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The Involvement of IL-34 in Inflammatory and Malignant Skin Diseases

Thi Viet Trinh Dang Ahmed M. Mehdi Snehlata Kumari Kiarash Khosrotehrani Ian H. Frazer David A. Hume Janin Chandra

Frazer Institute Faculty of Health Medicine and Behavioural Sciences The University of Queensland Brisbane AustraliaData Science Collaborative Research Platform The University of Queensland AustraliaDermatology Research Centre The University of Queensland Brisbane AustraliaMater Research Institute The University of Queensland Brisbane Australia

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关键词： CSF1R Epidermis IL-34 Langerhans cells Squamous cell carcinoma

摘要：

The mononuclear phagocyte system depends upon CSF1R and its 2 ligands, CSF1 and IL-34. IL-34 is expressed constitutively in the skin in mice and humans from a conserved keratinocyte-specific promoter, suggesting a specific function in epidermal homeostasis. IL-34 deficiency leads to loss of Langerhans cells, the major antigen-presenting cell of the epidermis. Decreased IL-34 expression has been reported in inflammatory and malignant epithelial skin diseases, including atopic dermatitis, psoriasis, eczema, UV-damaged skin, response to common skin sensitizers and various types of squamous cell carcinomas. We discuss the possible contribution of the loss of IL-34 to immune dysregulation in the skin.

盐酸青藤碱抑制急性T淋巴细胞白血病CEM细胞株的作用及转录组学分析

康林之刘振帅魏佳旭常娜朱大诚

江西中医药大学江西省南昌市330004延安大学陕西省延安市716000

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维普期刊数据库

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关键词： 盐酸青藤碱急性T淋巴细胞白血病 CEM细胞细胞凋亡 RNA-seq测序增殖抑制工程化细胞

摘要： 背景:盐酸青藤碱有抗多种肿瘤的作用,但目前尚不清楚盐酸青藤碱对急性T淋巴细胞白血病的作用。目的:探讨盐酸青藤碱对急性T淋巴细胞白血病CEM细胞的抑制作用。方法:应用不同浓度(0.5,1,2,4 mmol/L)盐酸青藤碱处理CEM细胞,CCK-8检测细胞增殖抑制率并计算IC50;倒置显微镜和吉姆萨染色观察CEM细胞形态变化;利用RNA-Seq测序分析差异基因表达并进行生物信息学分析。结合转录组测序结果,流式细胞术检测不同浓度(1,2,4 mmol/L)盐酸青藤碱作用后CEM细胞凋亡率;Western blot检测不同浓度(1,2,4 mmol/L)盐酸青藤碱作用后CEM细胞中Bcl-2、Bax、Caspase-9蛋白的表达。结果与结论:①盐酸青藤碱呈剂量和时间依赖性地抑制CEM细胞生长;②盐酸青藤碱干预后CEM细胞数量下降,核固缩;③RNA-seq测序筛出53个异常表达基因,基因本体分析主要富集在细胞过程、细胞解剖实体与粘连关系等,信号通路分析与肿瘤相关的是细胞凋亡;④盐酸青藤碱呈剂量依赖性地促进CEM细胞凋亡;⑤盐酸青藤碱上调CEM细胞中Bax、Caspase-9蛋白表达,下调Bcl-2蛋白表达。由此可见,盐酸青藤碱可诱导CEM细胞凋亡从而抑制细胞增殖,可能与其上调Bax和Caspase-9蛋白表达,以及下调Bcl-2蛋白表达有关。

Targeting acute myeloid leukemia resistance with two novel combinations demonstrate superior efficacy in TP53, HLA-B, MUC4 and FLT3 mutations

Elham Gholizadeh Ehsan Zangene Alun Parsons Mika Kontro Caroline A. Heckman Mohieddin Jafari

Department of Biochemistry and Developmental Biology Faculty of Medicine University of Helsinki Helsinki FinlandInstitute for Molecular Medicine Finland (FIMM) Helsinki Institute of Life Science iCAN Digital Cancer Medicine Flagship University of Helsinki Helsinki FinlandFoundation for the Finnish Cancer Institute Helsinki FinlandFaculty of Medicine and Health Technology Tampere University Tampere FinlandTampere Institute for Advanced Study Tampere University Tampere Finland

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关键词： Acute Myeloid Leukemia (AML) Drug Resistance Targeted Therapy Zebrafish Xenograft Model TP53 Mutation Combination Therapy

摘要：

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the clonal expansion of myeloid precursor cells. Despite the advent of venetoclax-based regimens, resistance mechanisms remain a major clinical challenge, particularly in patients with high-risk mutations such as TP53, MUC4, HLA-B and FLT3. Here, we evaluate two rational combination therapies, LY3009120 (pan-RAF) plus sapanisertib (mTOR) (LS), and ruxolitinib (JAK1/2) plus ulixertinib (ERK) (RU), across ten AML cell lines and a zebrafish embryo xenograft model. The study integrates real-time cell viability assays, xenograft imaging, and genetic analyses and relates responses to mutational profiles and benchmarks against first line treatment (venetoclax based combinations), the current standard for older and unfit AML. Both combinations outperformed or matched venetoclax-based comparators, with LS markedly reducing viability and RU showing robust efficacy in AML cell lines. In zebrafish, LS and RU suppressed leukemic burden with zero mortality and with modest effects on embryo length, indicating supportive but preliminary tolerability under the conditions tested. Mutation response analyses and clustering highlighted TP53, MUC4, HLA-B and FLT3 as correlates of LS and RU sensitivity, supporting mutation-informed prioritization. Collectively, our results nominate LS and RU as promising candidates, particularly in AML with TP53, FLT3, HLA-B or MUC4 alterations, and motivate prospective validation in stratified AML cohorts.

Myeloid ADAM17 induces ST2+ T regulatory cells that limit obesity-induced metabolic inflammation through changes in both membrane and soluble TNF

Joseph C. Lownik Matthew P. Zellner Jared Farrar Anuj Tharakan Francesco S. Celi Daniel H. Conrad Rebecca K. Martin

Department of Microbiology and Immunology Virginia Commonwealth University School of Medicine Richmond VA United StatesCenter for Clinical and Translational Research Virginia Commonwealth University School of Medicine Richmond VA United StatesDivision of Endocrinology Virginia Commonwealth University School of Medicine Richmond VA United States

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关键词： TNF alpha Obesity-induced inflammation ADAM17 TACE T regulatory cells Adipose tissue myeloid cells

摘要：
Obesity is a detrimental disease that affects almost all physiological functions of the person that is afflicted. Secreted TNF alpha (sTNF) levels are directly correlated in obesity with weight gain and morbidity, as well as metabolic dysregulation.¹ ADAM17 cleaves membrane TNF alpha (mTNF) into its soluble form, sTNF. This is well defined, but the mechanisms in metabolic dysregulation behind the regulation of TNF, the source of TNF, as well as the downstream action of TNF is less clear. Here, we demonstrate a bifunctional role of TNF, with both sTNF and mTNF having distinct action on adipose T regulatory cells (T_regs). First, we show that modulation of TNF on macrophages in mice where ADAM17 is deleted from the myeloid lineage (ADAM17^LysM) have a significant metabolic advantage as illustrated by an increase in glucose tolerance and decrease in body weight. Next, deep immune phenotyping of the fatpad of these mice after high fat diet (HFD) illustrated that there was an increased recruitment and activation of ST2⁺ T regulatory cells (T_regs). Utilizing mice with TNF deleted from the myeloid lineage (TNF^lysM), we were able to show that the accumulation and activation of these T_regs occurred through two separate mechanistic actions of TNF. One, sTNF regulates this T_reg population through action on adipocytes that results in soluble ST2 (sST2) production. Two, mTNF on macrophages further potentiates these cells through increased IL-33 production. This work additionally suggests that targeting the mTNF:TNFR2 axis may be a beneficial for improving metabolic health in obesity.

Obesity is a detrimental disease that affects almost all physiological functions of the person that is afflicted. Secreted TNF alpha (sTNF) levels are directly correlated in obesity with weight gain a

Nanoparticle-mediated liver targeted delivery of IFN-γ confers enhanced anti-fibrotic efficacy with reduced systemic toxicity

Jing Yang Zhu Liang Hui Zhao Jingping Huang Ying Song Jingyu Zhu Yishu Yan Yuntao Zhu

School of Life Sciences and Health Engineering Jiangnan University Wuxi 214122 ChinaDepartment of Hepatopancreatobiliary Surgery Jiangnan University Medical Center Wuxi 214002 China

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关键词： Branched polyethyleneimines IFN-γ Liver fibrosis Proinflammation Sulfated hyaluronic acid TGF-β/Smads signaling pathway

摘要：
IFN-γ has been shown to exert potent anti-fibrotic effects in early stages of liver fibrosis, but the drug development has been impeded by systemic toxicity arising from off-target receptor activation. To overcome this therapeutic challenge, a nanodelivery platform (~200 nm) through covalent conjugation of sulfated hyaluronan (S-HA) with branched polyethyleneimine (PEI) was developed. Upon loading with IFN-γ, the nanoplatform achieved significantly enhanced hepatic accumulation effect. The resulting S-HA-PEI-IFN-γ formulation significantly attenuated M1 type macrophage polarization and associated pro-inflammatory cytokine release induced by free IFN-γ treatment, the key contributors to systemic adverse effects. Mechanistically, the nanoparticle of S-HA-PEI within the formulation exhibited synergistic effect with IFN-γ to suppress hepatic stellate cell (HSC) activation by blocking TGF-β/Smads signaling pathway. In a CCl₄-induced murine liver fibrosis model, S-HA-PEI-IFN-γ administration achieved remarkable reduction in collagen deposition as compared to free IFN-γ treatment, accompanied by concurrent downregulation of Collagen-I (ColI) and α-smooth muscle actin (α-SMA) expression. By integrating targeted delivery, toxicity mitigation and synergistic anti-fibrotic effect, the S-HA-PEI-IFN-γ nano-therapeutic represents a promising transformative strategy for combating liver fibrosis.

IFN-γ has been shown to exert potent anti-fibrotic effects in early stages of liver fibrosis, but the drug development has been impeded by systemic toxicity arising from off-target receptor activation. To overcome this therapeutic challenge, a nanodelivery platform (~200 nm) through covalent conjugation of sulfated

伐昔洛韦联合普瑞巴林对老年急性带状疱疹后遗神经痛的疗效及对患者神经递质和细胞因子的影响观察

吉哲

江阴临港医院 214400

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关键词： 老年急性带状疱疹后遗神经痛伐昔洛韦普瑞巴林神经递质细胞因子

摘要： 目的探讨老年急性带状疱疹后遗神经痛采用伐昔洛韦+普瑞巴林治疗的效果。方法62例老年急性带状疱疹后遗神经痛患者,以随机方式将患者分为两组,各31例。对照组采用普瑞巴林+维生素治疗,观察组在对照组基础上联用伐昔洛韦治疗。对比两组治疗效果及治疗前后疼痛程度[视觉模拟评分法(VAS)评分]、睡眠质量[匹兹堡睡眠质量指数(PSQI)评分]、神经递质指标[血清P物质(SP)、β-内啡肽(β-EP)]、细胞因子[白细胞介素-6(IL-6)、白细胞介素-10(IL-10)和肿瘤坏死因子-α(TNF-α)]。结果观察组总有效率93.55%高于对照组的74.19%,差异明显(P<0.05)。治疗后,观察组VAS、PSQI评分分别为(2.20±0.45)、(3.19±0.70)分,低于对照组的(3.18±0.68)、(6.10±1.42)分,差异明显(P<0.05)。治疗后,观察组血清SP水平(3.45±0.78)pg/ml低于对照组的(5.97±1.03)pg/ml,β-EP水平(20.98±3.45)pg/ml高于对照组的(13.25±2.72)pg/ml,差异明显(P<0.05)。治疗后,观察组TNF-α(1.30±0.25)ng/ml、IL-6(6.15±0.26)pg/ml、IL-10(5.15±0.70)pg/ml低于对照组的(1.58±0.28)ng/ml、(9.35±2.15)pg/ml、(8.42±0.76)pg/ml,差异明显(P<0.05)。结论对老年急性带状疱疹后遗神经痛患者采用普瑞巴林联合伐昔洛韦治疗方案的效果理想,对患者神经递质具有良好的调节作用,且有助于降低细胞因子水平,值得采纳。

Dysregulation of the TNF-α-OTUD3-PPARγ signaling axis exacerbates retinal oxidative stress and inflammation in diabetic retinopathy

Zhang, Jialin Wang, Zhen Liu, Junjun Xu, Wenchang Lu, Lu Zhou, Na Song, Yongfeng

Shandong First Med Univ Cent Hosp Key Lab Endocrine Glucose & Lipids Metab & Brain A Minist EducDept Endocrinol Jinan 250013 Shandong Peoples R ChinaShandong First Med Univ Cent Hosp Dept Ophthalmol Jinan 250013 Shandong Peoples R ChinaShandong First Med Univ Shandong Prov Hosp Dept Clin Lab Jinan 250021 Shandong Peoples R China

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关键词： OTUD3 Diabetic retinopathy PPAR gamma TNF-alpha Oxidative stress

摘要： Aims: Diabetic retinopathy (DR) is one of the major complications of diabetes. In addition to hyperglycemia, various mechanisms contribute to the development of microvascular damage to the retina, which have not been fully elucidated. The aim of this study was to investigate Ovarian tumor domain-containing protein 3 (OTUD3)'s protection against DR by targeting peroxisome proliferator-activated receptor gamma (PPAR gamma)-mediated dysfunction and identifying therapeutic strategies. Materials and methods: We conducted clinical analysis of 208 type 2 diabetes mellitus (T2DM) patients with OTUD3 genotyping, combined with diabetic homozygous mutated (Otud3-/-) mouse models and retinal pigment epithelium (RPE) cell lines (OTUD3 knockdown/mutation). Key findings: We found increased hyperreflective foci (HRF) associated with an increased immune activation in diabetic Otud3-/- mice compared to Otud3 wild-type (Otud3+/+) mice. OTUD3 knockdown or mutated cells showed increased cell dysfunction and oxidative stress markers under inflammatory conditions. Further upstream transcription factors predict analysis suggest PPAR gamma as the potential target of OTUD3. Finally, we found PPAR gamma agonist could rescue the phenotype in RPE cells characterized by increased ROS levels, enhanced migration, and elevated apoptosis resulting from OTUD3 loss of function through knockdown or mutation. Significance: Our study offers novel insights into how deubiquitylase OTUD3 maintains the normal function of the retina by deubiquitylating PPAR gamma and provides a novel therapeutic target for this vision-threatening diabetic complications.

From whole-brain metrics to circuit-specific precision: advancing fMRI biomarkers for TNF inhibitor response in rheumatoid arthritis – Authors' reply

Andreas Hess Koray Tascilar Georg Schett Jürgen Rech

Institute of Pharmacology and Toxicology Erlangen GermanyDepartment of Neuroradiology Erlangen GermanyFAU NeW—Research Center New Bioactive Compounds Erlangen GermanyFriedrich-Alexander-Universität Erlangen-Nürnberg Erlangen GermanyDepartment of Internal Medicine 3 Rheumatology and Immunology Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen Erlangen 91054 GermanyDeutsches Zentrum Immuntherapie Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen Erlangen 91054 Germany

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Possible significance of anti-HLA DQ antibodies after lung transplantation – Single centre study

Anna Dukat-Mazurek Wojtek Karolak Hanna Zielińska Patrycja Specjał Grażyna Moszkowska Jacek Wojarski Karolina Lipka Justyna Fercho Marta Gallas Dariusz Rystwiej Fanny Sunesson Lin Akily William Karlsen Marcin Sawczuk Piotr Trzonkowski Sławomir Żegleń

Department of Medical Immunology Medical University of Gdansk PolandDepartment of Cardiac Surgery Medical University of Gdansk PolandFaculty of Health Sciences with the Institute of Maritime and Tropical Medicine Medical University of Gdansk PolandEmergency department of surgery (KAVA) J A Hedlunds väg 5 291 33 Kristianstad SwedenDepartment of Pneumonology and Allergology Medical University of Gdansk Poland

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关键词： Antibody mediated rejection Donor specific antibodies HLA immunization Lung transplantation anti-DQ antibodies

摘要：
The role of anti-HLA antibodies in solid organ transplantation has long been recognized, particularly with respect to graft rejection and patient survival. This study aimed to evaluate the impact of de novo donor-specific antibodies (DSA) on graft failure and mortality in Polish lung transplant recipients. The study included 112 patients who had a well-defined immune status prior to transplantation. The presence and specificity of anti-HLA antibodies were assessed using the Luminex platform. We identified 26 patients (23%) as having increased immunological risk. Pre-transplant DSAs were detected in 13 recipients. Post-transplantation, the development of de novo DSAs was evaluated, with a cumulative incidence of 11%. Our findings confirmed that lung transplant recipients with donor-specific immunization frequently develop antibodies targeting antigens at the HLA-DQ locus. Notably, 90% (9 out of 10) of immunized patients exhibited high mean fluorescence intensity (MFI) levels of anti-DQ antibodies. These antibodies were shown to be harmful, with mortality significantly higher in immunized patients: 50% of patients with anti-DQ antibodies died, compared to only 15% in those without DSAs. This is the first study of its kind in the Polish population, confirming that strategies to prevent and treat DQ DSAs may improve outcomes for lung transplant recipients.

The role of anti-HLA antibodies in solid organ transplantation has long been recognized, particularly with respect to graft rejection and patient survival. This study aimed to evaluate the impact of de novo donor-specific antibodies (DSA) on graft failure and mortality in Polish lung transplant recipients. The study included 112 patients who had a well-defined immune status prior to transplantation. The presence and specificity of anti-HLA antibodies were assessed using the Lumin

A PBX1-IL7R axis mediates liver fibrosis in non-alcoholic fatty liver disease

Yang, Zhen Zhang, Jinbo Wang, Qihang Xu, Huihui Qin, Xihu Lv, Fangqiao

Dalian Med Univ Grad Sch Dalian Peoples R ChinaNanjing Med Univ Changzhou Peoples Hosp 2 Affiliated Hosp 3 Dept Hepatobiliary Surg Changzhou Peoples R ChinaCapital Med Univ Sch Basic Med Sci Dept Cell Biol Municipal Lab Liver Protect & Regulat Regenerat Beijing Peoples R ChinaNanjing Med Univ Key Lab Targeted Intervent Cardiovasc Dis Nanjing Peoples R ChinaNanjing Med Univ Collaborat Innovat Ctr Cardiovasc Translat Med Dept Pathophysiol Nanjing Peoples R China

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关键词： NAFLD MASLD Liver fibrosis Myofibroblast Translational research

摘要： Aims: Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction associated steatotic liver disease (MASLD), represents a spectrum of chronic liver diseases that eventually lead to cirrhosis and hepatocellular carcinoma. Liver fibrosis is both a pathological feature and a contributing factor in NAFLD. In the present study we investigated whether targeting pre-B cell leukemia transcription factor 1 (PBX1) and interleukin 7 receptor (IL7R) might ameliorate liver fibrosis in the context of NAFLD. Methods and materials: NAFLD was induced in C57/B6j mice by feeding with a choline-deficient amino acid defined high-fat diet (CDAA-HFD). Key findings: Both PBX1 expression and IL7R expression were up-regulated in hepatic stellate cells (HSCs) isolated from the mice fed the CDAA-HFD compared to those isolated from the control mice. Myofibroblast-specific PBX1 depletion, by injecting the mice with AAV6 carrying short-hairpin RNA (shRNA) against PBX1, significantly attenuated liver fibrosis induced by CDAA-HFD feeding. Similarly, myofibroblast-specific IL7R depletion significantly mitigated NAFLD-associated liver fibrosis. Of note, liver injury and steatosis were not influenced by either PBX1 or IL7R depletion. Importantly, IL7R blockade with a neutralizing antibody likewise diminished NAFLD-associated liver fibrosis. Finally, a positive correlation between PBX1 expression, IL7R expression, and myofibroblast activation was identified in liver specimens from NAFLD patients. Significance: Our data demonstrate the feasibility of targeting the PBX1-IL7R axis for the intervention of NAFLDassociated liver fibrosis.

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