Objective:To analyze the expression of heat shock protein 90α (HSP90α) in pancreatic cancer tissues and its potential diagnostic value for pancreatic cancer.Methods:A retrospective study was conducted on surgical specimens and clinical data from 99 patients with pancreatic cancer who were treated at Qingdao Municipal Hospital from January 2018 to May 2023, including 58 males and 41 females, with the age of (63.5±23.5) years. Among them, 44 patients (44.4%) were used for pathological examination and prognostic analysis, while 55 patients (55.6%) were tested for plasma HSP90α levels to evaluate its diagnostic efficacy for pancreatic cancer. Blood samples from 119 healthy individuals undergoing routine physical examinations at the same hospital during the same period were collected, including 74 males and 45 females, with the age of (50.5±25.5) years, and plasma HSP90α levels were measured. Immunohistochemistry (IHC) was performed to detect the expression of HSP90α in cancerous and adjacent non-cancerous tissues. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of HSP90α, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125) for pancreatic cancer. Survival analysis was conducted using the Kaplan-Meier method, and the log-rank test was used to compare survival rates. The correlation between HSP90α positive expression in cancer tissues and mutant p53 positive expression was analyzed using Spearman correlation analysis.Results:Immunohistochemical analysis showed that the positive expression rate of HSP90α in pancreatic cancer tissues was 81.8%(36/44), higher than that in adjacent non-cancerous tissues 13.6%(6/44)( χ2=19.82, P<0.01). HSP90α positive expression in pancreatic cancer tissues was positively correlated with mutant p53 positive expression (correlation coefficient was 0.57, P<0.001). The median plasma HSP90α level in the pancreatic cancer group ( n=55) was 83.30 (48.30, 212.00) μg/L, which was significantly higher than that in the normal control group ( n=119), with a median of 37.00 (29.20, 43.50) μg/L, showing a statistically significant difference ( Z=-7.34, P<0.001). The area under the ROC curve (AUC) for plasma HSP90α in diagnosing pancreatic cancer was 0.85 (95% CI: 0.77-0.92), with an optimal cutoff value of 53.52 μg/L, yielding a sensitivity of 69.1% (38/55) and a specificity of 98.3% (117/119). The AUC for HSP90α in diagnosing pancreatic cancer was higher than that of CEA, CA19-9, and CA125. In the immunohistochemical analysis of cancer tissues, the one-year cumulative survival rate of the HSP90α-negative group ( n=8) was 87.5%, which was significantly higher than that of the HSP90α-positive group ( n=36), which was 18.8%( χ2=12.74, P<0.001). Conclusions:HSP90α is highly expressed in pancreatic cancer tissues, which is positively correlated with mutant p53 positive expression. Patients with positive HSP90α expression have a poorer prognosis. HSP90α demonstrates good diagnostic performance for pancreatic cancer and holds potential for clinical application.

Objective:To analyze the expression of heat shock protein 90α (HSP90α) in pancreatic cancer tissues and its potential diagnostic value for pancreatic cancer.Methods:A retrospective study was conducted on surgical specimens and clinical data from 99 patients with pancreatic cancer who were treated at Qingdao Municipal Hospital from January 2018 to May 2023, including 58 males and 41 females, with the age of (63.5±23.5) years. Among them, 44 patients (44.4%) were used for pathological examination and prognostic analysis, while 55 patients (55.6%) were tested for plasma HSP90α levels to evaluate its diagnostic efficacy for pancreatic cancer. Blood samples from 119 healthy individuals undergoing routine physical examinations at the same hospital during the same period were collected, including 74 males and 45 females, with the age of (50.5±25.5) years, and plasma HSP90α levels were measured. Immunohistochemistry (IHC) was performed to detect the expression of HSP90α in cancerous and adjacent non-cancerous tissues. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of HSP90α, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 125 (CA125) for pancreatic cancer. Survival analysis was conducted using the Kaplan-Meier method, and the log-rank test was used to compare survival rates. The correlation between HSP90α positive expression in cancer tissues and mutant p53 positive expression was analyzed using Spearman correlation analysis.Results:Immunohistochemical analysis showed that the positive expression rate of HSP90α in pancreatic cancer tissues was 81.8%(36/44), higher than that in adjacent non-cancerous tissues 13.6%(6/44)( χ2=19.82, P<0.01). HSP90α positive expression in pancreatic cancer tissues was positively correlated with mutant p53 positive expression (correlation coefficient was 0.57, P<0.001). The median plasma HSP90α level in the pancreatic cancer group ( n=55) was 83.30 (48.30, 212.00) μg/L, which was significantly higher than that in the normal control group ( n=119), with a median of 37.00 (29.20, 43.50) μg/L, showing a statistically significant difference ( Z=-7.34, P<0.001). The area under the ROC curve (AUC) for plasma HSP90α in diagnosing pancreatic cancer was 0.85 (95% CI: 0.77-0.92), with an optimal cutoff value of 53.52 μg/L, yielding a sensitivity of 69.1% (38/55) and a specificity of 98.3% (117/119). The AUC for HSP90α in diagnosing pancreatic cancer was higher than that of CEA, CA19-9, and CA125. In the immunohistochemical analysis of cancer tissues, the one-year cumulative survival rate of the HSP90α-negative group ( n=8) was 87.5%, which was significantly higher than that of the HSP90α-positive group ( n=36), which was 18.8%( χ2=12.74, P<0.001). Conclusions:HSP90α is highly expressed in pancreatic cancer tissues, which is positively correlated with mutant p53 positive expression. Patients with positive HSP90α expression have a poorer prognosis. HSP90α demonstrates good diagnostic performance for pancreatic cancer and holds potential for clinical application.

Objective:To explore the drug resistance of pathogens in puerperal infection of pregnant women with diabetes mellitus (GDM), and analyze the influence of puerperal infection on the expression of toll like receptor 4 (TLR4) inflammatory pathway in peripheral blood monocytes.Methods:A retrospective selection was conducted on 120 GDM postpartum women who underwent regular prenatal check ups and delivery at the 903th Hospital of the PLA (People′s Liberation Army) Joint Logistic Support Force from January 2020 to October 2022. The postpartum infection status, pathogenic characteristics of the infected pathogens, and drug resistance of the mothers were analyzed; According to the postpartum infection situation, the parturients were divided into an infected group and an uninfected group. Logistic regression analysis was used to analyze the relevant factors affecting postpartum infection, and the TLR4 protein and mRNA expression levels of peripheral blood mononuclear cells in the two groups were compared.Results:Among 120 GDM pregnant women, 21 cases (17.50%) developed post infection, including 8 cases (38.10%) of incision infection, 6 cases (28.57%) of uterine cavity infection, 4 cases (19.05%) of urinary system infection, and 3 cases (14.28%) of blood infection; A total of 43 pathogenic bacteria were detected, including 26 Gram negative bacteria (60.46%), 14 Gram positive bacteria (32.56%), and 3 fungi (6.98%). Among the main Gram negative bacteria, escherichia coli had the highest resistance rate to ceftazidime and tetracycline, and had not developed resistance to meropenem; Pseudomonas aeruginosa had the highest resistance rate to ceftazidime and gentamicin. Among the main Gram positive bacteria, staphylococcus aureus had the highest resistance rate to penicillin G and ceftazidime, and had not developed resistance to vancomycin; Enterococcus faecalis had the highest resistance rate to clindamycin. The results of multivariate logistic regression analysis showed that postpartum hemorrhage, premature rupture of membranes, and poor control of prenatal blood sugar were independent risk factors for postpartum infection in GDM mothers (all P<0.05). The expression rate of TLR4 protein, relative expression level of TLR4 mRNA, and levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-10 in the infected group were significantly higher than those in the non infected group (all P<0.05). Conclusions:The distribution and drug resistance of pathogenic bacteria in postpartum infections of GDM mothers have certain characteristics. Postpartum hemorrhage, premature rupture of membranes, and poor control of prenatal blood sugar are independent risk factors affecting postpartum infections in GDM mothers; The TLR4 inflammatory pathway in peripheral blood mononuclear cells may be involved in the occurrence and development of postpartum infection in GDM mothers.

Kidney fibrosis is an inevitable result of various chronic kidney diseases(CKDs)and significantly contributes to end-stage renal failure.Currently,there is no specific treatment available for renal fibrosis.ELA13(amino acid sequence:RRCMPLHSRVPFP)is a conserved region of ELABELA in all vertebrates;however,its biological activity has been very little studied.In the present study,we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1(TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion(UUO)mice.Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum,and reduce the expression of fibrosis biomarkers confirmed by Masson staining,immunohistochemistry,real-time polymerase chain reaction(RT-PCR),and western blot.Inflammation biomarkers were increased after UUO and decreased by administration of ELA13.Furthermore,we found that the levels of essential molecules in the mothers against decapentaplegic(Smad)and extracellular signal-regulated kinase(ERK)pathways were reduced by ELA13 treatment in vivo and in vitro.In conclusion,ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

Objective To investigate whether sarcopenia before concurrent chemoradiotherapy is prone to grade≥3 acute adverse reactions (AAR) and shorten survival in patients with advanced esophageal squamous cell carcinoma (ESCC). Methods Data of advanced patients with pathologically diagnosed ESCC and CCRT (FP regimen) from August 2018 to July 2022 were reviewed retrospectively.Skeletal muscle mass and body composition were measured using pre-treatment CT images, and patients were divided into sarcopenia and non-sarcopenia groups.Grade≥3 AAR was diagnosed based on CTCAE5.0 and acute radiation injury criteria of the US RTOG.Risk factors for developing grade≥3 AAR were analyzed, and survival rates were calculated by Kaplan-Meier method. Results Among 132 patients with ESCC (87 in the sarcopenia group and 45 in the non-sarcopenia group), 23(17.4%) experienced grade≥3 AAR.In multivariate regression analysis, independent risk factors for grade ≥3 AAR included the following: sarcopenia (OR: 6.034, 95%CI: 1.206-30.190, P=0.029), decreased SMD (OR: 0.693, 95%CI: 0.492-0.976, P=0.036), decreased SMI (OR: 0.841, 95%CI: 0.721-0.982, P=0.028), and increased FMI (OR: 2.433, 95%CI: 1.194-4.958;P=0.014).The OS rates were 16.01 months (95%CI: 14.89-17.13) in the sarcopenia group and 19.27 months (95%CI: 14.45-24.09) in the non-sarcopenia group (χ²=5.326, P=0.021) as well as 14.86 months (95%CI: 11.30-18.42) for patients with grade≥3 AAR and 16.67 months (95%CI: 14.91-18.43) for patients with grade 0-2 AAR (χ²=5.47, P=0.019).Among patients with grade≥3 AAR, the OS rates were 12.13 months (95%CI: 10.15-14.11) in the sarcopenia group and 18.69 months (95%CI: 12.85-21.88) in the non-sarcopenia group (χ²=4.466, P=0.035). Conclusion Sarcopenia, decreased skeletal muscle density, and increased fat mass are important predictors of grade≥3 AAR.The OS of patients with sarcopenia and grade≥3 AAR may be reduced.

Endoplasmic reticulum stress(ERS)is closely related to the mechanisms of multiple diseases,and regulation of ERS has become a therapeutic target for several diseases.Previous studies by our group have demonstrated that ERS can be alleviated and neuronal cells can be protected by downregulating ERS-related proteins such as GRP78,caspase12 and caspase3.The research on ERS inhibitors has progressed rapidly in recent years,and they can be classified into various types such as molecular chaperones,small molecule compounds and natural products,such as 4-phenylbutyric acid(4-PBA),tauroursodeoxycholic acid(TUDCA)and tumor necrosis factor α-stimulating factor 6(TSG-6),etc.These inhibitors can regulate the ERS signaling pathway through different pathways,such as:silent information regulator 1(SIRT1)promotes the expression of anti-apop-totic proteins by inhibiting the PERK-eIF2α-ATF4-CHOP pathway,thus reducing apoptosis.In addition,SIRT1 deacetylates XBP-1,regulates the IRE1α-XBP1 signaling pathway,and inhibits the expressions of GRP78 and CHOP,thereby reducing the protein load of endoplasmic reticulum(ER)and alleviating ERS;PDE4 inhibitor regu-lates c-Jun-mediated apoptotic pathway,reduces the interaction between IRE1 and TRAF2,and attenuates the level of c-Jun phosphorylation,thereby restoring ER homeostasis.In addition,PDE4 inhibitor activates the antioxidant-acting Nrf-2 pathway,decreases the concen-tration of intracellular calcium ion and reduces the pro-duction of ROS;TSG-6 exerts anti-inflammatory effects by regulating the secretion of inflammatory factors through PERK-eIF-2α-NF-κB p65 and IRE1α-TRAF2-NF-κB p65 signaling pathways.In-depth exploration of the potential mechanism of action of ERS inhibitors is of great signifi-cance for finding ways to treat related diseases by regu-lating ERS.

OBJECTIVE To investigate the mecha-nism of endoplasmic reticulum stress in cerebral isch-emic stroke from a theoretical perspective based on net-work pharmacology.METHODS GeneCards and OMIM databases were used to screen out the related targets of cerebral ischemic stroke and endoplasmic reticulum stress.And Venny2.1.0 was used to draw Venn's diagram to get the intersecting genes between cerebral ischemic stroke and endoplasmic reticulum stress.String data-base was used to get the protein-protein interaction(PPI)diagram and cytoscape was used for visualization analy-sis.The key genes were screened out by cytohubba plug-in,and enrichment analysis was performed.RESULTS Network pharmacology showed that there were 3744 cerebral ischemic stroke-related targets and 8675 endo-plasmic reticulum stress-related targets.After screening,41 common targets were got.There were 37 nodes,390 edges in the PPI network,namely,there were 37 interact-ing proteins and 390 interacting relationships.The key genes identified by cytohubba plug-in were IL-6,ALB,INS,TNF,AKT1,CASP3,MAPK3,TP53,SIRT1 and VEGF.The biological process involves reaction to oxida-tive stress,the regulation of neuron death,and negative regulation of cell differentiation,etc.;cellular components were related to the membrane raft,smooth endoplasmic reticulum,endoplasmic reticulum lumen and other com-ponents;molecular function aspects were related to sig-naling receptor activator activity,chaperone binding and protease binding.Enrichment analysis of pathway revealed that the intersecting targets were involved in PI3K/Akt pathway and protein processing in endoplasmic reticulum,etc.CONCLUSION The endoplasmic reticu-lum stress in cerebral ischemic stroke is related to the bi-ological processes of reaction to oxidative stress,the reg-ulation of neuron death,and negative regulation of cell differentiation,the mechanism may be related to neuroin-flammation and apoptosis.

During cerebral ischemia-reperfusion injury(CIRI),endoplasmic reticulum stress(ERS)leads to the development and progression of a series of deleterious physiological responses such as oxidative stress,dis-turbed calcium ion homeostasis,inflammation,apoptosis and autophagy.The unfolded protein response(UPR)is the main pathway activated by ERS,which regulates the expression of related factors within the endoplasmic reticu-lum(ER)and reduces protein translation levels.Prolonged and intense ERS may lead to cell death.Excessive ERS induces apoptosis mediated by C/EBP homologous pro-tein(CHOP),caspase-12 and c-Jun N-terminal kinase(JNK),thereby exacerbating brain damage.The thresh-old for the transition from adaptive mechanisms to apop-totic mechanisms during ERS depends on multiple fac-tors,including the cell status and environment,signaling pathway activity status,cumulative cascade,and the dose and time of ERS inducers.Further research is needed to completely elucidate the mechanism of ERS.Although the factors associated with the PERK and ATF6 path-ways are less extensively studied,their regulators still exist.Deficiency of protein tyrosine phosphatase 1B(PTP1B)leads to increased phosphorylation of PERK-eIF2α,while regulation of the proteasome and regulation of the XBP1 target gene WFS1 may also affect ATF6 sta-bility.In addition,differences in the structure,gene expres-sion,and metabolism of different types of neurons,as well as in their internal environment,may lead to differ-ences in their response to and impact on ERS.Differenc-es in UPR signaling pathways occur in hippocampal neurons and medial thalamic cells,and Purkinje cells and pyramidal cells may be more sensitive to ERS than other types of neurons.Our group's previous study found that ERS induced apoptosis in neurons after the onset of CIRI by regulating proteins such as GRP78,CHOP and caspase-12,but the effects of UPR activation on different cells need to be further investigated.

The epitranscriptomic mark N⁶-methyladenosine (m⁶A), which is the predominant internal modification in RNA, is important for plant responses to diverse stresses. Multiple environmental stresses caused by the tea-withering process can greatly influence the accumulation of specialized metabolites and the formation of tea flavor. However, the effects of the m⁶A-mediated regulatory mechanism on flavor-related metabolic pathways in tea leaves remain relatively uncharacterized. We performed an integrated RNA methylome and transcriptome analysis to explore the m⁶A-mediated regulatory mechanism and its effects on flavonoid and terpenoid metabolism in tea (Camellia sinensis) leaves under solar-withering conditions. Dynamic changes in global m⁶A level in tea leaves were mainly controlled by two m⁶A erasers (CsALKBH4A and CsALKBH4B) during solar-withering treatments. Differentially methylated peak-associated genes following solar-withering treatments with different shading rates were assigned to terpenoid biosynthesis and spliceosome pathways. Further analyses indicated that CsALKBH4-driven RNA demethylation can directly affect the accumulation of volatile terpenoids by mediating the stability and abundance of terpenoid biosynthesis-related transcripts and also indirectly influence the flavonoid, catechin, and theaflavin contents by triggering alternative splicing-mediated regulation. Our findings revealed a novel layer of epitranscriptomic gene regulation in tea flavor-related metabolic pathways and established a link between the m⁶A-mediated regulatory mechanism and the formation of tea flavor under solar-withering conditions.
RNA/metabolism* ; Epigenome ; Plant Proteins/metabolism* ; Plant Leaves/metabolism* ; Camellia sinensis/metabolism* ; Flavonoids ; Terpenes/metabolism* ; Tea/metabolism* ; Gene Expression Regulation, Plant

Vulnerable plaque rupture is the leading cause of acute cardiovascular diseases. Macrophages are main inflammatory cells closely related to the rupture of vulnerable plaques. Early diagnosis of vulnerable plaque can reduce the mortality of acute cardiovascular diseases. With the development of molecular imaging, the possibility for early identification of vulnerable plaques may come true. This review summarizes the changes of molecular markers of macrophages in vulnerable plaques and the molecular probes that can target macrophages.