Clinical application value of Huanglian Jiedu Pills in improving syndrome of excess heat and fire toxin based on phase Ⅱ clinical trial study on plasma ATP, 4-HNE, and ACTH levels / 中国中药杂志

A randomized, double-blind, placebo-controlled, multi-center phase Ⅱ clinical trial design was used in this study to recruit subjects who were in line with the syndrome of excess heat and fire toxin, and were diagnosed as recurrent oral ulcers, gingivitis, and acute pharyngitis. A total of 240 cases were included and randomly divided into a placebo group and a Huanglian Jiedu Pills group. The clinical efficacy of Huanglian Jiedu Pills in treating the syndrome of excess heat and fire toxin was evaluated by using the traditional Chinese medicine(TCM) syndrome scale. Enzyme-linked immunosorbent assay(ELISA) was used to determine and evaluate the levels of adenosine triphosphate(ATP), 4-hydroxynonenal(4-HNE), and adrenocorticotropic hormone(ACTH) in plasma of the two groups before and after administration and to predict their application value as clinical biomarkers. The results showed that the disappearance rate of main symptoms in the Huanglian Jiedu Pills group was 69.17%, and that in the placebo group was 50.83%. The comparison between the Huanglian Jiedu Pills group and the placebo group showed that 4-HNE before and after administration was statistically significant(P<0.05). The content of 4-HNE in the Huanglian Jiedu Pills group decreased significantly after administration(P<0.05), but that in the placebo group had no statistical significance and showed an upward trend. After administration, the content of ATP in both Huanglian Jiedu Pills group and placebo group decreased significantly(P<0.05), indicating that the energy metabolism disorder was significantly improved after administration of Huanglian Jiedu Pills and the body's self-healing ability also alleviated the increase in ATP level caused by the syndrome of excess heat and fire toxin to a certain extent. ACTH in both Huanglian Jiedu Pills group and placebo group decreased significantly after administration(P<0.05). It is concluded that Huanglian Jiedu Pills has a significant clinical effect, and can significantly improve the abnormal levels of ATP and 4-HNE in plasma caused by the syndrome of excess heat and fire toxin, which are speculated to be the effective clinical biomarkers for Huanglian Jiedu Pills to treat the syndrome of excess heat and fire toxin.

Role of purine signaling in liver immune regulation / 临床肝胆病杂志

Purines are mainly composed of ATP, NAD + , and nucleic acid. In addition to their key intracellular functions, NAD + , ATP, and their hydrolyzed products (including ADP, AMP, and adenosine) are important extracellular signals involved in physiological processes and pathological conditions. Purine signaling plays an important role in immune regulation of liver microenvironment. This article mainly summarizes the regulatory effect of purine signaling on immune cells in the liver and the effect of purine signaling on the progression of liver diseases by regulating the inflammatory and anti-inflammatory responses of immune cells in the liver.

Diagnostic value of ATP stress myocardial perfusion imaging in detecting coronary artery disease with quantitative coronary angiography as the gold standard / 中华核医学与分子影像杂志

Objective:To assess the diagnostic value of ATP stress myocardial perfusion imaging(MPI) in detecting coronary heart disease (CAD) with quantitative coronary angiography (QCA) as the gold standard.Methods:A total of 95 consecutive patients (65 males, 30 females, age (56.2±8.5) years) who underwent ATP stress/rest MPI and coronary angiography (CAG) within one month in Fuwai Hospital, Chinese Academy of Medical Sciences from May 2018 to December 2018 were enrolled prospectively. The adverse reactions of ATP stress test were observed. Semi-quantitative analysis was performed on MPI results, and the summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS) were obtained. Quantitative analysis was performed on CAG images, and the degree of QCA coronary artery stenosis was analyzed. Using QCA as the gold standard, the diagnostic efficiency of ATP stress MPI was calculated. Pearson correlation analysis was performed to analyzed the relationship between SSS and the degree of QCA coronary artery stenosis.Results:In 95 cases, the incidence of adverse reactions in ATP stress test was 73.7%(70/95), which could be relieved automatically after drug withdrawal. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of ATP stress MPI in diagnosing coronary artery stenosis ≥50% were 45.3%(24/53), 81.0%(34/42), 75.0%(24/32), 54.0%(34/63) and 61.1%(58/95) respectively, which were 15/16, 78.5%(62/79), 46.9%(15/32), 98.4%(62/63), and 81.1%(77/95) respectively in diagnosing coronary artery stenosis ≥70%. There was moderate correlation between SSS and the degree of QCA coronary artery stenosis ( r=0.418, P=0.017). Conclusion:ATP stress MPI has a clinical value in the diagnosis of myocardial ischemia in CAD.

Cardioprotective Effect of Cilostazol on Ischemia-Reperfusion Injury Model

Abstract Introduction: To clarify the potential protective role of cilostazol on rat myocardial cells with ischemia-reperfusion injury (IRI) models. Methods: The study was conducted with three groups of 10 Wistar rats (control group, rats without any coronary ischemia; sham group, rats with coronary ischemia but without cilostazol administration; and cilostazol group, rats with coronary ischemia and cilostazol administration). The level of myocardial injuries was measured by analyzing cardiac troponin T and creatine kinase MB levels in blood samples. In tissue samples, adenosine triphosphate (ATP), nitric oxide, superoxide dismutase (SOD), and malondialdehyde were used to determine the amount of tissue damage. Tissues were stained with hematoxylin-eosin method, and samples were examined under light microscope. Results: The mean level of ATP was 104.4 in the cilostazol group and 149.1 in the sham group (P=0.044). SOD level was significantly higher in the cilostazol group than in the sham group (2075.3 vs. 1783.7, P=0.043). According to histopathological examination, all samples were classified as G0 in the control group. In the sham group, one sample was categorized as G1, six samples as G2, and three samples as G3. In the cilostazol group, nine samples and one sample were categorized as G1 and G2, respectively (P=0.011). Conclusion: Cilostazol has beneficial effects on Wistar rats' myocardial cells in regard to decreasing inflammatory process, necrosis, and fibrosis. Our findings revealed that the use of cilostazol significantly decreased ATP and increased SOD levels in Wistar rats' myocardial cells after IRI.

Intraoperative adenosine for pheochromocytoma with myocardial infarction and SARS-CoV-2. Case report / Adenosina intraoperatoria para feocromocitoma con infarto miocárdico y SARS-CoV-2. Reporte de caso

Abstract Pheochromocytomas are neuroendocrine tumors capable of synthetizing, storing and releasing catecholaminergic hormones that may lead to lifethreatening hemodynamic instability. The COVID-19 pandemic has increased the risks and perioperative complexity of the patients undergoing pheochromocytoma-associated adrenalectomy. This article discusses the use of adenosine for the management of hypertensive crisis during this intervention, as well as the need to individualize the suitable timing for surgery after recent COVID-19 infection. This article discusses the case of a patient with a finding of right adrenal incidentaloma; further studies determined a metanephrines secreting pheochromocytoma. Following hospital admission for preoperative optimization, the eve of the procedure the patient developed an acute myocardial infarction and subsequently SARS-CoV-2 symptomatic infection. Intraoperatively, hypertensive peaks were managed with continuous adenosine perfusion. The patient was discharged after 48 hours. Preoperative optimization positively influences the intraoperative management of patients with pheochromocytoma. The intraoperative use of adenosine allows for adequate and safe control of hypertensive crises. Each situation must be individualized in patients pending surgery, with a recent COVID-19 infection.

Resumen Los feocromocitomas son tumores neuroendocrinos capaces de sintetizar, almacenar y liberar hormonas catecolaminérgicas que pueden provocar inestabilidad hemodinámica con compromiso vital. La pandemia por COVID-19 ha aumentado los riesgos y la complejidad perioperatoria de los pacientes sometidos a adrenalectomía por feocromocitoma. Describimos el uso de adenosina para manejar las crisis hipertensivas durante esta intervención, así como establecer la necesidad de individualizar el momento quirúrgico idóneo tras infección reciente por COVID-19. Presentamos el caso de un paciente con hallazgo de incidentaloma suprarrenal derecho cuya ampliación de estudio se orientó como feocromocitoma secretor de metanefrinas. Tras ingreso hospitalario para optimización preoperatoria, el día previo al procedimiento presentó un infarto agudo de miocardio y posteriormente una infección sintomática por SARS-CoV-2. Intraoperatoriamente se manejaron los picos hipertensivos con perfusión continua de adenosina. Tras 48 horas recibió el alta hospitalaria. La optimización preoperatoria influye positivamente en el manejo intraoperatorio de los pacientes con feocromocitoma. El uso intraoperatorio de adenosina permite un adecuado y seguro control de las crisis hipertensivas. En pacientes pendientes de cirugía con infección reciente por COVID-19 se requiere individualizar cada situación.

Effect of Five Huoxue Huayu Prescriptions on Blood Lipid Metabolism， Liver Tissue and ABCA1 and PPARγ Expression in New Zealand Rabbits with Blood Stasis Syndrome / 中国实验方剂学杂志

ObjectiveTo observe the effects of five Huoxue Huayu prescriptions on blood lipid metabolism， liver tissue and adenosine triphosphate binding cassette transporter A1 （ABCA1） and peroxisome proliferator-activated receptor γ（PPARγ） expression in New Zealand rabbits with blood stasis syndrome， and to compare their differences in order to provide laboratory evidence for clinical selection of prescriptions and drugs. MethodSeventy New Zealand rabbits were randomly divided into normal group （n=10） and model group （n=60）. The blood stasis syndrome was modeled by the method of starvation+high-fat feed+adrenaline. After the models were successfully established， they were randomly divided into Xuefu Zhuyutang（3.55 g·kg-1·d-1） group， Danshenyin（1.962 g·kg-1·d-1） group， Shixiaosan（0.56 g·kg-1·d-1） group， Huoluo Xiaolingdan（2.80 g·kg-1·d-1） group， and Taohong Siwutang（2.66 g·kg-1·d-1） group， and were given corresponding compound prescriptions by gavage. The normal group and model group were given the same dose of distilled water. After the treatment of 30 consecutive days， blood was taken from the abdominal aorta to detect the content of total cholesterol （TC）， triglycerides （TG）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol（LDL-C） and apolipoprotein A1 （ApoA1）. Hematoxylin-eosin（HE） staining was used to observe the changes in liver tissue. Real-time polymerase chain reaction （Real-time PCR） and Western blot were used to detect the mRNA and protein expression of ABCA1 and PPARγ in liver tissue， respectively. ResultCompared with the conditions in the normal group， increased mRNA and protein levels of HDL-C， LDL-C， TG， TC， and PPARγ （P<0.01）， decreased ApoA1 level （P<0.05） and decreased mRNA and protein levels of ABCA1 （P<0.01） were found in the model group. Compared with the conditions in the model group， the HDL-C level in the five Huoxue Huayu prescriptions was lowered （P<0.05）， and lowered TG level in Xuefu Zhuyutang group and Shixiaosan group （P<0.05）， decreased LDL-C and TC levels in Shixiaosan group （P<0.05）， and increased ApoA1 level in the Huoluo Xiaolingdan group （P<0.01） and Taohong Siwutang group （P<0.05） were observed. Furthermore， the mRNA and protein levels of ABCA1 in Xuefu Zhuyutang group， Shixiaosan group， Huoluo Xiaolingdan group and Taohong Siwutang group were elevated （P<0.05， P<0.01）， and the elevated levels were higher than that of Danshenyin group （P<0.05）. The mRNA level of PPARγ in the five Huoxue Huayu prescriptions was reduced （P<0.01）， and its protein level was also decreased in Xuefu Zhuyutang group， Shixiaosan group， Huoluo Xiaolingdan group and Taohong Siwutang group （P<0.01）. ConclusionThe five Huoxue Huayu prescriptions had a certain therapeutic effect on dyslipidemia，which might be achieved by up-regulating the expression of ApoA1 and ABCA1 to promote the production of HDL-C and strengthen the excretion of dysfunctional HDL-C. And Xuefu Zhuyutang had the optimal effect in lowering lipid.

Mitochondria targeting drugs for neurodegenerative diseases-Design, mechanism and application

Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.

Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability

Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.

Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.

Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.

The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.

Evaluation of adenosine triphosphate in emergency cardioversion of paroxysmal supraventricular tachycardia in children / 中华实用儿科临床杂志

Objective:To explore the safety and efficacy of adenosine triphosphate (ATP) in terminating paro-xysmal supraventricular tachycardia (PSVT) in children and the correlation between its efficacy, age and dose.Methods:A retrospective analysis was performed on the clinical data, efficacy and adverse effects of intravenous ATP in 120 children who had received ATP emergency cardioversion among 1 488 children with PSVT hospitalized in the Department of Pediatric Cardiology, Heart Center, First Hospital of Tsinghua University from September 2014 to November 2019.There were 80 boys and 40 girls with the age of (3.50±3.66) years (25 d-15 years). As for the group comparison, the measurement data was subject to the independent samples t test and Mann- Whitney U test; the enumeration data was subject to χ2 test. Results:Among the 120 children with PSVT, there were 42 cases (35.0%) <1 year old, and 24 cases(20.0%) combined with congenital heart disease.There were 8.3% of them (10/120 cases) suffering from tachycardiomyopathy (TCM) secondary to PSVT, whose LVEF increased from (32.70±11.69)% to (40.50±11.63)% after successful control of PSVT ( t=-3.647, P=0.005). The complete termination of PSVT by intravenous ATP was achieved in 53 of 120 cases (44.2%). ATP was given at 0.3 mg/kg, 0.2 mg/kg and 0.1 mg/kg in dose, and the significant effective rate was 56.5%(13/23 cases), 36.4%(32/88 cases) and 0, respectively, which showed that there was a significant difference in the therapeutic effect between different dose groups ( χ2=10.058, P=0.007). There was a significant difference regarding the complete termination rate between children <1 year old and those ≥1 year old [31.0%(13/42 cases) vs.51.3%(40/78 cases), χ2=4.575, P=0.032]. For refractory PSVT, the intravenous ATP was performed based on the absence of cardioversion with continuous pumping of other antiarrhythmic drugs, which achieved a significantly complete termination rate of 55.6% (10/18 cases). The rate of ATP adverse reactions was 2.5%(3/120 cases), presented with sinus arrest in children >1 year old with the dose of 0.2-0.3 mg/kg. Conclusions:It was relatively safe and effective to terminate PSVT in children with ATP, which was related to dose and age.For refractory PSVT, ATP can be intravenously pushed on the basis of continuous pumping of other antiarrhythmic drugs, which can achieve a higher complete termination rate.

Role of P2X7 receptor in colon cancer progression / 国际肿瘤学杂志

P2X7 receptor is an ion channel receptor with adenosine triphosphate (ATP) as its ligand, which is widely expressed in various immune cells and tissues. Activated P2X7 receptor is involved in a variety of physiological and pathological processes. P2X7 receptor is abnormally expressed in colon cancer, and plays a duel role of cancer-promoting and cancer-suppressing in colon cancer progression. When P2X7 receptor is activated by extracellular ATP, it can effectively inhibit proliferation and induce apoptosis of colon cancer cells through various mechanisms. In addition, P2X7 receptor can also promote the growth, invasion and metastasis of colon cancer. Understanding the activation of P2X7 receptor and its effect mechanism is of great significance for the treatment of colon cancer.

The disruption of protein-protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition

The 90-kiloDalton (kD) heat shock protein (Hsp90) is a ubiquitous, ATP-dependent molecular chaperone whose primary function is to ensure the proper folding of several hundred client protein substrates. Because many of these clients are overexpressed or become mutated during cancer progression, Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple oncoproteins and signaling pathways simultaneously. The first discovered Hsp90 inhibitors, geldanamycin and radicicol, function by competitively binding to Hsp90's N-terminal binding site and inhibiting its ATPase activity. However, most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four isoforms. Consequently, alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition, isoform-selective inhibition, and the disruption of Hsp90 protein-protein interactions. Since the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex, along with various co-chaperones and immunophilins, the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition.

Salt-inducible kinase 2 regulates energy metabolism in rats with cerebral ischemia-reperfusion / 浙江大学学报·医学版

To investigate the effects of salt-inducible kinase 2 (SIK2) on energy metabolism in rats with cerebral ischemia-reperfusion. Adult SD male rats were divided into 5 groups: sham group, ischemia group, reperfusion group, adenovirus no-load group, and SIK2 overexpression group with 5 animals in each group. The middle cerebral artery occlusion (MCAO) was induced with the modified Zea-Longa line thrombus method to establish the cerebral ischemia reperfusion model. Eight days before the MCAO, SIK2 overexpression was induced by injecting 7 μL adenovirus in the right ventricle, then MCAO was performed for followed by reperfusion HE staining was used to observe the pathological changes of cerebral tissue in rats; TTC staining was used to observe the volume of cerebral infarct. The levels of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) in rat brain tissue were detected by ELISA; the levels of SIK2 and hypoxia-inducible factor 1α (HIF-1α) in the rat brain tissues were detected by RT-qPCR and Western blotting. Compared with the sham group, SIK2 level was decreased in the ischemia group, and it was further declined in the reperfusion group (<0.05). Compared with the sham group and ischemic group, the pathological injury in reperfusion group were more severe, and the infarct size was larger; compared with the reperfusion group and adenovirus no-load group, the pathological injury of the SIK2 overexpression group was milder, and the infarct size is less. Compared with the sharn group, HIF-1α was increased in both ischemia group and reperfusion group, especially in ischemia group (all <0.05); HIF-1α level in the SIK2 overexpression group was higher than that in the reperfusion group and adenovirus no-load group (all <0.05). ATP level in ischemia group and reperfusion group was lower than that in the sham group, and the reperfusion group decreased more significantly than the ischemia group (<0.05); ADP content was increased in the ischemia and reperfusion group, and the ADP content in reperfusion group was significantly higher than that in the ischemia group (<0.05). ATP level in the SIK2 overexpression group was higher than that in the reperfusion group and adenovirus no-load group (all <0.05), and ADP was decreased in the SIK2 overexpression group (all <0.05). SIK2 can up-regulate the ATP level and down-regulate the ADP level in rat brain tissue and alleviate cerebral ischemia-reperfusion injury by increase the level of HIF-1α.

Self-assembled FeS-based cascade bioreactor with enhanced tumor penetration and synergistic treatments to trigger robust cancer immunotherapy

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death (ICD) to provoke a robust immune response for metastasis control. Here, a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation, chemodynamic (CDT) and photothermal therapy. Ultrasmall FeS-GOx nanodots were synthesized with glucose oxidase (GOx) as template and induced by paclitaxel (PTX) to form self-assembling FeS-GOx@PTX (FGP)

Research progress on the gene polymorphism of tacrolimus transporter in organ transplantation / 器官移植

Tacrolimus (Tac) is a commonly used immunosuppressant after organ transplantation, which has high immunosuppressive efficacy. However, the pharmacokinetics of Tac significantly differ among individuals, and gene polymorphism is the main influencing factor. In recent years, the gene polymorphism of drug transporter has become a novel research hotspot. Nevertheless, the effect of the gene polymorphism of transporter on Tac pharmacokinetics remains controversial. Consequently, the correlation between the gene polymorphism of transporter and Tac blood concentration plays a significant role in guiding Tac-based individualized immunosuppressive therapy. In this article, the research progresses on the gene polymorphism of adenosine triphosphate-binding cassette (ABC) transporter and solute carrier (SLC) transporter in organ transplantation was reviewed. The correlation between the gene polymorphism of transporter and Tac blood concentration was summarized, aiming to provide reference for Tac-based individualized therapy.

Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension

Hypertension is the largest risk factor for cardiovascular disease, the leading cause of mortality worldwide. As blood pressure regulation is influenced by multiple physiological systems, hypertension cannot be attributed to a single identifiable etiology. Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling, particularly the distal convoluted tubule (DCT)-native, thiazide-sensitive Na-Cl cotransporter (NCC). Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon's and Gitelman syndromes respectively. Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC. In particular, NCC activity is controlled by phosphorylation/dephosphorylation, and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination. Studies have even found parvalbumin to be an unexpected regulator of the NCC. In recent years, there have been considerable advances in our understanding of NCC control mechanisms, particularly

The progress on the relationship between P2X7 receptor and pancreatic cancer / 医学研究生学报

Pancreatic cancer is one of the cancers with poor prognosis at present, which has high resistance to various anti-tumor drugs as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. P2X7 receptors are extracellular adenosine triphosphate(ATP)-gated nonselective cation channels, which have many biological functions including being involved in cell signal transduction and cytokine secretion, mediate cell survival and growth. Studies have shown that P2X7 receptor is highly expressed in pancreatic cancer and promotes the proliferation, migration and invasion of pancreatic cancer cells by supporting proliferation of pancreatic stellate cells and regulating the expressed of the MMP2/MMP9 protein. The paper reviews the recent research advances of P2X7 receptor in pancreatic cancer.