Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicyla...Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicylates,corticosteroids,and biologics,offer limited efficacy,safety,and durability of response.The advancement in small-molecule Janus kinase(JAK)inhibitors has introduced a novel,oral therapeutic option that targets intracellular signaling pathways implicated in UC pathogenesis.Tofacitinib is the first approved JAK inhibitor for the treatment of moderate-to-severe UC.This drug,despite offering promising efficacy,has various safety concerns,especially the occurrence of thromboembolic events.These adverse effects have stressed the devel-opment of more selective agents such as upadacitinib and filgotinib.This mini-review explores the current perspectives of JAK inhibitors in UC,particularly focusing on their mechanisms of action,safety profiles,clinical trial outcomes,and emerging strategies to enhance their use.This review also highlights future directions,including the potential of selective JAK1 inhibition and the role of personalized medicine in refining therapeutic decisions.Understanding the emerging place of JAK inhibitors within the UC treatment strategies offers excellent opportunities to increase patient care and long-term disease management.展开更多
Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax ...Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax SPA and it has a well-known safety profile over a longer duration. Recently, many IL-17i and JAKi were approved for the treatment of nr-ax SPA;however, data comparing IL1-7i and JAKi in terms of efficacy and safety is lacking. This systematized review aimed to compare the existing efficacy and safety data of JAKi vs IL-17i in the treatment of patients with nr-ax SPA. Methods: A systematic literature search was performed using relevant keywords in many databases. According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, 2020), relevant articles were included and evaluated in this review. Efficacy and safety data were collected, analyzed and compared through week 52. The first check was done by the end of week 14 and week 16 for upadacitinib and IL-17i respectively. Results: Data from four RCTs evaluating upadacitinib, secukinumab, ixekizumab, and bimekizumab comprising 1425 patients were analyzed. Overall, a comparable efficacy and safety profile were observed across different treatment arms through week 52;however, non-significant variations were encountered in some outcome measures. The primary endpoint among these RCTs (ASAS40 response rate) was met and it was higher in patients treated with bimekizumab 160 mg sc Q 4 weeks in TNFi non responders (48%) and lowest in ixekizumab 80 mg sc Q 4 weeks treated patients, (35%) (p Conclusion: The above-mentioned three IL-17i and the only one JAKi demonstrated comparable safety and efficacy profiles with some minor variations. A head-to-head trial comparing the effectiveness and safety characteristics of JAKi vs IL-17i may be needed in patients with active nr-ax SpA.展开更多
BACKGROUND Inflammatory bowel disease(IBD)is a chronic,progressive inflammatory condition of the intestine.Mesenchymal stem cell(MSC)therapy for IBD has made significant progress in recent years.To better exploit the ...BACKGROUND Inflammatory bowel disease(IBD)is a chronic,progressive inflammatory condition of the intestine.Mesenchymal stem cell(MSC)therapy for IBD has made significant progress in recent years.To better exploit the therapeutic potential of MSCs,pretreatment strategies are employed to enhance their therapeutic capabilities.As a compound with diverse pharmacological effects,quercetin(QUR)is applied to pretreat human umbilical cord-derived MSCs(hUCMSCs)in this study,thereby augmenting their immunotherapeutic potential.AIM To evaluate the therapeutic efficacy of QUR-pretreated hUCMSCs.METHODS We induced colitis in a mouse model using a 2,4,6-trinitrobenzenesulfonic acid solution.Intraperitoneal injection of QUR-pretreated hUCMSCs significantly improved clinical and pathological manifestations of colitis compared to the model group.Interestingly,the therapeutic effect was superior to that of untreated hUCMSCs.Mice exhibited significantly reduced weight loss,diminished infiltration of inflammatory cells observed in hematoxylin and eosin staining,improved Disease Activity Index and Histological Activity Index scores.Furthermore,colonic tissue analysis revealed a significant upregulation of the anti-inflammatory cytokine interleukin 10(IL-10),accompanied by a downregulation of the pro-inflammatory cytokine IL-6.Further tests also suggested that QUR pretreatment led to inhibition of Janus kinase/signal transducer and activator of transcription(STAT)phosphorylation.RESULTS Our study demonstrated that QUR pretreatment of hUCMSCs significantly enhanced their immune-regulatory capacity.This approach effectively mitigated colonic inflammation in a mouse colitis model by modulating the IL-10/Janus kinase/STAT signaling pathway.CONCLUSION These findings suggest that QUR pretreatment acts synergistically to augment the inherent anti-inflammatory and immune-regulatory properties of hUCMSCs,resulting in enhanced therapeutic efficacy for IBD treatment.展开更多
Non-infectious uveitis(NIU),although a highly blinding but preventable cause of blindness around the world,has few approved pharmaceuticals for its treatment.Lack of access to effective treatment is likely a major cau...Non-infectious uveitis(NIU),although a highly blinding but preventable cause of blindness around the world,has few approved pharmaceuticals for its treatment.Lack of access to effective treatment is likely a major cause of poor visual outcomes in NIU.However,despite a revolution in rheumatologic disease treatment with the advent of multiple biologic therapeutics selectively targeting the immune response,there remains a gap in the long-term management of NIU.Adalimumab remains the only systemic medication approved for the treatment of NIU by the Food and Drug Administration(FDA).All other systemic treatments,including older anti-metabolites such as methotrexate and mycophenolate,are used offlabel for NIU,posing significant treatment challenges.Given the nature and rarity of the disease,there are few well designed,large,clinical trials evaluating the efficacy of novel therapeutic agents within this field.We therefore read with great interest Srivastava et al.’s randomized clinical trial on the efficacy of filgotinib,a Janus kinase inhibitor(JAKi),in active NIU(1).The early termination of the trial due to business considerations highlights the industry difficulty in FDA medication approval for NIU.展开更多
OBJECTIVE: Inactivation of the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3) signaling axis plays a crucial role in determining the fate of neural stem cells(NSCs).Qingnaoyizhi decocti...OBJECTIVE: Inactivation of the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3) signaling axis plays a crucial role in determining the fate of neural stem cells(NSCs).Qingnaoyizhi decoction(QNYZD) has been used for the treatment of vascular dementia and has shown to improve synaptic remodeling. The aim of this study was to evaluate the effect of cerebrospinal fluid(CSF) containing QNYZD(CSF-QNYZD) on the differentiation of cultured NSCs and the involvement of the JAK2/STAT3 pathway.METHODS: The protein expression levels of glial fibrillary acidic protein(GFAP), tubulin, drosophila mothers against decapentaplegic protein(SMAD-1), STAT3, and phosphorylated-STAT3 were detected by western immunoblot analysis in the groups: control, CSF, JAK/STAT inhibitor(AG490),CSF-QNYZD, and CSF-XDZ(CSF-Xidezhen). The differentiation of NSCs was determined by immunofluorescence staining. The proliferation of NSCs was measured using the Cell Counting Kit-8 proliferation assay.RESULTS: Compared with the control group,CSF-QNYZD and AG490 significantly increased the number and expression of tubulin-positive cells, reduced the number and expression of GFAP-positive cells, and down-regulated the expression of p-STAT3. However, CSF-QNYZD also decreased the expression of SMAD-1 and STAT3.CONCLUSION: Enhanced neuronal differentiation may be associated with the down-regulation of glial differentiation instead of promoting proliferationin treated NSCs. Furthermore, QNYZD may play a direct role in suppressing the formation of GFAP-positive cells and enhancing neuronal differentiation by inhibiting JAK2/STAT3 activation. Overall, these results provide insights into the possible mechanism underlying QNYZD-mediated neurogenesis.展开更多
OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHOD...OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHODS: Sixty male Sprague-Dawley rats wererandomly divided into six groups, with 10 animals in each group: the untreated sham-operated normal control group; the untreated UUO model control group, the high dose QSG-treated(16 gdm dose QSG-·kg-1-1) UUO group; the mediutreate·d(8 g·kg-1·d-1) UUO group; the low dose QSG-treated(4 g·kg-1·d-1) UUO group; and the valsartan-treated group(20 mg·kg-1·d-1). The two untreated control groups received physiological saline(1 m L/100 g per day). All the rats were sacrificed after a 4-week course of treatment. Serum creatinine and leptin; protein expressions of leptin receptor(OB-R), p-JAK2, p-STAT3, nuclear factors-κBp6(NF-k Bp65), and monocytechemotatic protein-1(MCP-1); m RNA of JAK2, STAT3, calcium-dependent adhesion(E-cadherin), alphasmooth muscle actin(α-SMA) in the kidney tissues;and the expressions of type ronectin(FN) and the pⅣat collagen(Col-homorphologyⅣ)and fib in kidney tissues were treated.RESULTS: Compared with the normal group, the BUN, Scr, and serum leptin levels and the expressions of MCP-1, p-JAK2, p-STAT3, NF-k Bp65 and OB-R in renal tissues, and the m RNA expressions of leptin, JAK2 protein, STAT3 protein, α-SMA protein in model group were significantly higher(P < 0.01)in the UUO model group. These parameters were significantly reduced in all the QSG-treated groups and the valsartan-treated group than the UUO model group(P < 0.05 or P < 0.01), with the lowest levels found in the medium dose QSG-treated group(P < 0.05). However, the expression levels of E-cadherin, FN, and Col-Ⅳ in the renal tissues were contrary to the expressions described above. Se-vere pathological injury was evident in the renal tissues of UUO model rats, which was alleviated in the QSG-treated and valsartan-treated groups, with the least damage found in the medium dose QSG-treated group.CONCLUSION: Our data suggest that the leptin-mediated JAK/STAT signaling pathway is involved in the process of renal interstitial fibrosis in UUO rats. QSG inhibited the activity of the signaling pathway, reduced the activity of NF-k B and inflammatory effect, and the transdifferentiation in the renal tubular epithelial cells. Treatment with QSG may delay the renal fibrosis and protect the renal function from damage following UUO in rats.展开更多
BACKGROUND Synovitis,acne,pustulosis,hyperostosis,and osteitis(SAPHO)syndrome is a rare autoinflammatory disease for which clinical treatment has not been standardized.Janus kinase(JAK)inhibitors represent a novel the...BACKGROUND Synovitis,acne,pustulosis,hyperostosis,and osteitis(SAPHO)syndrome is a rare autoinflammatory disease for which clinical treatment has not been standardized.Janus kinase(JAK)inhibitors represent a novel therapeutic option for rheumatoid arthritis,psoriatic arthritis,and some other autoinflammatory diseases.However,the clinical utility of JAK inhibitors in treating SAPHO syndrome has not been thoroughly investigated.In this study,we describe a patient with SAPHO syndrome who failed to respond to conventional treatment but demonstrated a remarkable and rapid response to the JAK inhibitor tofacitinib.CASE SUMMARY A 62-year-old female patient presented with swelling and pain at the sternoclavicular joints,back pain that limited her activities,arthralgia in the right knee,and cutaneous lesions.Her symptoms were unresponsive to nonsteroidal anti-inflammatory drugs,disease-modifying antirheumatic drugs,Tripterygium wilfordii hook f,and bisphosphonates.SAPHO syndrome was diagnosed in accordance with dermatological and osteoarticular manifestations and abnormal inflammatory factors.Multiple image studies have illustrated bone lesions and pathological fractures of vertebral bodies.Oral treatment with tofacitinib at 5 mg twice daily with methotrexate and bisphosphonates was initiated.The patient reported that her pain symptoms were relieved after 3 d and her cutaneous lesions were reduced after 4 wk of treatment.Vertebral lesions were improved after 6 mo on tofacitinib.No serious adverse effects were noted.CONCLUSION JAK inhibitor therapy may be a promising strategy to treat SAPHO syndrome.展开更多
OBJECTIVE:To investiage the possible mechanism underlying the effect of the Jianpi Qutan Fang(健脾祛痰方,JPQT)on Atherosclerosis(AS)which is the main pathological process of most cardiovascular diseases that affect mi...OBJECTIVE:To investiage the possible mechanism underlying the effect of the Jianpi Qutan Fang(健脾祛痰方,JPQT)on Atherosclerosis(AS)which is the main pathological process of most cardiovascular diseases that affect millions of adults worldwide.METHODS:In the present study,rats were fed with a high-fat-diet(HFD)with vitamin D3 for 16 weeks and were orally administered atorvastatin treatment and different doses of JPQT.Histopathological changes and ultrastructural changes in the aorta were evaluated through hematoxylin-eosin staining and transmission electron microscopy(TEM),respectively.Suppressor of cytokine signaling 1(SOCS1)/Janus kinase 1(JAK1)/signal transducer and activator of transcription 1(STAT1)signaling pathways were detected through Western blotting.RESULTS:JPQT treatment decreased the lipid levels of triglyceride,low-density lipoprotein,and cholesterol,the inflammatory cytokine levels of interleukin 1 beta(IL-1β),IL-6 and IL-8 in rat serum,but increased high-density lipoprotein and IL-10 serum levels.JPQT treatment ameliorated pathological changes in the aorta of AS model rats.Moreover,JPQT upregulated SOCS1 protein expression and down-regulated phosphorylated protein expression levels of p-JAK1 and p-STAT1.CONCLUSION:These results suggest that JPQT induces anti-atherosclerosis effects through anti-inflammatory and inhibiting JAK/STAT signaling pathways in HFD fed rats.展开更多
The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, th...The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, the cellular and molecular mechanisms underlying sepsis-induced brain damage remain elusive. In the present study, we found severe loss of neurons in the hippocampal CA1 region in rats with sepsis-induced brain damage following intraperitoneal injection of endotoxin, The expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 was significantly increased in brain tissues following lipopolysaccharide exposure. AG490 （JAK2 antagonist） and rapamycin （STAT3 antagonist） significantly reduced neuronal loss and suppressed the increased expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 in the hippocampal CA1 region in sepsis-induced brain damaged rats. Overall, these data suggest that blockade of the JAK/STAT signal transduction pathway is neuroprotective in sepsis-induced brain damage via the inhibition of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 exoression.展开更多
The management of refractory ulcerative colitis(UC)and acute severe UC(ASUC)is challenging due to the lack of standardized approaches in cases resistant to multiple treatments.In this editorial,I investigate the effic...The management of refractory ulcerative colitis(UC)and acute severe UC(ASUC)is challenging due to the lack of standardized approaches in cases resistant to multiple treatments.In this editorial,I investigate the efficacy and safety of Janus kinase inhibitors,particularly upadacitinib and tofacitinib,in controlling severe and refractory disease.I highlight a notable case report by Xu et al,which explores the case of a patient with primary nonresponse to two classes of biologics and two fecal microbiota transplants who exhibited a remarkable response to upadacitinib.Furthermore,I discuss the use of tofacitinib in refractory UC and ASUC,either as monotherapy or in combination with biologics,which has shown promising response rates.Additionally,emerging evidence of upadacitinib efficacy in ASUC is presented.Overall,these cases emphasize the complex nature of managing refractory ASUC and the potential of small-molecule therapies to achieve remission.Further research is needed to refine treatment strategies for patients with treatment-resistant UC.展开更多
Recent advancements in the treatment landscape of ulcerative colitis(UC)have ushered in a new era of possibilities,particularly with the introduction of Janus kinase(JAK)-signal transducer and activator of transcripti...Recent advancements in the treatment landscape of ulcerative colitis(UC)have ushered in a new era of possibilities,particularly with the introduction of Janus kinase(JAK)-signal transducer and activator of transcription inhibitors.These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes.With approved JAK inhibitors(JAKis),such as tofacitinib,filgotinib,and upadacitinib,clinicians now have powerful tools to modulate immune responses and gene expression,potentially revolutionizing the treatment algorithm for UC.Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission,presenting viable options for patients who have failed conventional therapies.Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy,particularly in patients with aggressive disease phenotypes or refractory to biologic agents.The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC,offering timely relief for patients with active disease and facilitating personalized treatment approaches.Despite safety concerns,including cardiovascular risks and infections,ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.展开更多
Psoriatic arthritis(PsA)is a type of chronic inflammatory arthritis which is associated with psoriasis.The early recognition and treatment for PsA are of critical importance.Janus kinase(JAK)inhibitors,as a kind of or...Psoriatic arthritis(PsA)is a type of chronic inflammatory arthritis which is associated with psoriasis.The early recognition and treatment for PsA are of critical importance.Janus kinase(JAK)inhibitors,as a kind of orally small molecules,have emerged as an encouraging class of drug in PsA treatment.This review provides a discussion of the role and current status of JAK inhibitors in the control of PsA.There are three JAK inhibitors approved for use in autoimmune diseases,for example,tofacitinib,baricitinib,and upadacitinib,and only tofacitinib has been approved in PsA treatment.The clinical trials of upadacitinib and filgotinib in PsA patients are undergoing.The efficacy and safety of these agents were briefly discussed.Although there are still issues in terms of their efficacy and safety currently,JAK inhibitors are expected to benefit more PsA patients in future.展开更多
Objectives： To investigate the mechanism of Liuwei Dihuang Pill （六味地黄丸, LDP） in treating postmenopausal osteoporosis （PMOP） with Shen （Kidney） yin deficiency. Methods： In this study, 205 cases of PMOP wer...Objectives： To investigate the mechanism of Liuwei Dihuang Pill （六味地黄丸, LDP） in treating postmenopausal osteoporosis （PMOP） with Shen （Kidney） yin deficiency. Methods： In this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group （Group A）, PMOP Shen-yang deficiency group （Group B）, PMOP without Shen deficiency group （Group C）, and control group （Group N）. Real-time polymerase chain reaction （RT-PCR） and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 （CLCF1）, ankyrin repeat and SOCS box containing 1 （ASB1）, and proldneticin 2 （PROK2） genes and the Janus kinase/signal transducer and activator of transcription （JAK/STAT） signaling pathway. Results： The mRNA （P〈0.05） and protein （P〈0.01） expression levels of the CLCF1 gone in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gone were obviously up-regulated （P〈0.01）. After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated （both P〈0.01）, and the average bone density of the top femur had significantly increased （P〈0.05）. In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3. Conclusions： The CLCF1 gone is an important gone associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gone expression and activation of the JAK/STAT signaling pathway.展开更多
OBJECTIVE:To observe the intervention of Chushizi(Fructus Broussonetiae)(CSZ)on drug-induced liver injury(DILI)in rats,as well as indicators of liver function,serum levels of inflammatory cytokines,and expression of p...OBJECTIVE:To observe the intervention of Chushizi(Fructus Broussonetiae)(CSZ)on drug-induced liver injury(DILI)in rats,as well as indicators of liver function,serum levels of inflammatory cytokines,and expression of proteins and m RNA associated with toll-like receptor 3(TLR3)and the signal transducer and activator of transcription 3(STAT3)pathway in the liver[TLR3,janus protein tyrosine kinase 2(JAK2),c-jun,c-fos,c-Jun N-terminal kinase 2(JNK2),and STAT3].METHODS:Forty specified pathogen free grade Sprague-Dawley rats were randomly divided into the control group,the model group,the silybin group and the CSZ group.Rats were given acetaminophen(APAP)to trigger DILI.Histopathology of the liver was observed by hematoxylin-eosin staining.The levels of alanine aminotransferase(ALT),aspartate transaminase(AST),direct bilirubin(DBIL),and total bilirubin(TBIL)in serum were detected by a semi-automatic biochemical instrument.Content of tumor necrosis factor alpha(TNF-α),interleukin(IL)-6,IL-13,and IL-22 in serum were detected by the enzyme-linked immunosorbent assay,the expression of TLR3,phosphorylation of JAK2(p-JAK2),while c-jun and c-fos proteins in the liver were determined by immunohistochemistry;expression of JNK2,and STAT3 in the liver were assayed by Western blot and real-time quantitative polymerase chain reaction.P-JNK2 and p-STAT3 in the liver were assayed by Western blot.RESULTS:After treatment,the activity of ALT,AST,and concentrations of TBIL,DBIL,TNF-α,IL-6,as well as IL-13 in serum,were lower than those in the model group,and expression of p-JAK2,TLR3,c-jun,c-fos,p-STAT3,and p-JNK2 could be downregulated.CONCLUSION:Our findings suggest that CSZ is a valid medicine to alleviate APAP-induced DILI,while its partial mechanism may regulate the TLR3/JNK/c-jun/c-fos/JAK/STAT3 pathway.展开更多
Background： Recently, calreticulin （CALR） gene mutations have been identified in patients with essential thrombocythemia （ET）. A high-frequency of ET cases without Janus kinase 2 （JAK2） mutations contain CALR m...Background： Recently, calreticulin （CALR） gene mutations have been identified in patients with essential thrombocythemia （ET）. A high-frequency of ET cases without Janus kinase 2 （JAK2） mutations contain CALR mutations and exhibit clinical characteristics different from those with mutant JAK2. Thus, we investigated the frequency and clinical features of Chinese patients of Han ethnicity with CALR mutations in ET. Methods： We recruited 310 Chinese patients of Han ethnicity with ET to analyze states of CALR, JAK2 V617F, and MPLW5 15 mutations by polymerase chain reaction and direct sequencing. We analyzed the relationship between the mutations and clinical features. Results： CALR, JAK2V617E and MPLW515 mutations were detected in 30% （n = 92）, 48% （n = 149）, and 1% （n = 4） of patients with ET, respectively. The mutation types of CALR involved deletion and insertion of base pairs. Most of them were Type 1 （52-bp deletion） and Type 2 （5-bp insertion, TTGTC） mutations, leading to de1367fs46 and ins385fs47, respectively. The three mutations were exclusive. Clinically, patients with mutated CALR had a lower hemoglobin level, lower white blood cell （WBC） count, and higher platelet count compared to those with mutated JAK2 （P 〈 0.05）. Furthermore, a significant difference was found in WBCs between wild-type patients （triple negative for JAK2, MPL, and CALR mutations） and patients with JAK2 mutations. Patients with CA LR mutations predominantly clustered into low or intermediate groups according to the International Prognostic Score of thrombosis for ET （P 〈 0.05）. Conclusions： CALR mutations were frequent in Chinese patients with ET, especially in those without JAK2 or MPL mutations. Compared withJAK2 mutant ET, CALR mutant ET showed a different clinical manifestation and an unfavorable prognosis. Thus, C4LR is a potentially valuable diagnostic marker and therapeutic target in ET.展开更多
Amyotrophic lateral sclerosis(ALS)is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles.As with other multifactorial diseases,it is likely that dru...Amyotrophic lateral sclerosis(ALS)is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles.As with other multifactorial diseases,it is likely that drugs will need to target multiple disease processes and cell types to be effective.We review here the role of Janus kinase(JAK)/Signal transducer and activator of transcription(STAT)signalling in ALS,confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph,and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons,glia,muscle fibres,and blood cells.Specifically,we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease.Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system.Therefore,we recommend that this drug be tested in appropriately designed clinical trials for ALS.展开更多
Objective:Sepsis-induced acute lung injury(ALI) is a clinically critical condition with a high mortality rate.Shenfu injection(SFI) is a Chinese herbal medicine extracted from red ginseng and Aconite,Radix Aconiti,wit...Objective:Sepsis-induced acute lung injury(ALI) is a clinically critical condition with a high mortality rate.Shenfu injection(SFI) is a Chinese herbal medicine extracted from red ginseng and Aconite,Radix Aconiti,with various pharmacological activities.This study aimed to investigate the potential mechanism of action of SFI in preventing sepsis-induced ALI.Materials and Methods:We established a mouse model of sepsis-induced ALI by cecal ligation and puncture(CLP).The mice were randomly divided into three groups(n=8):Sham,CLP,and SFI(10 mL/kg).Bronchoalveolar lavage fluid(BALF) and lung tissue were collected for pathological analysis,enzyme-linked immunosorbent assay,immunohistochemistry(IHC),and protein detection.Results:Our results showed that SFI significantly ameliorated pathological damage caused by CLP-induced ALI.SFI treatment significantly decreased the lung wet-to-dry weight ratio.In addition,SFI tr eatment significantly reduced the protein levels and cell numbers in the BALF SFI could significantly reduce the levels of tumor necrosis factor-α,interleukin-6(IL-6),and IL-1β in plasma and BALF.SFI significantly reduced the protein expression of B ax and cleaved caspase-3and increased the protein levels of Bcl-2.Western blotting and IHC results showed that SFI reduced the phosphorylation of Janus kinase2(JAK2) and signal transducer and activator of transcription 3(STAT3).Conclusions:In a septic ALI mouse model,SFI inhibited apoptosis and inflammation through the JAK2/STAT3 pathway,providing a candidate drug for the treatment of septic ALI.展开更多
OBJECTIVE:Electroacupuncture effect on neurological behavior and the expression of tyrosine kinase Janus kinase 2(JAK 2) of ischemic cortex in rats with the focal cerebral ischemia were investigated in this study.METH...OBJECTIVE:Electroacupuncture effect on neurological behavior and the expression of tyrosine kinase Janus kinase 2(JAK 2) of ischemic cortex in rats with the focal cerebral ischemia were investigated in this study.METHODS:The model of focal cerebral ischemia was established by the heat-coagulation induced the occlusion of the middle cerebral artery.The electro-acupuncture was applied on Baihui(GV 20) and Dazhui(GV 14),and AG490 was applied by intracerebroventricular infusion.The expressions of JAK2 mRNA and phospharylatedJAK2(p-JAK2) in the ischemic cortex were observed by in situ hybridization and western blotting.RESULTS:The expressions of JAK2 mRNA and p-JAK2 were rarely found in sham surgery group.In model group,the expression of JAK2 mRNA and JAK2 phosphorylation had increased.After 1 day of cerebral ischemia,the expression had reached its peak.After cerebral ischemia,the expressions of JAK2 mRNA and p-JAK2 were consistent with the neurological deficit score.Electroacupuncture treatment and AG490 intervention were able to improve the neurological deficit score after cerebral ischemia,and down-regulate the expressions of JAK2 mRNAand JAK2 phosphorylation.CONCLUSION:After cerebral ischemia,the excessive expressions of JAK2 and the JAK2 phosphorylation would be one of mechanisms by which the brain injury got worse.The therapy of electro-acupuncture could reduce the expression of JAK2,and inhibit JAK2 phosphorylated activation,so as to block the abnormal activation of signal transduction pathway which was induced by JAK2.展开更多
We previously demonstrated using noninvasive technologies that the interferon-gamma （IFN-γ） receptor complex is preassembled [ 1 ]. In this report we determined how the receptor complex is preassembled and how the ...We previously demonstrated using noninvasive technologies that the interferon-gamma （IFN-γ） receptor complex is preassembled [ 1 ]. In this report we determined how the receptor complex is preassembled and how the ligand-mediated conformational changes occur. The interaction of Statl with IFN-γR1 results in a conformational change localized to IFN- γR1. Jakl but not Jak2 is required for the two chains of the IFN-γ receptor complex （IFN-γR1 and IFN-γR2） to interact; however, the presence of both Jakl and Jak2 is required to see any ligand-dependant conformational change. Two IFN- γR2 chains interact through species-specific determinants in their extracellular domains. Finally, these determinants also participate in the interaction of IFN-γR2 with IFN-γR1. These results agree with a detailed model of the IFN-γ receptor that requires the receptor chains to be pre-associated constitutively for the receptor to be active.展开更多
文摘Ulcerative colitis(UC)is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’quality of life.Traditional medicinal strategies available,including amino salicylates,corticosteroids,and biologics,offer limited efficacy,safety,and durability of response.The advancement in small-molecule Janus kinase(JAK)inhibitors has introduced a novel,oral therapeutic option that targets intracellular signaling pathways implicated in UC pathogenesis.Tofacitinib is the first approved JAK inhibitor for the treatment of moderate-to-severe UC.This drug,despite offering promising efficacy,has various safety concerns,especially the occurrence of thromboembolic events.These adverse effects have stressed the devel-opment of more selective agents such as upadacitinib and filgotinib.This mini-review explores the current perspectives of JAK inhibitors in UC,particularly focusing on their mechanisms of action,safety profiles,clinical trial outcomes,and emerging strategies to enhance their use.This review also highlights future directions,including the potential of selective JAK1 inhibition and the role of personalized medicine in refining therapeutic decisions.Understanding the emerging place of JAK inhibitors within the UC treatment strategies offers excellent opportunities to increase patient care and long-term disease management.
文摘Background: Non-radiographic axial spondyloarthritis is a progressive and disabling inflammatory disease affecting young adults, with limited treatment options. TNFi are more efficacious than JAKi and IL1-7i in nr-ax SPA and it has a well-known safety profile over a longer duration. Recently, many IL-17i and JAKi were approved for the treatment of nr-ax SPA;however, data comparing IL1-7i and JAKi in terms of efficacy and safety is lacking. This systematized review aimed to compare the existing efficacy and safety data of JAKi vs IL-17i in the treatment of patients with nr-ax SPA. Methods: A systematic literature search was performed using relevant keywords in many databases. According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA, 2020), relevant articles were included and evaluated in this review. Efficacy and safety data were collected, analyzed and compared through week 52. The first check was done by the end of week 14 and week 16 for upadacitinib and IL-17i respectively. Results: Data from four RCTs evaluating upadacitinib, secukinumab, ixekizumab, and bimekizumab comprising 1425 patients were analyzed. Overall, a comparable efficacy and safety profile were observed across different treatment arms through week 52;however, non-significant variations were encountered in some outcome measures. The primary endpoint among these RCTs (ASAS40 response rate) was met and it was higher in patients treated with bimekizumab 160 mg sc Q 4 weeks in TNFi non responders (48%) and lowest in ixekizumab 80 mg sc Q 4 weeks treated patients, (35%) (p Conclusion: The above-mentioned three IL-17i and the only one JAKi demonstrated comparable safety and efficacy profiles with some minor variations. A head-to-head trial comparing the effectiveness and safety characteristics of JAKi vs IL-17i may be needed in patients with active nr-ax SpA.
基金Supported by the Science and Technology Research Project of Hubei Province,No.2021CFB210Central Guiding Local Science and Technology Development Fund Project(Science and Technology Department of Xizang Autonomous Region),No.XZ202401YD0002C。
文摘BACKGROUND Inflammatory bowel disease(IBD)is a chronic,progressive inflammatory condition of the intestine.Mesenchymal stem cell(MSC)therapy for IBD has made significant progress in recent years.To better exploit the therapeutic potential of MSCs,pretreatment strategies are employed to enhance their therapeutic capabilities.As a compound with diverse pharmacological effects,quercetin(QUR)is applied to pretreat human umbilical cord-derived MSCs(hUCMSCs)in this study,thereby augmenting their immunotherapeutic potential.AIM To evaluate the therapeutic efficacy of QUR-pretreated hUCMSCs.METHODS We induced colitis in a mouse model using a 2,4,6-trinitrobenzenesulfonic acid solution.Intraperitoneal injection of QUR-pretreated hUCMSCs significantly improved clinical and pathological manifestations of colitis compared to the model group.Interestingly,the therapeutic effect was superior to that of untreated hUCMSCs.Mice exhibited significantly reduced weight loss,diminished infiltration of inflammatory cells observed in hematoxylin and eosin staining,improved Disease Activity Index and Histological Activity Index scores.Furthermore,colonic tissue analysis revealed a significant upregulation of the anti-inflammatory cytokine interleukin 10(IL-10),accompanied by a downregulation of the pro-inflammatory cytokine IL-6.Further tests also suggested that QUR pretreatment led to inhibition of Janus kinase/signal transducer and activator of transcription(STAT)phosphorylation.RESULTS Our study demonstrated that QUR pretreatment of hUCMSCs significantly enhanced their immune-regulatory capacity.This approach effectively mitigated colonic inflammation in a mouse colitis model by modulating the IL-10/Janus kinase/STAT signaling pathway.CONCLUSION These findings suggest that QUR pretreatment acts synergistically to augment the inherent anti-inflammatory and immune-regulatory properties of hUCMSCs,resulting in enhanced therapeutic efficacy for IBD treatment.
基金Unrestricted departmental grant from Research to Prevent Blindness.T.M.J.receives funding from the National Institutes of Health(K12TR005104).
文摘Non-infectious uveitis(NIU),although a highly blinding but preventable cause of blindness around the world,has few approved pharmaceuticals for its treatment.Lack of access to effective treatment is likely a major cause of poor visual outcomes in NIU.However,despite a revolution in rheumatologic disease treatment with the advent of multiple biologic therapeutics selectively targeting the immune response,there remains a gap in the long-term management of NIU.Adalimumab remains the only systemic medication approved for the treatment of NIU by the Food and Drug Administration(FDA).All other systemic treatments,including older anti-metabolites such as methotrexate and mycophenolate,are used offlabel for NIU,posing significant treatment challenges.Given the nature and rarity of the disease,there are few well designed,large,clinical trials evaluating the efficacy of novel therapeutic agents within this field.We therefore read with great interest Srivastava et al.’s randomized clinical trial on the efficacy of filgotinib,a Janus kinase inhibitor(JAKi),in active NIU(1).The early termination of the trial due to business considerations highlights the industry difficulty in FDA medication approval for NIU.
基金Supported by 973 Project for Basic Research of Traditional Chinese Medicine(No.2010CB530405)the National Natural Science Foundation of China(Effects and Mechanisms of Storax on NF-ΚB-Mediated Inflammatory Response During Cerebral Ischemia-Reperfusion Injure,No.81273815)+1 种基金the Foundation for the Author of National Excellent Doctoral Dissertation of China(No.201082)the China Postdoctoral Fund of Sciences(The Effect of Cerebrospinal Fluid Containing Yishenhuazhuo Decotion on the Self-Renewal and Differentiation of Neural Stem Cell,No.2012M520587)
文摘OBJECTIVE: Inactivation of the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3) signaling axis plays a crucial role in determining the fate of neural stem cells(NSCs).Qingnaoyizhi decoction(QNYZD) has been used for the treatment of vascular dementia and has shown to improve synaptic remodeling. The aim of this study was to evaluate the effect of cerebrospinal fluid(CSF) containing QNYZD(CSF-QNYZD) on the differentiation of cultured NSCs and the involvement of the JAK2/STAT3 pathway.METHODS: The protein expression levels of glial fibrillary acidic protein(GFAP), tubulin, drosophila mothers against decapentaplegic protein(SMAD-1), STAT3, and phosphorylated-STAT3 were detected by western immunoblot analysis in the groups: control, CSF, JAK/STAT inhibitor(AG490),CSF-QNYZD, and CSF-XDZ(CSF-Xidezhen). The differentiation of NSCs was determined by immunofluorescence staining. The proliferation of NSCs was measured using the Cell Counting Kit-8 proliferation assay.RESULTS: Compared with the control group,CSF-QNYZD and AG490 significantly increased the number and expression of tubulin-positive cells, reduced the number and expression of GFAP-positive cells, and down-regulated the expression of p-STAT3. However, CSF-QNYZD also decreased the expression of SMAD-1 and STAT3.CONCLUSION: Enhanced neuronal differentiation may be associated with the down-regulation of glial differentiation instead of promoting proliferationin treated NSCs. Furthermore, QNYZD may play a direct role in suppressing the formation of GFAP-positive cells and enhancing neuronal differentiation by inhibiting JAK2/STAT3 activation. Overall, these results provide insights into the possible mechanism underlying QNYZD-mediated neurogenesis.
基金Supported by the National Natural Science Foundation of China(Based on JAK/STAT Signaling Pathway to Discuss the Effects of Qingshen Granules for Anti Renal Fibrosis,General Program,No.81473673Based on P-selectin/PSGL-1 mediated MAPK Signaling Pathway to Discuss the Effects of Qingshen granules for Vascular Endothelial Injury Due to Renal Fibrosis,General Program,No.81673931)+1 种基金National Science Fund for Distinguished Young Scholars of China(Based on NF-k B Signaling Pathway and Oxidative Stress to Discuss the Effects of Qingshen granules in Transdifferentiation of Renal Tubular Epithelial Cells,No.81403372)Anhui Natural Science Foundation(Based on Leptin-JAK/STAT-inflammatory pathway to study the effects of Qingshen granules for anti renal fibrosis,No.1508085MH198)
文摘OBJECTIVE:To investigate the effects of Qingshen granules(QSG) on janus kinase/signal transducer and activator of transcription(JAK/STAT) signaling pathway in a rat model of unilateral ureteral obstruction(UUO).METHODS: Sixty male Sprague-Dawley rats wererandomly divided into six groups, with 10 animals in each group: the untreated sham-operated normal control group; the untreated UUO model control group, the high dose QSG-treated(16 gdm dose QSG-·kg-1-1) UUO group; the mediutreate·d(8 g·kg-1·d-1) UUO group; the low dose QSG-treated(4 g·kg-1·d-1) UUO group; and the valsartan-treated group(20 mg·kg-1·d-1). The two untreated control groups received physiological saline(1 m L/100 g per day). All the rats were sacrificed after a 4-week course of treatment. Serum creatinine and leptin; protein expressions of leptin receptor(OB-R), p-JAK2, p-STAT3, nuclear factors-κBp6(NF-k Bp65), and monocytechemotatic protein-1(MCP-1); m RNA of JAK2, STAT3, calcium-dependent adhesion(E-cadherin), alphasmooth muscle actin(α-SMA) in the kidney tissues;and the expressions of type ronectin(FN) and the pⅣat collagen(Col-homorphologyⅣ)and fib in kidney tissues were treated.RESULTS: Compared with the normal group, the BUN, Scr, and serum leptin levels and the expressions of MCP-1, p-JAK2, p-STAT3, NF-k Bp65 and OB-R in renal tissues, and the m RNA expressions of leptin, JAK2 protein, STAT3 protein, α-SMA protein in model group were significantly higher(P < 0.01)in the UUO model group. These parameters were significantly reduced in all the QSG-treated groups and the valsartan-treated group than the UUO model group(P < 0.05 or P < 0.01), with the lowest levels found in the medium dose QSG-treated group(P < 0.05). However, the expression levels of E-cadherin, FN, and Col-Ⅳ in the renal tissues were contrary to the expressions described above. Se-vere pathological injury was evident in the renal tissues of UUO model rats, which was alleviated in the QSG-treated and valsartan-treated groups, with the least damage found in the medium dose QSG-treated group.CONCLUSION: Our data suggest that the leptin-mediated JAK/STAT signaling pathway is involved in the process of renal interstitial fibrosis in UUO rats. QSG inhibited the activity of the signaling pathway, reduced the activity of NF-k B and inflammatory effect, and the transdifferentiation in the renal tubular epithelial cells. Treatment with QSG may delay the renal fibrosis and protect the renal function from damage following UUO in rats.
文摘BACKGROUND Synovitis,acne,pustulosis,hyperostosis,and osteitis(SAPHO)syndrome is a rare autoinflammatory disease for which clinical treatment has not been standardized.Janus kinase(JAK)inhibitors represent a novel therapeutic option for rheumatoid arthritis,psoriatic arthritis,and some other autoinflammatory diseases.However,the clinical utility of JAK inhibitors in treating SAPHO syndrome has not been thoroughly investigated.In this study,we describe a patient with SAPHO syndrome who failed to respond to conventional treatment but demonstrated a remarkable and rapid response to the JAK inhibitor tofacitinib.CASE SUMMARY A 62-year-old female patient presented with swelling and pain at the sternoclavicular joints,back pain that limited her activities,arthralgia in the right knee,and cutaneous lesions.Her symptoms were unresponsive to nonsteroidal anti-inflammatory drugs,disease-modifying antirheumatic drugs,Tripterygium wilfordii hook f,and bisphosphonates.SAPHO syndrome was diagnosed in accordance with dermatological and osteoarticular manifestations and abnormal inflammatory factors.Multiple image studies have illustrated bone lesions and pathological fractures of vertebral bodies.Oral treatment with tofacitinib at 5 mg twice daily with methotrexate and bisphosphonates was initiated.The patient reported that her pain symptoms were relieved after 3 d and her cutaneous lesions were reduced after 4 wk of treatment.Vertebral lesions were improved after 6 mo on tofacitinib.No serious adverse effects were noted.CONCLUSION JAK inhibitor therapy may be a promising strategy to treat SAPHO syndrome.
基金the National Natural Science Foundation of China:Explore the Regulatory Mechanism of Coronary Endothelial Immune Inflammation Mediated by Micro RNA155-SOCS1 Axis in Bama Pigs based on “Xin Shou Qi Yu Pi”(No.81703970)the National 973 Program on Key Basic Research Project:Study on the Therapeutic Mechanism and Rule of Treating Angina Pectoris based on “Cong Pi Lun Zhi”(No.2013CB531704)
文摘OBJECTIVE:To investiage the possible mechanism underlying the effect of the Jianpi Qutan Fang(健脾祛痰方,JPQT)on Atherosclerosis(AS)which is the main pathological process of most cardiovascular diseases that affect millions of adults worldwide.METHODS:In the present study,rats were fed with a high-fat-diet(HFD)with vitamin D3 for 16 weeks and were orally administered atorvastatin treatment and different doses of JPQT.Histopathological changes and ultrastructural changes in the aorta were evaluated through hematoxylin-eosin staining and transmission electron microscopy(TEM),respectively.Suppressor of cytokine signaling 1(SOCS1)/Janus kinase 1(JAK1)/signal transducer and activator of transcription 1(STAT1)signaling pathways were detected through Western blotting.RESULTS:JPQT treatment decreased the lipid levels of triglyceride,low-density lipoprotein,and cholesterol,the inflammatory cytokine levels of interleukin 1 beta(IL-1β),IL-6 and IL-8 in rat serum,but increased high-density lipoprotein and IL-10 serum levels.JPQT treatment ameliorated pathological changes in the aorta of AS model rats.Moreover,JPQT upregulated SOCS1 protein expression and down-regulated phosphorylated protein expression levels of p-JAK1 and p-STAT1.CONCLUSION:These results suggest that JPQT induces anti-atherosclerosis effects through anti-inflammatory and inhibiting JAK/STAT signaling pathways in HFD fed rats.
文摘The Janus kinase and signal transducer and activator of transcription （JAK/STAT） signal transduction pathway is involved in sepsis-induced functional damage to the heart, liver, kidney, and other organs. However, the cellular and molecular mechanisms underlying sepsis-induced brain damage remain elusive. In the present study, we found severe loss of neurons in the hippocampal CA1 region in rats with sepsis-induced brain damage following intraperitoneal injection of endotoxin, The expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 was significantly increased in brain tissues following lipopolysaccharide exposure. AG490 （JAK2 antagonist） and rapamycin （STAT3 antagonist） significantly reduced neuronal loss and suppressed the increased expression of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 in the hippocampal CA1 region in sepsis-induced brain damaged rats. Overall, these data suggest that blockade of the JAK/STAT signal transduction pathway is neuroprotective in sepsis-induced brain damage via the inhibition of toll-like receptor 4, tumor necrosis factor a, and interleukin-6 exoression.
文摘The management of refractory ulcerative colitis(UC)and acute severe UC(ASUC)is challenging due to the lack of standardized approaches in cases resistant to multiple treatments.In this editorial,I investigate the efficacy and safety of Janus kinase inhibitors,particularly upadacitinib and tofacitinib,in controlling severe and refractory disease.I highlight a notable case report by Xu et al,which explores the case of a patient with primary nonresponse to two classes of biologics and two fecal microbiota transplants who exhibited a remarkable response to upadacitinib.Furthermore,I discuss the use of tofacitinib in refractory UC and ASUC,either as monotherapy or in combination with biologics,which has shown promising response rates.Additionally,emerging evidence of upadacitinib efficacy in ASUC is presented.Overall,these cases emphasize the complex nature of managing refractory ASUC and the potential of small-molecule therapies to achieve remission.Further research is needed to refine treatment strategies for patients with treatment-resistant UC.
文摘Recent advancements in the treatment landscape of ulcerative colitis(UC)have ushered in a new era of possibilities,particularly with the introduction of Janus kinase(JAK)-signal transducer and activator of transcription inhibitors.These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes.With approved JAK inhibitors(JAKis),such as tofacitinib,filgotinib,and upadacitinib,clinicians now have powerful tools to modulate immune responses and gene expression,potentially revolutionizing the treatment algorithm for UC.Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission,presenting viable options for patients who have failed conventional therapies.Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy,particularly in patients with aggressive disease phenotypes or refractory to biologic agents.The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC,offering timely relief for patients with active disease and facilitating personalized treatment approaches.Despite safety concerns,including cardiovascular risks and infections,ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.
基金This project was supported by grants from the National Natural Science Foundation of China(No.81771746 and No.81900795)。
文摘Psoriatic arthritis(PsA)is a type of chronic inflammatory arthritis which is associated with psoriasis.The early recognition and treatment for PsA are of critical importance.Janus kinase(JAK)inhibitors,as a kind of orally small molecules,have emerged as an encouraging class of drug in PsA treatment.This review provides a discussion of the role and current status of JAK inhibitors in the control of PsA.There are three JAK inhibitors approved for use in autoimmune diseases,for example,tofacitinib,baricitinib,and upadacitinib,and only tofacitinib has been approved in PsA treatment.The clinical trials of upadacitinib and filgotinib in PsA patients are undergoing.The efficacy and safety of these agents were briefly discussed.Although there are still issues in terms of their efficacy and safety currently,JAK inhibitors are expected to benefit more PsA patients in future.
基金Supported by National Natural Science Foundation of China(Nos.81173280,81302995,81403420)Fujian Medical Innovation project(No.2011-CX-30)+1 种基金Science and Technology Department of Fujian Province autonomous non-profit research institutes topics project(No.2011R1038-5)Fujian Academy of Traditional Chinese autonomous topics Project(No.2012fjzyyk-5)
文摘Objectives： To investigate the mechanism of Liuwei Dihuang Pill （六味地黄丸, LDP） in treating postmenopausal osteoporosis （PMOP） with Shen （Kidney） yin deficiency. Methods： In this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group （Group A）, PMOP Shen-yang deficiency group （Group B）, PMOP without Shen deficiency group （Group C）, and control group （Group N）. Real-time polymerase chain reaction （RT-PCR） and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 （CLCF1）, ankyrin repeat and SOCS box containing 1 （ASB1）, and proldneticin 2 （PROK2） genes and the Janus kinase/signal transducer and activator of transcription （JAK/STAT） signaling pathway. Results： The mRNA （P〈0.05） and protein （P〈0.01） expression levels of the CLCF1 gone in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gone were obviously up-regulated （P〈0.01）. After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated （both P〈0.01）, and the average bone density of the top femur had significantly increased （P〈0.05）. In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3. Conclusions： The CLCF1 gone is an important gone associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gone expression and activation of the JAK/STAT signaling pathway.
基金Supported by the National Natural Science Foundation of China(Study on the Compatibility Relationship and Mechanism of Vinegar Kansui and Roasted Licorice Based on the Theory of Medicine Syndrome,No.81503268)the Top Program of Science and Technology Research Youth in Colleges and Universities of Hebei Province(Study on the Preventive and Therapeutic Effect and Mechanism of Jiedu Hugan Recipe on Drug-Induced Liver Injury,No.BJ2016038)+1 种基金the Central Finance Public Health Project 2017the General Survey of Traditional Chinese Medicine Resources(No.Z135080000022)。
文摘OBJECTIVE:To observe the intervention of Chushizi(Fructus Broussonetiae)(CSZ)on drug-induced liver injury(DILI)in rats,as well as indicators of liver function,serum levels of inflammatory cytokines,and expression of proteins and m RNA associated with toll-like receptor 3(TLR3)and the signal transducer and activator of transcription 3(STAT3)pathway in the liver[TLR3,janus protein tyrosine kinase 2(JAK2),c-jun,c-fos,c-Jun N-terminal kinase 2(JNK2),and STAT3].METHODS:Forty specified pathogen free grade Sprague-Dawley rats were randomly divided into the control group,the model group,the silybin group and the CSZ group.Rats were given acetaminophen(APAP)to trigger DILI.Histopathology of the liver was observed by hematoxylin-eosin staining.The levels of alanine aminotransferase(ALT),aspartate transaminase(AST),direct bilirubin(DBIL),and total bilirubin(TBIL)in serum were detected by a semi-automatic biochemical instrument.Content of tumor necrosis factor alpha(TNF-α),interleukin(IL)-6,IL-13,and IL-22 in serum were detected by the enzyme-linked immunosorbent assay,the expression of TLR3,phosphorylation of JAK2(p-JAK2),while c-jun and c-fos proteins in the liver were determined by immunohistochemistry;expression of JNK2,and STAT3 in the liver were assayed by Western blot and real-time quantitative polymerase chain reaction.P-JNK2 and p-STAT3 in the liver were assayed by Western blot.RESULTS:After treatment,the activity of ALT,AST,and concentrations of TBIL,DBIL,TNF-α,IL-6,as well as IL-13 in serum,were lower than those in the model group,and expression of p-JAK2,TLR3,c-jun,c-fos,p-STAT3,and p-JNK2 could be downregulated.CONCLUSION:Our findings suggest that CSZ is a valid medicine to alleviate APAP-induced DILI,while its partial mechanism may regulate the TLR3/JNK/c-jun/c-fos/JAK/STAT3 pathway.
文摘Background： Recently, calreticulin （CALR） gene mutations have been identified in patients with essential thrombocythemia （ET）. A high-frequency of ET cases without Janus kinase 2 （JAK2） mutations contain CALR mutations and exhibit clinical characteristics different from those with mutant JAK2. Thus, we investigated the frequency and clinical features of Chinese patients of Han ethnicity with CALR mutations in ET. Methods： We recruited 310 Chinese patients of Han ethnicity with ET to analyze states of CALR, JAK2 V617F, and MPLW5 15 mutations by polymerase chain reaction and direct sequencing. We analyzed the relationship between the mutations and clinical features. Results： CALR, JAK2V617E and MPLW515 mutations were detected in 30% （n = 92）, 48% （n = 149）, and 1% （n = 4） of patients with ET, respectively. The mutation types of CALR involved deletion and insertion of base pairs. Most of them were Type 1 （52-bp deletion） and Type 2 （5-bp insertion, TTGTC） mutations, leading to de1367fs46 and ins385fs47, respectively. The three mutations were exclusive. Clinically, patients with mutated CALR had a lower hemoglobin level, lower white blood cell （WBC） count, and higher platelet count compared to those with mutated JAK2 （P 〈 0.05）. Furthermore, a significant difference was found in WBCs between wild-type patients （triple negative for JAK2, MPL, and CALR mutations） and patients with JAK2 mutations. Patients with CA LR mutations predominantly clustered into low or intermediate groups according to the International Prognostic Score of thrombosis for ET （P 〈 0.05）. Conclusions： CALR mutations were frequent in Chinese patients with ET, especially in those without JAK2 or MPL mutations. Compared withJAK2 mutant ET, CALR mutant ET showed a different clinical manifestation and an unfavorable prognosis. Thus, C4LR is a potentially valuable diagnostic marker and therapeutic target in ET.
文摘Amyotrophic lateral sclerosis(ALS)is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles.As with other multifactorial diseases,it is likely that drugs will need to target multiple disease processes and cell types to be effective.We review here the role of Janus kinase(JAK)/Signal transducer and activator of transcription(STAT)signalling in ALS,confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph,and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons,glia,muscle fibres,and blood cells.Specifically,we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease.Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system.Therefore,we recommend that this drug be tested in appropriately designed clinical trials for ALS.
基金supported by the Inner Mongolia University for the Nationalities General Project (NMDYB17171)
文摘Objective:Sepsis-induced acute lung injury(ALI) is a clinically critical condition with a high mortality rate.Shenfu injection(SFI) is a Chinese herbal medicine extracted from red ginseng and Aconite,Radix Aconiti,with various pharmacological activities.This study aimed to investigate the potential mechanism of action of SFI in preventing sepsis-induced ALI.Materials and Methods:We established a mouse model of sepsis-induced ALI by cecal ligation and puncture(CLP).The mice were randomly divided into three groups(n=8):Sham,CLP,and SFI(10 mL/kg).Bronchoalveolar lavage fluid(BALF) and lung tissue were collected for pathological analysis,enzyme-linked immunosorbent assay,immunohistochemistry(IHC),and protein detection.Results:Our results showed that SFI significantly ameliorated pathological damage caused by CLP-induced ALI.SFI treatment significantly decreased the lung wet-to-dry weight ratio.In addition,SFI tr eatment significantly reduced the protein levels and cell numbers in the BALF SFI could significantly reduce the levels of tumor necrosis factor-α,interleukin-6(IL-6),and IL-1β in plasma and BALF.SFI significantly reduced the protein expression of B ax and cleaved caspase-3and increased the protein levels of Bcl-2.Western blotting and IHC results showed that SFI reduced the phosphorylation of Janus kinase2(JAK2) and signal transducer and activator of transcription 3(STAT3).Conclusions:In a septic ALI mouse model,SFI inhibited apoptosis and inflammation through the JAK2/STAT3 pathway,providing a candidate drug for the treatment of septic ALI.
基金Supported by the Funds of National Basic Research Program of China(973 program,No.2010CB530500)National Natural Science Foundation of China(No.30973788)+1 种基金Guangdong province science and technology projects (No.2010B031500016)Guangdong Natural Science Foundation(No.9351040701000001)
文摘OBJECTIVE:Electroacupuncture effect on neurological behavior and the expression of tyrosine kinase Janus kinase 2(JAK 2) of ischemic cortex in rats with the focal cerebral ischemia were investigated in this study.METHODS:The model of focal cerebral ischemia was established by the heat-coagulation induced the occlusion of the middle cerebral artery.The electro-acupuncture was applied on Baihui(GV 20) and Dazhui(GV 14),and AG490 was applied by intracerebroventricular infusion.The expressions of JAK2 mRNA and phospharylatedJAK2(p-JAK2) in the ischemic cortex were observed by in situ hybridization and western blotting.RESULTS:The expressions of JAK2 mRNA and p-JAK2 were rarely found in sham surgery group.In model group,the expression of JAK2 mRNA and JAK2 phosphorylation had increased.After 1 day of cerebral ischemia,the expression had reached its peak.After cerebral ischemia,the expressions of JAK2 mRNA and p-JAK2 were consistent with the neurological deficit score.Electroacupuncture treatment and AG490 intervention were able to improve the neurological deficit score after cerebral ischemia,and down-regulate the expressions of JAK2 mRNAand JAK2 phosphorylation.CONCLUSION:After cerebral ischemia,the excessive expressions of JAK2 and the JAK2 phosphorylation would be one of mechanisms by which the brain injury got worse.The therapy of electro-acupuncture could reduce the expression of JAK2,and inhibit JAK2 phosphorylated activation,so as to block the abnormal activation of signal transduction pathway which was induced by JAK2.
文摘We previously demonstrated using noninvasive technologies that the interferon-gamma （IFN-γ） receptor complex is preassembled [ 1 ]. In this report we determined how the receptor complex is preassembled and how the ligand-mediated conformational changes occur. The interaction of Statl with IFN-γR1 results in a conformational change localized to IFN- γR1. Jakl but not Jak2 is required for the two chains of the IFN-γ receptor complex （IFN-γR1 and IFN-γR2） to interact; however, the presence of both Jakl and Jak2 is required to see any ligand-dependant conformational change. Two IFN- γR2 chains interact through species-specific determinants in their extracellular domains. Finally, these determinants also participate in the interaction of IFN-γR2 with IFN-γR1. These results agree with a detailed model of the IFN-γ receptor that requires the receptor chains to be pre-associated constitutively for the receptor to be active.
