Mechanism of cGAS/STING Signaling Pathway in Regulating Lung Cancer and Traditional Chinese Medicine Treatment： A Review / 中国实验方剂学杂志

According to the latest global cancer statistics， the incidence and mortality of lung cancer rank first in China. Classical therapies remain the most common cancer treatment options， such as surgical resection， radiotherapy， and chemotherapy， but not all cancer patients respond to classical therapies， which require new lung cancer treatment strategies. After decades of research and development， cancer immunotherapy has achieved certain curative effect， which provides new possibilities for cancer treatment. Cyclic guanosine monophosphate-adenosine monophosphate synthase （cGAS） is a cytosolic DNA sensor. It can induce protective immune defense responses against various DNA-containing pathogens and provide anti-tumor immunity by activating the interferon （IFN） gene stimulator （STING） protein. At present， relevant researchers in China and abroad have done a lot of research on the occurrence and development of lung cancer and the pathophysiological mechanism of drug intervention in the treatment of lung cancer. The results show that cGAS/STING signaling pathway plays an important role in the development of the disease， and traditional Chinese medicine monomers or compounds can intervene in lung cancer cells by regulating the cGAS/STING signaling pathway， induce their autophagy and death， regulate their cycle operation， promote senescence， inhibit their proliferation and tumor angiogenesis， promote their invasion and metastasis， and promote the immune activation of anti-lung cancer cells， so as to inhibit or delay the occurrence and development of lung cancer. In recent years， the related research results have been updated rapidly， and the previous literature has not included the latest research results in time， which causes a lot of inconvenience for many scholars to search the literature. Based on this， this paper mainly summarized the mechanism of cGAS/STING signaling pathway intervention in lung cancer in China and abroad in recent years， as well as the research progress of related traditional Chinese medicine intervention， so as to provide new ideas for the development of lung cancer in molecular biology， drug treatment research， and clinical new drug research and provide a reference for further mechanism research.

Cell-to-Cell Communications of cGAS-STING Pathway in Tumor Immune Microenvironment / 浙江大学学报·医学版

Targeting cGAS-STING pathway is a promising strategy in tumor treatment. The pattern recognition receptor cGAS identifies dsDNA and catalyzes the formation of the second messenger 2'3'-cGAMP, activating the downstream interferons and pro-inflammatory cytokines through the adaptor protein STING. Notably, in tumor immune microenvironment, key components of cGAS-STING pathway are transferred among neighboring cells. The intercellular transmission under these contexts serves to sustain and amplify innate immune responses while facilitating the emergence of adaptive immunity. The membrane-based system, including extracellular vesicles transport, phagocytosis and membrane fusion transmit dsDNA, cGAMP and activated STING, enhancing the immune surveillance and inflammatory. The membrane proteins, including specific protein channel and intercellular gap junctions, transfer cGAMP and dsDNA, which are crucial to regulate immune responses. And the ligand-receptor interactions for interferons transmission amplifies the anti-tumor response. This review elaborates on the regulatory mechanisms of cell-to-cell communications of cGAS-STING pathway in tumor immune microenvironment. We further explore how these mechanisms modulate immunological processes and discuss potential interventions and immunotherapeutic strategies targeting these signaling cascades.

Mechanism of Yiyuan Qiwei Pills in Treatment of Diabetes Mellitus-induced Erectile Dysfunction / 中国实验方剂学杂志

ObjectiveTo observe the therapeutic effect of Yiyuan Qiwei pills （YYQW） on diabetes mellitus-induced induced erectile dysfunction （DMED） in rats and explore its regulation on the nitric oxide （NO）-cyclic guanosine monophosphate （cGMP） signaling pathway. MethodFifty-five healthy SD male rats of clean grade aged 2-3 months underwent intraperitoneal injection of streptozotocin （STZ） to induce the DMED model， and another 10 healthy SD male rats of clean grade aged 2-3 months were assigned to the control group. The model rats were randomly divided into a model group， a sildenafil group （5 mg·kg-1， ig）， and low-， medium-， and high-dose YYQW groups （1.5， 3.0， 6.0 g·kg-1， ig）. The rats in the model group and the control group were given normal saline by gavage at 10 mL·kg-1， once a day for two months. After intervention， the penile erectile function of rats in each group was measured by a pressure detection system. The pathological changes and ultrastructure of penile corpus cavernosum were observed by hematoxylin-eosin （HE） staining and transmission electron microscopy， respectively. The level of NO in the corpus cavernosum was detected by nitrate reductase. Enzyme-linked immunosorbent assay （ELISA） was used to detect the levels of cGMP and advanced glycation end products （AGEs）. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of endothelial nitric oxide synthase （eNOS）， neurogenic nitric oxide synthase （nNOS）， total nitric oxide synthase （NOS）， and phosphodiesterase type5 （PDE5） in rat penile tissues. The expression of above proteins was detected by Western blot. ResultCompared with the control group， the model group showed decreased intracavernous pressure （ICP）， NO， and cGMP levels， reduced mRNA and protein expression of nNOS and NOS， and increased PDE5 mRNA and protein expression （P<0.05）. Compared with the model group， the sildenafil group and the YYQW groups displayed increased ICP， NO， and cGMP levels， elevated mRNA and protein expression levels of nNOS and NOS， and reduced PDE5 mRNA and protein expression levels （P<0.05）. There were no pathological changes in the tissues and cell ultrastructure of the corpus cavernosum in the control group， while serious pathological changes were observed in the model group. Additionally， the sildenafil group and the YYQW groups were superior to the model group， the optimal effect was observed in the high-dose YYQW group. ConclusionYYQW can improve the penile erectile function of DMED rats and reduce the pathological damage of corpus cavernosum. The mechanism may be related to the promotion of nNOS and NOS expression， the inhibition of PDE5 expression， and the activation of the NO/cGMP signaling pathway.

Mechanism of Yiyuan Qiwei Pills in Treatment of Diabetes Mellitus-induced Erectile Dysfunction / 中国实验方剂学杂志

ObjectiveTo observe the therapeutic effect of Yiyuan Qiwei pills （YYQW） on diabetes mellitus-induced induced erectile dysfunction （DMED） in rats and explore its regulation on the nitric oxide （NO）-cyclic guanosine monophosphate （cGMP） signaling pathway. MethodFifty-five healthy SD male rats of clean grade aged 2-3 months underwent intraperitoneal injection of streptozotocin （STZ） to induce the DMED model， and another 10 healthy SD male rats of clean grade aged 2-3 months were assigned to the control group. The model rats were randomly divided into a model group， a sildenafil group （5 mg·kg-1， ig）， and low-， medium-， and high-dose YYQW groups （1.5， 3.0， 6.0 g·kg-1， ig）. The rats in the model group and the control group were given normal saline by gavage at 10 mL·kg-1， once a day for two months. After intervention， the penile erectile function of rats in each group was measured by a pressure detection system. The pathological changes and ultrastructure of penile corpus cavernosum were observed by hematoxylin-eosin （HE） staining and transmission electron microscopy， respectively. The level of NO in the corpus cavernosum was detected by nitrate reductase. Enzyme-linked immunosorbent assay （ELISA） was used to detect the levels of cGMP and advanced glycation end products （AGEs）. Real-time quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of endothelial nitric oxide synthase （eNOS）， neurogenic nitric oxide synthase （nNOS）， total nitric oxide synthase （NOS）， and phosphodiesterase type5 （PDE5） in rat penile tissues. The expression of above proteins was detected by Western blot. ResultCompared with the control group， the model group showed decreased intracavernous pressure （ICP）， NO， and cGMP levels， reduced mRNA and protein expression of nNOS and NOS， and increased PDE5 mRNA and protein expression （P<0.05）. Compared with the model group， the sildenafil group and the YYQW groups displayed increased ICP， NO， and cGMP levels， elevated mRNA and protein expression levels of nNOS and NOS， and reduced PDE5 mRNA and protein expression levels （P<0.05）. There were no pathological changes in the tissues and cell ultrastructure of the corpus cavernosum in the control group， while serious pathological changes were observed in the model group. Additionally， the sildenafil group and the YYQW groups were superior to the model group， the optimal effect was observed in the high-dose YYQW group. ConclusionYYQW can improve the penile erectile function of DMED rats and reduce the pathological damage of corpus cavernosum. The mechanism may be related to the promotion of nNOS and NOS expression， the inhibition of PDE5 expression， and the activation of the NO/cGMP signaling pathway.

Research progress of phosphodiesterase inhibitors in inflammatory bowel disease treatment / 浙江大学学报·医学版

Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.

Antioxidative Propolis From Stingless Bees (Heterotrigona Itama) Preserves Endothelium-Dependent Aortic Relaxation of Diabetic Rats: The Role of Nitric Oxide and Cyclic Guanosine Monophosphate

Propolis from stingless bees (Heterotrigona itama) is a resinous compound that exhibits antihyperglycaemia, free radical scavenging, and cardioprotective properties. The effect of propolis on diabetic vessels has not been investigated. Thus, this research aimed to determine the effect of propolis supplementation on the level of antioxidants and its mechanism of action in the aorta of diabetic rats. Male Sprague-Dawley rats were divided into five groups (n=8/group): healthy (control), untreated diabetes (DM), metformin-treated diabetes (DM+M, 300 mg/kg/day metformin), propolis-treated diabetes (DM+P, 300 mg/kg/day propolis extract) and diabetes with combined treatment (DM+M+P, dosage as former). Oral supplementation was conducted for four weeks immediately upon successful induction of diabetes by streptozotocin (60 mg/kg, intraperitoneal injection). At the end of the study, the rats were euthanised, and thoracic aorta was processed into tissue homogenates to determine the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase-1 (GPx-1) and soluble receptor for advanced glycation end-products (sRAGE). Aorta segments were harvested to examine their relaxation response towards graded concentration of acetylcholine (Ach; 10-8-10-4) M following precontraction with phenylephrine (PE; 10-6 M). Vasorelaxation towards a cumulative dose of propolis (0.01-1.00%) using PE-precontracted healthy aorta (n=6/experiments) was investigated under various simulated conditions: physiological buffer, L-NAME (10-4 M), methylene blue (10-5 M), indomethacin (10-5 M) and elevated glucose (25 mM). Propolis maintained antioxidative enzymes and sRAGE decoy molecules in the aortic tissue of the diabetic rats. The amelioration of diabetes-induced impairment of endothelium-dependent relaxation by propolis was mediated through the nitric oxide(NO)-cyclic guanosine monophosphate (cGMP) pathway. This non-clinical study reports vasoprotective property of propolis in diabetes mellitus.

Studies on Pathophysiology and Possible Cause of Hie-Symptom ─Findings on Sublingual and Body Surface Temperature, Venous Gas Partial Pressure and the Effects of Oral Administration of PDE-5 Inhibitor Tadarafil─ / 日本温泉気候物理医学会雑誌

  Background and Purpose: Hie-symptom is more common in women, with complains of strong cold sensation of fingers and lower limbs during cold weather. From the cyanotic findings of hands and thighs and dark venous blood, blood stasis due to excessive peripheral vein contraction was suspected. Then we studied the changes of sublingual and body surface temperature, venous gas partial pressure in the warm and cold conditions. To examine the role of thermo-dilating effects of nitric oxide (NO), the effects oral administration PDE 5 inhibitor Tadarafil (TDF) were also studied.   Subjects and Methods: The subjects were 10 women (31 +- 8.8 yrs) with Hie-symptom and 7 women (26+-3.7 yrs) without Hie-symptom, BMI, blood pressure, heart rate,sublingual and peripheral body surface temperature (hand and lower limb), venous and arterial blood gas partial pressure, and fingertip arterial oxygen saturation were measured. The measurement was carried out at warm indoors (about 23°C) and cold outdoors (about 12°C). Then 10 mg TDF tablet was taken and all measurements were repeated again at the same time on the next day.   Results: There was no difference in fingertip arterial blood oxygen saturation in both groups either at indoor or outdoor conditions, and even after taking TDF. In the cold outdoor, the subjects with Hie-symptom, compared to without Hie-symptom, showed significantly lower body surface temperature and venous blood pO2, and increased pCO2. After taking TDF, although sublingual temperature and the decrease in body surface temperature outside the room improved in both groups, the improvement was greater in Hie-symptom.  Consideration and Conclusion: Because of normal fingertip arterial blood oxygen saturation, Hie-symptom is not considered to be a disorder of the cardiopulmonary/arterial system. From a significant decrease in peripheral body surface temperature, and peripheral venous blood pO2, and an increase in pCO2 of Hie-symptom in cold outdoors, it is considered that blood stasis by excessive constriction of peripheral veins or arteriovenous anastomosis (AVA) by the cold. The better effects of oral TDF, in Hie-symptom seems to predict the involvement of NO or cGMP in blood stasis.

Studies on Pathophysiology and Possible Cause of Hie-Symptom ─Findings on Sublingual and Body Surface Temperature, Venous Gas Partial Pressure and the Effects of Oral Administration of PDE-5 Inhibitor Tadarafil─ / 日本温泉気候物理医学会雑誌

  Background and Purpose: Hie-symptom is more common in women, with complains of strong cold sensation of fingers and lower limbs during cold weather. From the cyanotic findings of hands and thighs and dark venous blood, blood stasis due to excessive peripheral vein contraction was suspected. Then we studied the changes of sublingual and body surface temperature, venous gas partial pressure in the warm and cold conditions. To examine the role of thermo-dilating effects of nitric oxide (NO), the effects oral administration PDE 5 inhibitor Tadarafil (TDF) were also studied.   Subjects and Methods: The subjects were 10 women (31 +- 8.8 yrs) with Hie-symptom and 7 women (26+-3.7 yrs) without Hie-symptom, BMI, blood pressure, heart rate,sublingual and peripheral body surface temperature (hand and lower limb), venous and arterial blood gas partial pressure, and fingertip arterial oxygen saturation were measured. The measurement was carried out at warm indoors (about 23°C) and cold outdoors (about 12°C). Then 10 mg TDF tablet was taken and all measurements were repeated again at the same time on the next day.   Results: There was no difference in fingertip arterial blood oxygen saturation in both groups either at indoor or outdoor conditions, and even after taking TDF. In the cold outdoor, the subjects with Hie-symptom, compared to without Hie-symptom, showed significantly lower body surface temperature and venous blood pO2, and increased pCO2. After taking TDF, although sublingual temperature and the decrease in body surface temperature outside the room improved in both groups, the improvement was greater in Hie-symptom.  　Consideration and Conclusion: Because of normal fingertip arterial blood oxygen saturation, Hie-symptom is not considered to be a disorder of the cardiopulmonary/arterial system. From a significant decrease in peripheral body surface temperature, and peripheral venous blood pO2, and an increase in pCO2 of Hie-symptom in cold outdoors, it is considered that blood stasis by excessive constriction of peripheral veins or arteriovenous anastomosis (AVA) by the cold. The better effects of oral TDF, in Hie-symptom seems to predict the involvement of NO or cGMP in blood stasis.

Banxia Xiexin Decoction () Treats Diabetic Gastroparesis through PLC-IP / 中国结合医学杂志

OBJECTIVE@#To test the effect of Banxia Xiexin Decoction (, BXD) on the contraction and relaxation of gastric smooth muscle (SM) in diabetic gastroparesis (DGP) model rats, and to explore the mechanism of BXD in the prevention and treatment of DGP through experiments of signal pathway both in vivo and in vitro.@*METHODS@#Sixty Sprague-Dawley rats were divided into 6 groups according to a random number table: control group, model group, high-, medium- and low-dose BXD groups (9.2, 4.6 and 1.8 g/(kg·d), respectively), and domperidone group (10 mg/(kg·d)), 10 rats per group. DGP model was established initially by a single intraperitoneal injection of streptozotocin (STZ), and was confirmed by recording gastric emptying, intestinal transport velocity and gastric myoelectric activity of rats after 2 months. Each group was treated with a corresponding drug for 4 weeks. The mRNA and protein expressions of phospholipase C (PLC), inositol triphosphate (IP@*RESULTS@#Compared with the model group, high- and medium-dose BXD and domperidone significantly increased the expressions of PLC, IP@*CONCLUSIONS@#Treatment with high- and medium-dose BXD significantly attenuated STZ-induced experimental DGP in rats. The therapeutic effect of BXD on DGP rats might be associated with the PLC-IP

Influence of acupuncture combined with rehabilitation therapy on limb motor function and serum cAMP and cGMP in patients with hemiplegia of cerebral ischemic stroke / 中国针灸

OBJECTIVE@#To evaluate the therapeutic effect of the combined treatment with balance acupuncture therapy and exercise re-learning rehabilitation therapy and the impact on serum cAMP and cGMP in the patients with hemiplegia of cerebral ischemic stroke.@*METHODS@#A total of 90 patients of hemiplegia of cerebral ischemic stroke were randomized into an observation group and a control group, 45 cases in each one. All of the patients in the two groups received health education, diet guidance, routine symptomatic treatment as well as exercise re-learning rehabilitation therapy. Additionally, in the observation group, balance acupuncture therapy was applied, in which, the acupoints on the aspect of the human body, on the governor vessel and bladder meridian were adopted in the morning and those on the aspect of the human body, on the conception vessel and kidney meridian were stimulated in the afternoon. In the control group, the regular acupuncture was given. In the two groups, both acupuncture and rehabilitation therapies were given 5 days a week, 2 week-treatment as one course and totally 2 courses were required. Separately, before and after treatment, the score of Fugl-Meyer assessment (FMA) and the score of Chinese stroke scale (CSS) were recorded, the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) detected in serum and the clinical therapeutic effect were evaluated in the two groups.@*RESULTS@#After treatment, FMA score was increased in the patients of either of the groups as compared with that before treatment (<0.01) and CSS score decreased as compared with that before treatment (<0.01). After treatment, FMA score in the observation group was higher than that in the control group (<0.01) and CSS score was lower than the control group (<0.01). After treatment, the level of serum cAMP of the patients in either of the groups was increased as compared with that before treatment (<0.01) and that of cGMP decreased as compared with that before treatment (<0.01). After treatment, the level of cAMP in the observation group was higher than that in the control group (<0.01) and that of cGMP was lower than the control group (<0.01). The total effective rate was 93.3% (42/45) in the observation group, better than 73.3% (33/45) in the control group (<0.01).@*CONCLUSION@#The balance acupuncture therapy combined with exercise re-learning rehabilitation effectively improves the motor function of the affected limb, relieves injury and regulate the levels of serum cAMP and cGMP in the patients with hemiplegia of ischemic stroke.

Pancreatic kininogenase improves erectile function in streptozotocin-induced type 2 diabetic rats with erectile dysfunction / 亚洲男科学杂志(英文版)

Erectile dysfunction (ED) associated with type 2 diabetes is a severe problem that requires effective treatment. Pancreatic kininogenase (PK) has the potential to improve the erectile function of ED patients. This study aims to investigate the effect of PK on erectile function in streptozotocin-induced type 2 diabetic ED rats. To achieve this goal, we divided male Sprague-Dawley rats into five groups. One group was not treated, and the other four groups were treated with saline, sildenafil, PK or sildenafil, and PK, respectively, for 4 weeks after the induction of type 2 diabetic ED. Then, intracavernous pressure under cavernous nerve stimulation was measured, and penile tissue was collected for further study. Endothelial nitric oxide synthase levels, smooth muscle content, endothelium content, cyclic guanosine monophosphate (cGMP) levels in the corpus cavernosum, and neuronal nitric oxide synthase levels in the dorsal penile nerve were measured. Improved erectile function and endothelium and smooth muscle content in the corpus cavernosum were observed in diabetic ED rats. When treating diabetic ED rats with PK and sildenafil at the same time, a better therapeutic effect was achieved. These data demonstrate that intraperitoneal injection of PK can improve erectile function in a rat model of type 2 diabetic ED. With further research on specific mechanisms of erectile function improvement, PK may become a novel treatment for diabetic ED.

Effect of hyperoxia on NRP-cGMP signaling pathway in brain tissue of newborn rats / 吉林大学学报(医学版)

Objective: To construct the brain tissue damage models of newborn rats induced by hyperoxia, and to explore the effect of hyperoxia on the natriuretic peptide receptor-cyclic guanosine monophosphate (NRP-cGMP) signaling pathway in brain tissue of the newborn rats. Methods: A total of 60 newly born Wistar rats were divided into control group and hyperoxia model group, and there were 30 rats in each group. At the 1st, 3rd and 7th days after hyperoxia exposure, the brain tissues of 10 rats randomly selected from each group were gotten, and the body weights of the rats in two groups were detected. HE staining was used to observe the morphology of brain tissue of the rats in two groups; the ultrastructures of brain tissue of the rats in two groups were observed under transmission electron microscope. Western blotting method was used to detect the expression levels of natriuretic peptide receptor A (NPR-A) and natriuretic peptide receptor B (NPR-B) in brain tissue of the rats in two groups. ELISA method was used to determine the levels of cGMP in brain tissue of the rats in two groups. Results: The body weight of the rats in hyperoxia model group was significantly lower than that in control group at the 1st, 3rd and 7th days after hyperoxia exposure (P<0. 05). The HE staining results showed that at the 3rd day after hyperoxia exposure, the volume of the hippocampal pyramidal cells of the rats in hyperoxia model group was reduced, and the arrangement was sparse; at the 7th day after hyperoxia exposure, the hippocampal cells showed deep staining and shrinkage, and the cell boundaries were not clear. Under electron microscope, at the 3rd day after hyperoxia exposure, the mitochondrial double membrane structure of the rats in hyperoxia model group was destroyed, a few crest disappeared, and the number of mitochondria and synapses was decreased; the above damage conditions were aggravated at the 7th day after birth. The Western blotting results showed that at the 1st, 3rd and 7th days after hyperoxia exposure, the expression level of NPR-A in brain tissue of the rats in hyperoxia model group was higher than that in control group (P<0. 05). But only at the 1st day after hyperoxia exposure, the expression level of NPR-B in brain tissue of the rats in hyperoxia model group was higher than that in control group (P<0. 05). The ELASA results showed that at the 1st, 3rd and 7th days after hyperoxia exposure, the level of cGMP in brain tissue of the rats in hyperoxia model group was higher than that in control group (P

Beneficial Effect of Berberis amurensis Rupr. on Penile Erection / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate whether the methanol extract of Berberis amurensis Rupr. (BAR) augments penile erection using in vitro and in vivo experiments.</p><p><b>METHODS</b>The ex vivo study used corpus cavernosum strips prepared from adult male New Zealand White rabbits. In in vivo studies for intracavernous pressure (ICP), blood pressure, mean arterial pressure (MAP), and increase of peak ICP were continuously monitored during electrical stimulation of Sprague-Dawley rats.</p><p><b>RESULTS</b>Preconstricted with phenylephrine (PE) in isolated endotheliumintact rabbit corus cavernosum, BAR relaxed penile smooth muscle in a dose-dependent manner, which was inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and H-[1,2,4]-oxadiazole-[4,3-α]-quinoxalin-1-one, a soluble guanylyl cclase inhibitor. BAR significantly relaxed penile smooth muscles dose-dependently in ex vivo, and this was inhibited by pretreatment with L-NAME H-[1,2,4]-oxadiazole-[4,3-α]-quinoxalin-1-one. BAR-induced relaxation was significantly attenuated by pretreatment with tetraethylammonium (TEA, P<0.01), a nonselective K channel blocker, 4-aminopyridine (4-AP, P<0.01), a voltage-dependent K channel blocker, and charybdotoxin (P<0.01), a large and intermediate conductance Ca sensitive-K channel blocker, respectively. BAR induced an increase in peak ICP, ICP/MAP ratio and area under the curve dose dependently.</p><p><b>CONCLUSION</b>BAR augments penile erection via the nitric oxide/cyclic guanosine monophosphate system and Ca sensitive-K (BK and IK) channels in the corpus cavernosum.</p>

Pancreatic kininogenase improves erectile function in streptozotocin-induced type 2 diabetic rats with erectile dysfunction / 亚洲男科学杂志(英文版)

Erectile dysfunction (ED) associated with type 2 diabetes is a severe problem that requires effective treatment. Pancreatic kininogenase (PK) has the potential to improve the erectile function of ED patients. This study aims to investigate the effect of PK on erectile function in streptozotocin-induced type 2 diabetic ED rats. To achieve this goal, we divided male Sprague-Dawley rats into five groups. One group was not treated, and the other four groups were treated with saline, sildenafil, PK or sildenafil, and PK, respectively, for 4 weeks after the induction of type 2 diabetic ED. Then, intracavernous pressure under cavernous nerve stimulation was measured, and penile tissue was collected for further study. Endothelial nitric oxide synthase levels, smooth muscle content, endothelium content, cyclic guanosine monophosphate (cGMP) levels in the corpus cavernosum, and neuronal nitric oxide synthase levels in the dorsal penile nerve were measured. Improved erectile function and endothelium and smooth muscle content in the corpus cavernosum were observed in diabetic ED rats. When treating diabetic ED rats with PK and sildenafil at the same time, a better therapeutic effect was achieved. These data demonstrate that intraperitoneal injection of PK can improve erectile function in a rat model of type 2 diabetic ED. With further research on specific mechanisms of erectile function improvement, PK may become a novel treatment for diabetic ED.

Antiplatelet aggregation of naringenin via cyclic nucleotide signaling: in vitro studies / 中国病理生理杂志

AIM: To investigate effect of naringenin on ADP-induced platelet aggregation and its possible mechanism.METHODS: The levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were measured in the platelets with ADP stimulation using ELISA in the presence or absence of different concentrations of naringenin.The effect of naringenin at different concentrations on the change of phosphodiesterase (PDE) activity was measured by high efficiency liquid chromatography.The effects of naringenin at different concentrations on phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at positions Ser157 and Ser239 in washed platelets with ADP stimulation were analyzed by Western blot.The phosphorylation of VASP at Ser239 was also analyzed in the presence of protein kinase A (PKA), protein kinase G (PKG), or protein kinase C (PKC) inhibitors before incubation with naringenin.The platelet aggregation was measured in the presence of PKA or PKG inhibitors before incubation with naringenin.RESULTS: Naringenin elevated cGMP levels significantly but not cAMP levels in the platelets with ADP stimulation in a dose-dependent manner.Naringenin inhibited PDE activity.Naringenin increased the phosphorylation of VASP at Ser239 in a dose-dependent manner in the platelets with ADP stimulation but only modest changes in the phosphorylation at position Ser157.The phosphorylation level of VASP at Ser239 position was inhibited when the platelets were treated with PKA inhibitor before incubation with naringenin.Incubation of platelets with neither PKG nor PKC inhibitors before treatment with naringenin affect the phosphorylation of VASP at Ser239.Pretreatment with PKA inhibitor but not PKG inhibitor significantly reversed the antiplatelet aggregation by naringenin in ADP-stimulated platelets.CONCLUSION: Naringenin may inhibit platelet activation through the elevation of cGMP-and PKA-mediated VASP phosphorylation.

Antipyretic mechanism of Xinhuang Tablet on fever rabbits induced by milk / 中草药

Objective: To investigate the mechanism of Xinhuang Tablet on fever rabbits induced by milk. Methods: Using the milk-reduced rabbit fever model to research the antipyretic mechanism of Xinhuang Tablet, blood plasma and hypothalamus were collected to measure the indicators related to body temperature, such as IL-1α, IL-1β, IL-6, TNF-α, PGE2, cAMP, cGMP, AVP, and Na+, K+-ATP ase. Results: In the model of milk-reduced rabbit fever, Xinhuang Tablet can significantly decline the contents of IL-1α, IL-1β, IL-6, PGE2, and TNF-α in the hypothalamus, decline the content of cAMP and ratio of cAMP/cGMP, decline the energy of Na-K-ATPase, and increase the variety of body temperature regulation related factors, such as content of AVP, in order to play a role of antipyretic. Conclusion: The antipyretic mechanism and adjustment of Xinhuang Tablet were associated with body temperature regulation related factors in the hypothalamus, such as IL-1α, IL-1β, IL-6, PGE2, TNF-α, cAMP, cAMP/cGMP, Na+, K+-ATP ase, and AVP; Its indomethacin can decline the contents of IL-1α, IL-6, PGE2, and TNF-α, increase the content of AVP, decline the energy of Na+, K+-ATP ase which plays the antipyretic effects of non-steroidal anti-inflammatory drugs, and the containing Chinese medicines can further decline the contents of IL-1β, IL-6, PGE2, and cAMP as well as the ratio of cAMP/cGMP in the hypothalamus of rabbits, synergy with indomethacin, in order to extend the indomethacin's antipyretic action time and enhance the indomethacin's strength.

Ginsenoside Re Enriched Fraction (GS-F3K1) from Ginseng Berries Ameliorates Ethanol-Induced Erectile Dysfunction via Nitric Oxide-cGMP Pathway

Erectile dysfunction (ED) is a highly prevalent disorder that affects millions of men and considered to be an early symptom of atherosclerosis and a precursor of various systemic vascular disorders. The aim of the present study was to prepare ginsenoside Re enriched fraction (GS-F3K1, ginsenoside Re 10%, w/w) from ginseng berries flesh and to investigate the enhanced activities of GS-F3K1 on alcohol-induced ED. GS-F3K1 was prepared by the continuous liquid and solid separating centrifugation and circulatory ultrafiltration from ginseng berries flesh. GS-F3K1 was administered for 5 weeks in ethanol-induced ED rat by oral administration of 20% ethanol. To investigate the effects of GS-F3K1 on ED model, the levels of nitrite expression, cyclic guanosine monophosphate (cGMP) and erectile response of the penile corpus cavernosum of rat were measured. The erectile response of the corpus cavernosum was restored after GS-F3K1 administration, to a level similar to the normal group. The level of nitrite and cGMP expression in the corpus cavernosum of GS-F3K1-administered male rats was increased significantly compared to positive control group. GS-F3K1 from ginseng berries should effectively restore ethanol-induced ED in male rats and could be developed as a new functional food for the elderly men.

Research advance in cGAS-STING pathway: A pathway unlock the anti-HIV function of immune system / 国际药学研究杂志

Stimulator of interferon genes(STING) are important adaptor proteins in innate immune-related signal pathway. The upstream protein,cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS), is cytosolic DNA sensor. Detection of cytosolic DNA, cGAS-STING pathway can be activated and subsequently activate the type I interferon(IFN) antiviral response. Recent studies indicated that retroviruses especially HIV can activate the host innate immune system through cGAS-STING pathway and trigger robust immune response. In this review, we briefly describe the mechanism of innate immune activated by the newly discovered cGAS-STING pathway and highlight recent progress in STING agonist.

cGAS-cGAMP Signaling and Antiviral Defense

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that plays an important role in innate immunity. Transfection of DNA or DNA virus infection results in the induction of type I interferon production in fibroblasts, macrophages, and dendritic cells which is dependent on cGAS. Recently, cGas (-/-) mice have been reported to be more vulnerable to fatal infection with herpes simplex virus 1 (HSV1) as compared to wild-type mice.

Effects of preconditioning with phosphodiesterase-5 inhibitor on the Biological Properties of human amniotic mesenchymal stem cells / 实用医学杂志

Objective To investigate the biological properties of human amniotic mesenchymal stem cells (hAMSCs) which were preconditioned with phosphodiesterase-5 inhibitor (Vardenfil). Methods hAMSCs were in vitro isolated and cultured, hAMSCs were pre-treated with vardenfil in final concentration of 10 μmol/L. The morphology of Vard-hAMSCs was observed, and the immunological characteristics, proliferative capacity, and ability of anti-oxidative damage of hAMSCs and Vard-hAMSCs were analyzed by flow cytometry. Double labeling immunofluorescent staining was used to count the differences of differential potential between neural cells of hAMSCs and Vard-hAMSCs. Results (1)Flow cytometry revealed that both hAMSCs and Vard-hAMSCs positively expressed CD90、CD105 and CD73, and negatively expressed CD34、CD45、CD11b and HLA-DR. The SPF and PI in Vard-hAMSCs group were (0.57 ± 0.40)% and (2.20 ± 1.60)% respectively, there was no statistical significance compared with hAMSCs group; (2)After 4 hours treated by H2O2, the apoptosis rate in Vard-hAMSCs group were (7.67 ± 0.82)%,which were markedly lower than that in the hAMSCs group and specific blocker group; (3)Under the same induction condition, positive rates of MAP-2 and GFAP in Vard-hAMSCs group were (49.8 ± 6.42)%and (55.2 ± 6.10)% respectively detected by double labeling immunofluorescent staining, which were significantly higher than the control group. Conclusion The strategy that hAMSCs are treated with vandenfil can enrich the ability of anti-oxidative damage and the differential potential for neural cells in a certain time, and the morphology, immunological characteristics, proliferative capacity of Vard-hAMSCs have no significant change. It suggests that pre-treatment with vandenfil may provide a optimized experimental strategey for hAMSCs which were used to treat nervous system disease.