RGS4 promotes the progression of gastric cancer through the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition

BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.

Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway:a potential therapeutic approach for neurodegenerative diseases

The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

Pan-TRK positive uterine sarcoma in immunohistochemistry without neurotrophic tyrosine receptor kinase gene fusions:A case report

BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.

急性心力衰竭伴高血压患者血清CKMB、CPK及CKMB/CPK比值的临床意义

目的分析急性心力衰竭伴高血压患者血清肌酸磷酸激酶(CPK)和磷酸肌酸激酶同工酶(CKMB)及CKMB/CPK比值的表达情况及其临床意义。方法回顾性选取2019年1月—2020年6月收治的急性心力衰竭伴高血压患者94例,均于治疗前行APACHEⅡ评估、血清CKMB、CPK检测和治疗后疗效评估,比较不同病情程度和不同临床预后患者的血清CKMB、CPK及CKMB/CPK比值水平,分析病情程度与血清CKMB、CPK及CKMB/CPK比值的相关性,及其在预后预测中的价值。结果中度组(21<APACHEⅡ<40分)和重度组(APACHEⅡ≥40分)的血清CKMB、CPK及CKMB/CPK比值高于轻度组(APACHEⅡ≤20分)(P<0.05),重度组血清CKMB、CPK及CKMB/CPK比值高于中度组。血清CKMB(r=0.779,P=0.003)、CPK(r=0.701,P=0.008)及CKMB/CPK比值(r=0.824,P=0.000)均与APACHEⅡ评分呈正相关(P<0.05)。有效病例组的血清CKMB、CPK及CKMB/CPK比值均低于无效病例组(P<0.05)。血清CKMB/CPK比值预测急性心力衰竭伴高血压患者预后的准确率(86.98%)、敏感性(88.11%)、特异性(89.93%)高于血清CKMB(分别为75.58%、76.53%、69.93%)和血清CPK(分别为75.73%、74.19%、71.18%)(P<0.05)。结论急性心力衰竭伴高血压患者存在明显的血清CKMB、CPK及CKMB/CPK比值异常,且血清CKMB、CPK及CKMB/CPK比值异常与病情严重程度、临床预后密切相关,尤其是CKMB/CPK比值在临床预后预测中具有较高的临床价值。

Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

提高烘丝机入口水分CPK合格率的研究

为减小制丝生产过程中烘丝机入口水分的波动,提高烘丝机入口水分CPK的合格率,调查分析影响烘丝机入口水分波动的因素。结果表明,烘丝机入口水分CPK合格率与来料物料均匀性、平整性有关。

Present and prospect of transarterial chemoembolization combined with tyrosine kinase inhibitor and PD-1 inhibitor for unresectable hepatocellular carcinoma

In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(TKI)and programmed cell death protein-1(PD-1)inhibitor for the treatment of unresectable hepatocellular carcinoma(HCC).Herein,we focus specifically on the mechanisms of this triple therapy,administration sequence and selection of each medication,and implications for future clinical trials.Based on the interaction mechanisms between medications,the triple therapy of TACE+TKI+PD-1 is proposed to complement the deficiency of each monotherapy,and achieve synergistic antitumor effects.Although this triple therapy has been evaluated by several retrospective trials,it is still controversial whether the triple therapy achieves better clinical benefits,due to the flawed study design and heterogeneity in medications.In addition,the administration sequence,which may greatly affect the clinical benefit,needs to be fully considered at clinical decision-making for obtaining better prognosis.We hope that this editorial could contribute to the design and optimization of future trials.

Advanced Lung Adenocarcinoma with EGFR 19-del Mutation Transformed into SCC after EGFR-tyrosine Kinase inhibitors Treatment:A Case report

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung cancer(NSCLC).CASE SUMMARY A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment.Secondary pathological tissue biopsy confirmed squamous cell carcinoma(SCC)transformation.Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time,while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC.Notably,EGFR-TKIs resistance includes primary and acquired.Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs,with SCC transformation being relatively rare.Our results provide more detailed results of the patient’s diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma.CONCLUSION Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.

过表达胡杨PeCPK7提高拟南芥耐盐性

【目的】研究胡杨PeCPK7在植物耐盐过程中的作用,旨在进一步揭示植物耐盐的生理与分子调控机制。【方法】根据NCBI基因组数据库中胡杨PeCPK7 CDS序列,克隆PeCPK7基因,利用DNAMAN进行氨基酸序列比对,并用Mega 7软件进行进化树构建。以过表达PeCPK7拟南芥(PeCPK7-OE1、PeCPK7-OE2和PeCPK7-OE3)、野生型(WT)和转空载体对照(VC)拟南芥株系为试验材料,对各基因型拟南芥进行不同盐浓度处理,从生理生化和分子生物学水平研究胡杨PeCPK7在盐胁迫中的响应机制。【结果】(1)PeCPK7蛋白与其他物种中的CPK7有高度相似性,并与毛果杨PtrCPK7家族亲缘关系最近。(2)盐处理胡杨幼苗,PeCPK7的相对表达量在盐胁迫6 h后达到最大值,至48 h时恢复至最初状态。(3)PeCPK7定位于细胞质中。(4)在盐处理后,过表达PeCPK7拟南芥株系的生存率和根长均显著高于野生型(WT)和转空载体(VC)拟南芥;并且根细胞膜受损伤程度显著低于WT和VC。(5)在根中积累的Na^(+)和H_(2)O_(2)显著低于WT和VC,Ca^(2+)显著高于WT和VC;并且Na^(+)外排和K^(+)内流显著高于WT和VC。(6)盐胁迫下,过表达株系的超氧化物歧化酶、过氧化物酶和过氧化氢酶活性升高幅度显著高于WT和VC。(7)过表达株系的叶绿素含量、PSⅡ最大光量子效率、实际光合量子产量、相对电子传递速率和光合速率高于WT和VC,而胞间CO_(2)浓度低于WT和VC。【结论】过表达胡杨PeCPK7能够提高拟南芥的耐盐能力,本研究将为利用基因工程提高植物的耐盐性提供理论依据。

Synergy in Rice Immunity:Exploring Strategies of Coordinated Disease Defense Through Receptor-Like Kinases and Receptor-Like Cytoplasmic Kinases

Receptor-like kinases(RLKs)and receptor-like cytoplasmic kinases(RLCKs)play an indispensable role in the perception and transmission of extracellular signals in plants.In rice,these kinases actively participate in immune responses against a variety of pathogens,including fungi,bacteria,and viruses.However,research on the specific response mechanisms and the spectrum of different kinase activities against various pathogens remains insufficient.This review provides an in-depth and comprehensive overview of the types and functions of RLKs and RLCKs involved in disease resistance,emphasizing the central role of certain RLKs and RLCKs in the plant immune system.These kinases can recognize specific molecular patterns of pathogens and rapidly initiate an immune response in rice.Furthermore,the activity and functional regulation of these key kinases are tightly controlled by various post-translational modifications,such as phosphorylation and ubiquitination.This meticulous regulation ensures that the rice immune system's response is both precise and timely,effectively balancing the intensity of the immune response and preventing potential issues caused by either hyperactivity or insufficiency.By synthesizing current research findings,this review not only broadens our understanding of the role of RLKs and RLCKs in plant immunity but also provides new perspectives and strategies for future research on disease resistance breeding in rice.Future studies are expected to delve deeper into the signaling networks and regulatory mechanisms of these kinases,exploring their potential in agricultural production to develop rice varieties with enhanced disease resistance.

提升剃齿公法线CPK应用研究

传统剃齿机通过控制剃主轴与被加工工件的中心距来控制公法线尺寸的变化,导致在剃齿加工时,齿部公法线随着机床温度变化而变化,导致公法线的CPK值不达标,需通过100%的检验方式确保零件的合格。与现在的高精度加工方式、检测需求不相适应。通过增加位移传感器的控制以实现剃齿刀主轴与被加工工件中心距的稳定性,实现提升剃齿公法线CPK的目的。

A review on potential heterocycles for the treatment of glioblastoma targeting receptor tyrosine kinases

Glioblastoma,the most aggressive form of brain tumor,poses significant challenges in terms of treatment success and patient survival.Current treatment modalities for glioblastoma include radiation therapy,surgical intervention,and chemotherapy.Unfortunately,the median survival rate remains dishearteningly low at 12–15 months.One of the major obstacles in treating glioblastoma is the recurrence of tumors,making chemotherapy the primary approach for secondary glioma patients.However,the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms.Consequently,considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs.To tackle glioma,numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEKERK-MPAK.By targeting specific signaling pathways,heterocyclic compounds have demonstrated efficacy in glioma therapeutics.Additionally,key kinases including phosphatidylinositol 3-kinase(PI3K),serine/threonine kinase,cytoplasmic tyrosine kinase(CTK),receptor tyrosine kinase(RTK)and lipid kinase(LK)have been considered for investigation.These pathways play crucial roles in drug effectiveness in glioma treatment.Heterocyclic compounds,encompassing pyrimidine,thiazole,quinazoline,imidazole,indole,acridone,triazine,and other derivatives,have shown promising results in targeting these pathways.As part of this review,we propose exploring novel structures with low toxicity and high potency for glioma treatment.The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier.By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics,we can maximize their therapeutic value and minimize adverse effects.Considering the complex nature of glioblastoma,these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.

Mouse KL2 is a unique MTSE involved in chromosome-based spindle organization and regulated by multiple kinases during female meiosis

Microtubule-severing enzymes(MTSEs)play important roles in mitosis and meiosis of the primitive organisms.However,their roles in mammalian female meiosis,which accounts for over 80%of gamete-originated human reproductive diseases,remain unexplored.In the current study,we reported that katanin-like 2(KL2)was the only MTSE concentrating at chromosomes.Furthermore,the knockdown of KL2 significantly reduced the chromosome-based increase in the microtubule(MT)polymer,increased aberrant kinetochore-MT(K-MT)attachment,delayed meiosis,and severely affected normal fertility.We demonstrated that the inhibition of aurora B,a key kinase for correcting aberrant K-MT attachment,significantly eliminated KL2 expression from chromosomes.Additionally,KL2 interacted with phosphorylated eukaryotic elongation factor-2 kinase,and they competed for chromosome binding.Phosphorylated KL2 was also localized at spindle poles,with its phosphorylation regulated by extracellular signal-regulated kinase 1/2.In summary,the current study reveals a novel function of MTSEs in mammalian female meiosis and demonstrates that multiple kinases coordinate to regulate the levels of KL2 at chromosomes.

Game changer:How Janus kinase inhibitors are reshaping the landscape of ulcerative colitis mana

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.

Effects of invigorating-spleen and anticancer prescription on extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway in colon cancer mice model

BACKGROUND Colon cancer(CC)is one of the most common malignant tumors in the gastrointestinal system.Overall,CC had the third highest incidence but the second highest mortality rate globally in 2020.Nowadays,CC is mainly treated with capecitabine chemotherapy regimen,supplemented by radiotherapy,immunotherapy and targeted therapy,but there are still limitations,so Chinese medicine plays an important role.AIM To investigate the effects of invigorating-spleen and anticancer prescription(ISAP)on body weight,tumor inhibition rate and expression levels of proteins in extracellular-signal-regulated kinase(ERK)/mitogen-activated protein kinase(MAPK)signaling pathway in CC mice model.METHODS The CC mice model were established and the mice were randomly divided into 5 groups,including the control group,capecitabine group,the low-dose,mediumdose and high-dose groups of ISAP,with 8 mice in each group,respectively.After 2 weeks of intervention,the body weight and tumor inhibition rate of mice were observed,and the expression of RAS,ERK,phosphorylated ERK(p-ERK),C-MYC and matrix metalloproteinase 2(MMP2)proteins in the tissues of tumors were detected.RESULTS Compared with the control group,the differences of body weight before and after treatment was much smaller in the groups of ISAP,with the smallest difference in the high-dose group of ISAP,while the capecitabine group had the greatest difference,indicating ISAP had a significant inhibiting effect on the growth of transplanted tumor in mice.The expression of RAS protein was decreased in the low-and medium-dose groups of ISAP,and the change of p-ERK was significant in the medium-and high-dose groups of ISAP.MMP2 protein expression was significantly decreased in both the low-dose and medium-dose groups of ISAP.There were no significant changes in ERK in the ISAP group compared to the capecitabine group,while RAS,MMP2,and C-MYC protein expression were reduced in the ISAP group.The expression level of C-MYC protein decreased after treated with ISAP,and the decrease was the most significant in the medium-dose group of ISAP.CONCLUSION ISAP has a potential inhibiting effect on transplanted tumor in mice,and could maintain the general conditions,physical strength and body weight of mice.The expression levels of RAS,p-ERK,MMP2 and c-myc were also decreased to a certain extent.By inhibiting the expression of upstream proteins,the expression levels of downstream proteins in ERK/MAPK signaling pathway were significantly decreased.Therefore,it can be concluded that ISAP may exert an anti-tumor effect by blocking the ERK/MAPK signaling pathway and inhibiting the expression of MMP2 and c-myc proteins.

Biopharmaceutical and pharmacokinetic attributes to drive nanoformulations of small molecule tyrosine kinase inhibitors

Buoyed by the discovery of small-molecule tyrosine kinase inhibitors(smTKIs),significant impact has been made in cancer chemotherapeutics.However,some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties.Almost all of these molecules exhibit significant inter-and intra-patient variations in plasma concentration-time profiles.Thus,therapeutic drug monitoring,dose adjustments and precision medicine are being contemplated by clinicians.Complex formulations or nanoformulation-based drug delivery systems offer promising approaches to provide drug encapsulation or spatiotemporal control over the release,overcoming the biopharmaceutical and pharmacokinetic limitations and improving the therapeutic outcomes.In this context,the present review comprehensively tabulates and critically analyzes all the relevant properties(T1/2,solubility,pKa,therapeutic index,IC50,metabolism etc.)of the approved smTKIs.A detailed appraisal is conducted on the advancements made in complex formulations of smTKIs,with a focus on strategies to enhance their pharmacokinetic profile,tumor targeting ability,and therapeutic efficacy.Various nanocarrier platforms,have been discussed,highlighting their unique features and potential applications in cancer therapy.Nanoformulations have been shown to improve bioavailability and reduce dosing frequency for several smTKIs in animal models.It is inferred that extensive efforts will be made in developing complex formulations of smTKIs in near future.The review concludes with key recommendations for the developing of smTKIs to facilitate early clinical translation.

Advances in MET tyrosine kinase inhibitors in gastric cancer

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally.Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment strategies.MET is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound healing.However,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient outcomes.As such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase inhibitors.This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and crizotinib.Building on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.

The dual role of casein kinase 1,DTG1,in regulating tillering and grain size in rice

Tiller number and grain size are important agronomic traits that determine grain yield in rice.Here,we demonstrate that DEFECTIVE TILLER GROWTH 1(DTG1),a member of the casein kinase 1 protein family,exerts a co-regulatory effect on tiller number and grain size.We identified a single amino acid substitution in DTG1(I357K)that caused a decrease in tiller number and an increase in grain size in NIL-dtg1.Genetic analyses revealed that DTG1 plays a pivotal role in regulation of tillering and grain size.The DTG1^(I357K) allelic variant exhibited robust functionality in suppressing tillering.We show that DTG1 is preferentially expressed in tiller buds and young panicles,and negatively regulates grain size by restricting cell proliferation in spikelet hulls.We further confirm that DTG1 functioned in grain size regulation by directly interacting with Grain Width 2(GW2),a critical grain size regulator in rice.The CRISPR/Cas9-mediated elimination of DTG1 significantly enhanced tiller number and grain size,thereby increasing rice grain yield under field conditions,thus highlighting potential value of DTG1 in rice breeding.

Diabetes and high-glucose could upregulate the expression of receptor for activated C kinase 1 in retina

BACKGROUND Diabetic retinopathy(DR)is a major ocular complication of diabetes mellitus,leading to visual impairment.Retinal pigment epithelium(RPE)injury is a key component of the outer blood retinal barrier,and its damage is an important indicator of DR.Receptor for activated C kinase 1(RACK1)activates protein kinase C-ε(PKC-ε)to promote the generation of reactive oxygen species(ROS)in RPE cells,leading to apoptosis.Therefore,we hypothesize that the activation of RACK1 under hypoxic/high-glucose conditions may promote RPE cell apoptosis by modulating PKC-ε/ROS,thereby disrupting the barrier effect of the outer blood retinal barrier and contributing to the progression of DR.AIM To investigate the role and associated underlying mechanisms of RACK1 in the development of early DR.METHODS In this study,Sprague-Dawley rats and adult RPE cell line-19(ARPE-19)cells were used as in vivo and in vitro models,respectively,to explore the role of RACK1 in mediating PKC-εin early DR.Furthermore,the impact of RACK1 on apoptosis and barrier function of RPE cells was also investigated in the former model.RESULTS Streptozotocin-induced diabetic rats showed increased apoptosis and upregulated expression of RACK1 and PKC-εproteins in RPE cells following a prolonged modeling.Similarly,ARPE-19 cells exposed to high glucose and hypoxia displayed elevated mRNA and protein levels of RACK1 and PKC-ε,accompanied by an increases in ROS production,apoptosis rate,and monolayer permeability.However,silencing RACK1 significantly downregulated the expression of PKC-εand ROS,reduced cell apoptosis and permeability,and protected barrier function.CONCLUSION RACK1 plays a significant role in the development of early DR and might serve as a potential therapeutic target for DR by regulating RPE apoptosis and barrier function.

Detection of LAMA2 c.715C>G:p.R239G mutation in a newborn with raised creatine kinase: A case report

BACKGROUND We report a rare case of primary clinical presentation featuring elevated creatine kinase(CK)levels in a neonate,which is associated with the LAMA2 gene.In this case,a heterozygous mutation in exon5 of the LAMA2 gene,c.715C>G(resulting in a change of nucleotide number 715 in the coding region from cytosine to gua-nine),induced an amino acid alteration p.R239G(No.239)in the patient,repre-senting a missense mutation.This observation may be elucidated by the neonatal creatine monitoring mechanism,a phenomenon not previously reported.CASE SUMMARY We analysed the case of a neonate presenting solely with elevated CK levels who was eventually discharged after supportive treatment.The chief complaint was identification of increased CK levels for 15 d and higher CK values for 1 d.Ad-mission occurred at 18 d of age,and despite prolonged treatment with creatine and vitamin C,the elevated CK levels showed limited improvement.Whole exo-me sequencing revealed the presence of a c.715C>G mutation in LAMA2 in the newborn,correlating with a clinical phenotype.However,the available informa-tion offers insufficient evidence for clinical pathogenicity.CONCLUSION Mutations in LAMA2 are associated with the clinical phenotype of increased neonatal CK levels,for which no specific treatment exists.Whole genome sequen-cing facilitates early diagnosis.