyzed. The targeting relation between miR‐211‐5p and JAK2 was also verified. The experimental results revealed that Eupatilin improved the pathological conditions of PMOP rats by promoting the proliferation and mineralization of osteoblasts. MiR‐211‐5p was down‐regulated and JAK2/STAT3 was upregulated in PMOP rats. Upregulation of miR‐211‐5p further improved the pathological conditions of PMOP rats based on Eupatilin treatment. MiR‐211‐5p inhibited the JAK2/STAT3 pathway. JAK2 offset the effects of elevated miR‐211‐5p on PMOP rats. Overall, Eupatilin attenuates PMOP through elevating miR‐211‐5p and repressing JAK2/STAT3 pathway, which suggests the utility of Eupatilin as a potential drug for POMP treatment. [ABSTRACT FROM AUTHOR]

Myocarditis is an inflammation of the heart muscle often associated with viral infections and can lead to dilated cardiomyopathy. Interferon-induced transmembrane protein 3 (IFITM3) is a small endosomal membrane protein with anti-viral activity against multiple viruses and is also implicated in non-infectious diseases such as cancer and Alzheimer's Disease. Since the IFITM3 proteins are expressed both in T cells and in cardiomyocytes, it is reasonable to hypothesize that these molecules could affect myocarditis either through their effect on the autoimmune response or through direct modulation of cardiomyocyte damage. The aim of this study was to investigate the role of IFITM3 in experimental autoimmune myocarditis (EAM)-mediated myocardial injury. Immunization of rats with cardiac myosin results in substantial cardiac inflammation and is associated with increased expression of IFITM3 after 21 days. In vivo IFITM3 shRNA knockdown using the lentivirus transfection method reduced cardiac injury while restoring IFITM3 expression reversed the protective effect of IFITM3 RNA interference. To determine the direct impact of IFITM3, the rat ventricular cell line, H9c2, was treated with palmitic acid which causes apoptosis in these cells. Suppressing IFITM3 expression protects H9c2 cells while overexpressing IFITM3 enhances cell injury. JAK inhibitors reduced IFITM3-mediated myocardial cell injury. In conclusion, IFITM3 may mediate myocardial injury in EAM rats and palmitic acid-induced damage to H9c2 cells through the JAK2/STAT3 pathway. [Display omitted] • IFITM3 may mediate myocardial injury in EAM rats and palmitic acid-induced damage to H9c2 cells through the JAK2/STAT3 pathway. • IFITM3 may be an effective target for the prevention and treatment of myocardial injury. • IFITM3 is expected to provide effective drug development strategies. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of ropivacaine on the malignant biological behaviors of prostate cancer cells and its potential mechanism. Methods Human prostate cancer cells（PC-3) were treated with different doses of ropivacaine（0, 1, 2.5, 5, 10, and 15 mmol/L) to determine the optimal concentration of ropivacaine by cell survival curve analysis. PC-3 cells were cultured and randomly divided into four groups including the control group, the ropivacaine group, the colivelin group, and the combined group of ropivacaine and colivelin（JAK2/STAT3 activator) group. After treated with ropivacaine and colivelin, cell proliferation, apoptosis, migration, and invasion in each group were detected by CCK-8 assay, flow cytometry assay, cell scratch assay, and Transwell invasion assay. The expressions of apoptosis related proteins such as PARP, Bax, Bcl-2, and the expressions of EMT related proteins such as Vimentin, E-cadherin in each group were analyzed by western blot. The subcutaneous tumor nude mica models from PC-3 cells were constructed and divided into the control group, the ropivacaine group, the colivelin group, and the combined group of ropivacaine and colivelin group. After treated with ropivacaine and colivelin, the growth of subcutaneous tumors in each group was observed and their tumor cell proliferation was evaluated by Ki67 expression. The apoptosis of tumor tissues in each group was measured using TUNEL staining. The expressions of the related proteins to JAK2/STAT3 pathway in each group were examined by western blot. Results Compared with those in the control group, the apoptosis rate of cells, the protein expressions of Bax, cleaved PARP, E-cadherin, and the cell apoptosis proportion in tumor tissue in the ropivacaine group were all significantly increased（P＜0.05), but the survival rate of cells, the rate of cell migration, the number of invaded cells, the protein expressions of Bcl-2 and Vimentin, the proliferation ratio of cells in tumor tissues, the expression of p-JAK2/JAK2 and p-STAT3/STAT3 decreased（P＜0.05). On the contrary, in the colivelin group, the apoptosis rate of cells, the protein expressions of Bax, cleaved PARP, E-cadherin, and the cell apoptosis proportion in tumor tissues were all obviuosly decreased（P＜0.05), but the survival rate of cells, the rate of migration, the number of invaded cells, the protein expressions of Bcl-2 and Vimentin, the proliferation ratio of cells in tumor tissues, the expressions of p-JAK2/JAK2, p-STAT3/STAT3increased（P＜0.05). Compared with those in the ropivacaine group, the cell apoptosis rate, the protein expressions of Bax, cleaved PARP, and E-cadherin, and the cell apoptosis proportion in tumor tissues in the ropivacaine+colivelin group were all prominently reduced（P＜0.05), but the survival rate of cells, the migration rate of cells, the number of the invaded cells, the protein expressions of Bcl-2 and Vimentin, the proliferation ratio of cells in tumor tissue, the expressions of p-JAK2/JAK2, and p-STAT3/STAT3 increased（P＜0.05). Conclusion Ropivacaine obviously inhibits the activation of JAK2/STAT3 pathway to suppress the proliferation, migration, invasion activities of prostate cancer cells, promotes their apoptosis and delays their growth in nude mice, ultimately represses their malignant biological behavior. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia. [ABSTRACT FROM AUTHOR]

Leukemia is a malignant tumor of the hematologic system. Studies have shown that cernuumolide J (TMJ-105), an extract of Carpesium cernuum, has anti-cancer effects, but the underlying mechanism is unclear. In this study, we investigated the effect of TMJ-105 on the proliferation of human leukemia HEL cells and its molecular mechanism. MTT analysis showed TMJ-105 had revealed that it shows significant IC50 in HEL cells at lower doses (1.79 ± 0.29 μmol/L) than in K562 cells (3.89 ± 0.80 μmol/L), and the suppression of HEL cell proliferation was time- and concentration-dependent. Meanwhile, TMJ-105 induced G2/M phase blockage, leading to DNA damage in HEL cells. TMJ-105 promoted HEL cells to release of reactive oxygen species (ROS) and changed mitochondrial membrane potential (MMP). Furthermore, TMJ-105 induced apoptosis by upregulating the cleaved-caspase9 and cleaved-caspase3 protein expression, while caspase pan inhibitor (Z-VAD-FMK) blocked the inhibition effect. Finally, TMJ-105 downregulated the phosphorylation of JAK2, STAT3 and Erk, and activated the phosphorylation of JNK and p38. Collectively, these results demonstrated that TMJ-105 inhibited proliferation of leukemia cells and the underlying mechanism via the JAK2/STAT3 axis and MAPKs signaling pathway. Based on these results, the present study suggested the sesquiterpene lactone TMJ-105 is a new chemotherapeutic agent for the treatment of leukemia.

Background: Fibronectin type III domain containing 1 (FNDC1) has been associated with the metastasis of many tumors, but its function in lung cancer remains uncertain. Methods: FNDC1 expression was analyzed in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), evaluate its prognostic value. Gene Set Enrichment Analysis (GSEA) enrichment analysis of differential expression of FNDC1 in lung cancer. The expression of FNDC1 was detected in five types of lung cancer cells, and screened to establish FNDC1 stable knockdown cell strains. To observe the migration and invasion ability of lung cancer cells after FNDC1 knockdown. Finally, we used rhIL-6 to interfere with the stable knockdown of FNDC1 in A549 cells and observed the recovery of migration and invasion. Result: Our results showed that FNDC1 expression was increased in 21 tumor tissues, including lung cancer, and was associated with poor prognosis in five cancers, including lung adenocarcinoma (LUAD) (P < 0.05). GSEA enrichment analysis showed that FNDC1 was related to the pathways involved the JAK-STAT signaling pathway. Stable knockdown of FNDC1 in A549 and H292 cells resulted in decreased migration and invasion ability of both cells, accompanied by decreased expression of MMP-2 and Snail, and a significant decline in the expression of p-JAK2 and p-STAT3. The suppressive effect of FNDC1 knockdown on lung cancer cell metastasis counteracted by the JAK-STAT agonist rhIL-6 were presented in the nude mouse metastatic tumor model. Conclusion: FNDC1 is implicated in poor prognosis of a diverse range of malignant tumors, which can promote metastasis and invasion of lung cancer through the JAK2-STAT3 signaling pathway.

Abstract Background SLC25A17, a peroxisomal solute carrier, has been implicated in various physiological and pathological processes. However, its precise roles and underlying mechanisms in triple-negative breast cancer (TNBC) remain incompletely understood. Methods The expression and survival data of breast cancer were derived from TCGA and GEO databases. A variety of in vitro assays were conducted, including proliferation, apoptosis, cell cycle, migration, and invasion. Reactive oxygen species (ROS) were measured by immunofluorescence microscopy and flow cytometry. The levels of autophagy were assessed by mRFP-GFP-LC3 confocal microscopy scanning, western blotting, and electron microscopy. Results SLC25A17 was highly expressed in breast cancer tissues, which was found to be associated with unfavorable prognosis. Functional assays demonstrated that SLC25A17 knockdown suppressed proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. Moreover, it prompted apoptosis and autophagy. On the other hand, SLC25A17 knockdown promoted autophagy through triggering ROS accumulation, which was counteracted by N-acetyl-l-cysteine (NAC). Furthermore, the pro-apoptotic effect of SLC25A17 knockdown was reversed when treated with autophagy inhibitor 3-MA in TNBC cells, suggesting that SLC25A17 knockdown-induced autophagic cell death. Mechanistically, SLC25A17 performed its function through regulation JAK2/STAT3 signaling in TNBC. In a nude mice xenograft study, SLC25A17 knockdown markedly decreased breast tumor growth and metastasis. Conclusion SLC25A17 up-regulation may be a critical factor driving TNBC progression by modulating ROS production and autophagy. Consequently, targeting SLC25A17 could be an effective therapeutic strategy against TNBC.

Abstract Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. Here, we show that K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway. Collectively, this study may provide a preliminary basis for further cancer treatment of hepatocellular carcinoma.

Objective To determine whether baricitinib regulates macrophage polarization through Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway to reduce the severity of pulmonary fibrosis in mice with scleroderma. Methods Thirty 8-week-old female C57BL/6 mice were randomly divided into control group (Ctl, n=6), scleroderma group (SSc, n=12) and scleroderma+baricitinib group (SSc+Ba, n=12). The mice of the SSc and SSc+Ba group were inflicted with a subcutaneous injection of 7.5 mg/kg bleomycin in the back, and an intragastric gavage of 5 mg/kg baricitinib. ELISA was used to detect the plasma levels of inflammatory factors, IL-1β, IL-4, IL-6 and IL-10. HE staining and Masson staining were employed to determine the thickness of skin dermis and pathological changes and collagen content in lung tissue. The mRNA expression of IL-1β, IL-4, IL-6 and IL-10 in lung tissue was measured by RT-PCR, and the protein levels of macrophage markers CD86, CD163 and JAK2/STAT3 in lung tissue were detected by Western blotting. Afterwards, flow cytometry was applied for the expression of F4/80, CD86 and CD163 to determine the polarization of macrophages. Immunofluorescence assay was used to detect CD86 and CD163 to clarify the polarization of macrophages in lung tissue. Results Compared with the Ctl group, the dermis at the injection site in the back was significantly thickened (P < 0.001), the score of pulmonary fibrosis was obviously increased (P < 0.001), and the collagen content in skin and lung tissue was notably elevated in the SSc group (P < 0.001). The above changes were alleviated to varying degrees in the SSc+Ba group (P < 0.01). The SSc group had significantly higher plasma levels of IL-1β (P < 0.05) and IL-6 (P < 0.001) as well as elevated their mRNA levels in lung tissue (P < 0.05) than the Ctl group. Baritinib treatment decreased the plasma concentrations of the above factors (P < 0.01) and their mRNA levels in lung tissue (P < 0.01). JAK2/STAT3 was highly expressed in the SSc group (P < 0.01), and baricitinib reduced the activation of JAK2/STAT3 pathway (P < 0.05). Western blotting and immunofluorescence assay indicated that CD86 protein (marker of M1 macrophages) was highly expressed (P < 0.01) and CD163 protein (marker of M2 macrophages) was in low expression (P < 0.05) in lung tissue in the SSc group than the Ctl group. In the SSc+Ba group, CD86 protein was reduced (P < 0.05) and CD163 protein was increased (P < 0.05) in lung tissue. Flow cytometry showed that the proportion of F4/80+CD86+CD163- M1 macrophages in the spleen was increased (P < 0.001), and the proportion of F4/80+CD86- CD163+ M2 macrophages was decreased in the SSc group when compared with Ctl group (P < 0.01). In the SSc+Ba group, the proportion of M1 was decreased (P < 0.01), and that of M2 was increased (P < 0.001). Conclusion Baricitinib inhibits M1 macrophage polarization through JAK2/STAT3 signaling pathway, thus reducing the fibrosis of lung tissue in SSc mice.

Chengxi Zhang,1,2 Xiaoqian Li,1,2 Dan Gao,1,2 Huahe Zhu,3 Shun Wang,1,2 Bo Tan,4 Aidong Yang1,2 1School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Center for Traditional Chinese Medicine and Epidemic Disease, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, People’s Republic of China; 3Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Aidong Yang; Bo Tan, Tel +86-21-135 6482 0109 ; +86-21-137 6418 9001, Fax +86-21-51322141 ; +86-21-20256699, Email aidongy@126.com; tbot@163.comPurpose: Tingli Dazao Xiefei Decoction (TDXD) is a Traditional Chinese Medicine (TCM) formula used to treat acute lung injury (ALI). However, the precise mechanism of TDXD in treating ALI remains unclear. We investigated the therapeutic mechanism of TDXD against ALI using a complementary approach combining network pharmacology, molecular docking, and in vitro and in vivo experiments.Material and Methods: Potential drug targets of TDXD and relevant target genes associated with ALI were retrieved from Chinese medicines and disease genes databases. Bioinformatics technology was employed to screen potential active ingredients and core targets. Validation experiments were conducted using a lipopolysaccharide (LPS)-induced ALI mouse (C57BL/6J) model, LPS-induced inflammatory RAW264.7 cells, and molecular docking between active compounds of TDXD and potential targets.Results: Network pharmacology suggested that the mechanism of TDXD against ALI involved phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) / phosphatase and tensin homolog (PTEN) and Janus kinase 2 (JAK2) / signal transducer and activator of transcription 3 (STAT3) pathways. Quercetin, β-sitosterol, kaempferol, isorhamnetin, and L-stepholidine were identified as the main active compounds of TDXD that exerted anti-ALI effects. Molecular docking indicated that these compounds exhibited good binding capabilities (≤ − 5kcal/mol) to key targets in PI3K/AKT/PTEN and JAK2/STAT3 signaling pathways. In the animal model, TDXD alleviated injuries and inflammatory responses in lung tissues, accompanied by inhibition of expression of tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), STAT3, and Suppressor of Cytokine Signaling 3 (SOCS3) mRNA, and key proteins in PI3K/AKT/PTEN and JAK2/STAT3 pathways (all P values < 0.05). Cell based experiments showed that TDXD dose-dependently inhibited the expression of essential proteins in PI3K/AKT/PTEN and JAK2/STAT3 pathways (P < 0.05).Conclusion: This study revealed that the mechanism of TDXD in ALI treatment might involve simultaneous regulation of PI3K/AKT/PTEN and JAK2/STAT3 pathways.Keywords: network pharmacology, molecular docking, lipopolysaccharide, PI3K/AKT/PTEN, JAK2/STAT3

Background: SLC25A17, a peroxisomal solute carrier, has been implicated in various physiological and pathological processes. However, its precise roles and underlying mechanisms in triple-negative breast cancer (TNBC) remain incompletely understood. Methods: The expression and survival data of breast cancer were derived from TCGA and GEO databases. A variety of in vitro assays were conducted, including proliferation, apoptosis, cell cycle, migration, and invasion. Reactive oxygen species (ROS) were measured by immunofluorescence microscopy and flow cytometry. The levels of autophagy were assessed by mRFP-GFP-LC3 confocal microscopy scanning, western blotting, and electron microscopy. Results: SLC25A17 was highly expressed in breast cancer tissues, which was found to be associated with unfavorable prognosis. Functional assays demonstrated that SLC25A17 knockdown suppressed proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. Moreover, it prompted apoptosis and autophagy. On the other hand, SLC25A17 knockdown promoted autophagy through triggering ROS accumulation, which was counteracted by N-acetyl-l-cysteine (NAC). Furthermore, the pro-apoptotic effect of SLC25A17 knockdown was reversed when treated with autophagy inhibitor 3-MA in TNBC cells, suggesting that SLC25A17 knockdown-induced autophagic cell death. Mechanistically, SLC25A17 performed its function through regulation JAK2/STAT3 signaling in TNBC. In a nude mice xenograft study, SLC25A17 knockdown markedly decreased breast tumor growth and metastasis. Conclusion: SLC25A17 up-regulation may be a critical factor driving TNBC progression by modulating ROS production and autophagy. Consequently, targeting SLC25A17 could be an effective therapeutic strategy against TNBC. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a relapsing inflammatory disease with a unique aetiology. The treatment of UC is challenging, and the current clinical therapeutics for colitis have limited efficacy. Thus, finding new and effective treatment options remains urgent. Baricitinib, an inhibitor of Janus kinase (JAK), has been clinically used to treat rheumatoid arthritis (RA). However, its potential effects on UC have not been fully elucidated. In this study, we aimed to explore the effects of baricitinib on UC and its underlying mechanism. Dextran sulphate sodium (DSS)-induced murine model of chronic colitis was used to investigate the intervention efficacy following oral administration of baricitinib. The levels of key cytokines, such as IL-6, IFN-γ and IL-17A, were determined. Moreover, western blotting for IκBα, p-IκBα, JAK2, p-JAK2, STAT3 and p-STAT3 protein expression was performed to investigate the associated signalling pathways. Our findings demonstrated that baricitinib can significantly relieve DSS-induced UC in mice. After baricitinib intervention, IL-6, IFN-γ and IL-17A levels were decreased both in vitro and in vivo. Moreover, the elevated expression levels of p-IκBα, p-JAK2, and p-STAT3 were significantly reduced after treatment. Collectively, these results suggest that baricitinib is a potential therapeutic agent for alleviation of DSS-induced colitis. This study provides a method for subsequent investigations on potential curative drugs development of the for colitis. [ABSTRACT FROM AUTHOR]

This study aimed to explore the molecular mechanism of LCN2 regulating aerobic glycolysis on abnormal proliferation of HCC cells. Based on the prediction of GEPIA database, the expression levels of LCN2 in hepatocellular carcinoma tissues were detected by RT-qPCR analysis, western blot, and immunohistochemical staining, respectively. In addition, CCK-8 kit, clone formation, and EdU staining were used to analyze the effect of LCN2 on the proliferation of hepatocellular carcinoma cells. Glucose uptake and lactate production were detected using kits. In addition, western blot was used to detect the expressions of aerobic glycolysis-related proteins. Finally, western blot was used to detect the expressions of phosphorylation of JAK2 and STAT3. We found LCN2 was upregualted in hepatocellular carcinoma tissues. CCK-8 kit, clone formation, and EdU staining results showed that LCN2 could promote the proliferation in hepatocellular carcinoma cells (Huh7 and HCCLM3 cells). Western blot results and kits confirmed that LCN2 significantly promotes aerobic glycolysis in hepatocellular carcinoma cells. Western blot results showed that LCN2 could significantly upregulate the phosphorylation of JAK2 and STAT3. Our results indicated that LCN2 activated the JAK2/STAT3 signaling pathway, promoted aerobic glycolysis, and accelerated malignant proliferation of hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. Here, we show that K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway. Collectively, this study may provide a preliminary basis for further cancer treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition. The search for multi-target traditional Chinese medicines or ingredients for treating AD has attracted much attention. Corydalis rhizome (CR) is a traditional Chinese medicine. Its main components are alkaloids, which have therapeutic effects that can potentially be used for treating AD. However, no systematic study has been conducted to explore the anti-AD efficacy of CR, as well as its active compounds and mechanisms of action. Objective: The present study aimed to clarify CR’s active constituents and its pharmacological mechanisms in treating AD. Methods: A D-galactose & scopolamine hydrobromide-induced AD mouse model was used and CR was administered orally. The prototypical alkaloid components were identified in the serum. The core components, key targets, and possible mechanisms of action of these alkaloids were revealed through network pharmacology. Molecular docking of the key target was performed. Finally, the mechanism was validated by lipopolysaccharide (LPS)-induced activation of BV2 microglia. Results: The results showed that CR improved anxiety-like behavior, spatial and non-spatial recognition, and memory capacity in AD mice. It also achieved synergistic AD treatment by modulating neurotransmitter levels, antineuroinflammation, and anti-oxidative stress. The core components that enhance CR’s efficacy in treating AD are protoberberine-type alkaloids. The CR may induce the polarization of LPS-activated BV2 microglia from phenotype M1 to M2. This is partially achieved by modulating the IL-6/JAK2/STAT3 signaling pathway, which could be the mechanism by which CR treats AD through anti-inflammation. Conclusion: The present study provided a theoretical and experimental basis for the clinical application of CR in treating AD. It also provides information that aids the secondary development, and precise clinical use of CR. [ABSTRACT FROM AUTHOR]

Retinoblastoma (RB) is an intraocular tumor in children. Accumulated evidence confirms that microRNAs (miRNAs) exert critical functions in RB. This research aimed to investigate the miR‐452‐5p function in RB. MiR‐452‐5p expressions in RB were tested with quantitative real‐time polymerase chain reaction (PCR). MiR‐452‐5p functions in RB were evaluated via Cell Counting Kit‐8, 5‐Ethynyl‐2′‐deoxyuridine assay, flow cytometry, Western blot, and Transwell. MiR‐452‐5p mechanism in RB was assessed using bioinformatics software Starbase and dual‐luciferase reporter gene assay. Meanwhile, miR‐452‐5p function in RB in vivo was examined by constructing tumor xenografts in nude mice, immunohistochemistry, and Western blot assays. MiR‐452‐5p was overexpressed in RB tissues and cells, and miR‐452‐5p expression was positively correlated with RB clinicopathology including the Largest tumor base (mm) and Differentiation. Functionally, miR‐452‐5p knockdown restrained RB cell proliferation, invasion, epithelial–mesenchymal transition (EMT), and facilitated cell apoptosis. Mechanistically, suppressors of cytokine signaling (SOCS3) knockdown restored the inhibitory effects of miR‐452‐5p knockdown on RB cells. Meanwhile, in vivo studies further corroborated that miR‐452‐5p knockdown reduced RB tumor growth, EMT, and accelerated apoptosis in vivo. Also, miR‐452‐5p knockdown increased SOCS3 protein levels, and decreased phosphorylated Janus kinase 2/Janus kinase 2 (JAK2), phosphorylated signal transducer and activator of transcription 3/signal transducer and activator of transcription 3 (STAT3) in vivo. MiR‐452‐5p accelerated RB cell growth and invasion by SOCS3/JAK2/STAT3. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

The aim of this article is to introduce the roles and mechanisms of the JAK2/STAT3 pathway in various cardiovascular diseases, such as myocardial fibrosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, and myocardial ischemiareperfusion. In addition, the effects of phytochemical ingredients and different natural plants, mainly traditional Chinese medicines, on the regulation of different cardiovascular diseases via the JAK2/STAT3 pathway are discussed. Surprisingly, the JAK2 pathway has dual roles in different cardiovascular diseases. Future research should focus on the dual regulatory effects of different phytochemical ingredients and natural plants on JAK2 to pave the way for their use in clinical trials.

Objective(s): Ovarian ischemia/reperfusion (I/R) is an extremely complex pathological problem that begins with oxygen deprivation, progresses to excessive free radical production, and intensifies inflammation. The JAK2/STAT3 signaling pathway is a multipurpose signaling transcript channel that plays a role in several biological functions. Trimetazidine (TMZ) is a cellular anti-ischemic agent. This study aims to investigate the effects of TMZ on ovarian I/R injury in rats.Materials and Methods: sixty four rats were divided into 8 groups at random: healthy(group1); healthy+TMZ20(group2); ischemia (I) (group 3); I+TMZ10(group4); I+ TMZ20(group5); I/R(group6); I/R+TMZ10(group7); I/R+TMZ20(group8). Vascular clamps were placed just beneath the ovaries and over the uterine horns for 3 hr to induce ischemia. The clamps were removed for the reperfusion groups, and the rats were reperfused with care to ensure that the blood flowed into the ovaries, subjecting them to reperfusion for 3 hr. TMZ was administered orally by gavage 6 and 1 hr before operations. At the end of the experiment, ovarian tissues were removed for biochemical, molecular, and histopathological investigation.Results: TMZ administration ameliorated ischemia/reperfusion-induced disturbances in GSH and MDA levels. TMZ treatment inhibited I/R-induced JAK2/STAT3 signaling pathway activation in ovarian tissues. TMZ administration also improved the increase in the mRNA expressions of IL-1β, TNF-α, and NF-κB caused by ischemia/reperfusion injury. Moreover, TMZ treatment improved histopathologic injury in ovarian tissues caused by ischemia/reperfusion.Conclusion: TMZ treatment protected rats against ovarian ischemia/reperfusion injury by alleviating oxidative stress and inflammatory cascades. These findings may provide a mechanistic basis for using TMZ to treat ovarian ischemia-reperfusion injury.

Multiple myeloma (MM) is characterized by excessive aggregation of B-cell-derived malignant plasma cells in the hematopoietic system of bone marrow. Previously, we synthesized an innovative molecule named dihydrocelastrol (DHCE) from celastrol, a triterpene purified from medicinal plant Tripterygium wilfordii. Herein, we explore the therapeutic properties and latent signal transduction mechanism of DHCE action in bortezomib (BTZ)-resistant (BTZ-R) MM cells. In this study, we first report that DHCE shows antitumor activities in vitro and in vivo and exerts stronger inhibitory effects than celastrol on BTZ-R cells. We find that DHCE inhibits BTZ-R cell viability by promoting apoptosis via extrinsic and intrinsic pathways and suppresses BTZ-R MM cell proliferation by inducing G0/G1 phase cell cycle arrest. In addition, inactivation of JAK2/STAT3 and PI3K/Akt pathways are involved in the DHCE-mediated antitumor effect. Simultaneously, DHCE acts synergistically with BTZ on BTZ-R cells. PSMB5, a molecular target of BTZ, is overexpressed in BTZ-R MM cells compared with BTZ-S MM cells and is demonstrated to be a target of STAT3. Moreover, DHCE downregulates PSMB5 overexpression in BTZ-R MM cells, which illustrates that DHCE overcomes BTZ resistance through increasing the sensitivity of BTZ in resistant MM via inhibiting STAT3-dependent PSMB5 regulation. Overall, our findings imply that DHCE may become a potential therapeutic option that warrants clinical evaluation for BTZ-R MM.