Advances in clinical and safety studies of phosphodiesterase 4 inhibitors / 药学学报

Phosphodiesterase 4 (PDE4) is an important member of the phosphodiesterase enzyme family that specifically catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP), activates the downstream phosphorylation cascade pathway by altering cAMP concentration, and is strongly associated with multiple diseases. Inhibition of PDE4 is clinically investigated as a therapeutic strategy in a broad range of disease areas, including respiratory system diseases, autoimmune disorders, central nervous system diseases, and dermatological conditions. However, the incidence of adverse reactions such as nausea and vomiting is relatively high in the marketed PDE4 inhibitors, which has stalled their clinical development. In this review, we provide an overview of the clinical progression and safety issues of the marketed PDE4 inhibitors. We also review the main causes underlying PDE4-mediated adverse effects by combining the structural analysis of the PDE4 protein, the mechanism of action of PDE4 inhibitors, and the related side effect mechanism research, aiming to provide a reference for the development of safe and effective PDE4 inhibitors.

Xueshuantong for Injection (Lyophilized, ) Alleviates Streptozotocin-Induced Diabetic Retinopathy in Rats / 中国结合医学杂志

OBJECTIVE@#To investigate the ameliorate effect and underlying mechanism of Xueshuantong for Injection (Lyophilized, , XST) in streptozocin (STZ)-induced diabetic retinopathy (DR) rats.@*METHODS@#Diabetes mellitus (DM) model was induced by intraperitoneal (i.p.) injection of STZ (60 mg/kg) in Sprague-Dawley rats. Diabetic rats were randomized into 3 groups (n=10) according to a random number table, including DM, XST50 and XST100 groups. XST treatment groups were daily i.p. injected with 50 or 100 mg/kg XST for 60 days, respectively. The control and DM groups were given i.p. injection with saline. Blood glucose level and body weight were recorded every week. Histological changes in the retina tissues were observed with hematoxylin-eosin staining. Apoptosis and inflammation related factors, including cleaved caspase-3, glial fifibrillary acidic protein (GFAP), tumor necrosis factor-α (TNF-α) and intercellular cell adhesion molecule-1 (ICAM-1) were detected by Western blot or real-time polymerase chain reaction. Then, the levels of advanced glycation end product (AGE) and its receptor (RAGE) were investigated. Tight junctions proteins (Zonula occludens-1 (ZO-1), Occludin and Claudin-5) of blood-retinal barrier were detected by Western blot. The levels of retinal fifibrosis, transforming growth factor-β1 (TGF-β1)-Smad2/3 signaling pathway were evaluated at last.@*RESULTS@#There was no signifificant difference in the body weight and blood glucose level between XST and DM groups (P>0.05). Compared with the DM group, XST treatment signifificantly increased the retinal thickness of rats (P<0.05 or P<0.01), and suppressed cleaved caspase-3 expression (P<0.01). XST increased the protein expressions of ZO-1, Occludin and Claudin-5 and decreased the mRNA expressions of matrix metalloproteinase 2 (MMP-2) and MMP-9 (P<0.05 or P<0.01). Moreover, XST signifificantly reduced the productions of AGE and RAGE proteins in the retina of rats (P<0.05 or P<0.01), suppressed the over-expression of TNF-α, and decreased the elevated level of ICAM-1 in retina of rats (P<0.05 or P<0.01). XST signifificantly reduced the levels of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), TGF-β1 and phosphorylation of Smad2/3 protein in rats (P<0.05 or P<0.01).@*CONCLUSIONS@#XST had protective effects on DR with possible mechanisms of inhibiting the inflammation and apoptosis, up-regulating the expression of tight junction proteins, suppressing the productions of AGE and RAGE proteins, and blocking the TGF-β/Smad2/3 signaling pathway. XST treatment might play a role for the future therapeutic strategy against DR.

Advances in understanding the role of sphingosine kinase-2 in tumorigenesis and its inhibitors / 药学学报

In recent years the role of sphingosine kinase 2 (SphK2), a key enzyme in the sphingolipid pathway, in the process of tumorigenesis has gradually been elucidated. Recent research has shown that SphK2 inhibitors can be used as anticancer drugs alone or in combination with existing drugs to increase the therapeutic sensitivity of drug-resistant tumors. Among them, one selective SphK2 inhibitor, ABC294640, shows excellent oral bioavailability and biodistribution in vivo and has now entered Phase II clinical research. Therefore, developing innovative drugs based on SphK2 is of great interest. Herein, we discuss progress in understanding the role of SphK2 in tumorigenesis and review the recent development of inhibitors of SphK2.

Synthesis and biological evaluation of novel tanshinone IIA derivatives for treating pain / 中国天然药物

Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC 120 nmol·L) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.

Synthesis and biological evaluation of novel tanshinone IIA derivatives for treating pain / 中国天然药物

Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC 120 nmol·L) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.

Mitochondrial ATP-sensitive potassium channels and cardiovascular diseases / 中国药理学通报

With the aging of population and the changes of lifes-tyle, the cardiovascular diseases have become a serious threat to human health. Meanwhile, the cardiovascular death has become the chief death reason during recent epidemiological survey, so the prevention and treatment of cardiovascular diseases have be-come the focus of researches now. Mitochondrial ATP-sensitive potassium channels ( mitoKATP ) is an inward rectifier potassium channel located in the mitochondrial inner membrane, which has the effect of improving the energy metabolism, inhibiting the ap-optosis, relieving the overload of Ca2+ and stabilizing the inter-nal environment. Recently, some researchers have also found that mitoKATP can influence the development of cardiovascular diseases in different ways. This paper summarizes the structure and function of mitoKATP and the relationship between cardiovas-cular diseases and mitoKATP , aiming to clarify its role in the de-velopment of cardiovascular diseases.

A method of establishing type 2 diabetic cardiomyopathy model in mice / 中国病理生理杂志

AIM:To establish a mouse model of type 2 diabetic cardiomyopathy induced by sustained high-fat diet(HFD)feeding and single intraperitoneal injection of streptozotocin(STZ).METHODS: The 5 ~6-week-old C57BL/6J mice were randomly divided into 2 groups(n=20 per group): the mice in control group received a sustained regular diet;the mice in HFD+STZ group received a sustained HFD and were intraperitoneally injected with STZ(100 mg/kg)at the 5th week.The body weight and blood glucose were measured at 0,5,6,11 and 16 weeks.The mice in control group and HFD +STZ group were analyzed with echocardiography,HE staining,ELISA and immunohistochemistry at the 11th and 16th weeks.RESULTS:The body weight of the mice in HFD +STZ group was higher than that in control group(P<0.05)during each modeling period,and was slightly decreased 1 week after STZ injection.The blood glucose of the mice in HFD+STZ group was higher than 13.89 mmol/L 1 week after STZ injection.The serum insulin of the mice in HFD+STZ group was lower than that in control group(P<0.05)at the 11th week and the 16th week.Echocardio-graphy, HE staining and immunohistochemistry analysis showed that the mice in HFD +STZ group had mild ventricular dysfunction and cardiomyocyte hypertrophy, and cardiomyocyte area and apoptosis rate were obvious higher than those in control group(P<0.05)at the 16th week,while these indicators were not obviously changed in HFD +STZ group com-pared with control group at the 11th week.CONCLUSION:The sustained HFD feeding and single intraperitoneal injec-tion of STZ successfully establish a mouse model of type 2 diabetic cardiomyopathy.

Pharmacology of mangostins and their derivatives: A comprehensive review / 中国天然药物

Mangosteen (Garcinia mangostana Linn.) is a well-known tropical tree indigenous to Southeast Asia. Its fruit's pericarp abounds with a class of isoprenylated xanthones which are referred as mangostins. Numerous in vitro and in vivo studies have shown that mangostins and their derivatives possess diverse pharmacological activities, such as antibacterial, antifungal, antimalarial, anticarcinogenic, antiatherogenic activities as well as neuroprotective properties in Alzheimer's disease (AD). This review article provides a comprehensive review of the pharmacological activities of mangostins and their derivatives to reveal their promising utilities in the treatment of certain important diseases, mainly focusing on the discussions of the underlying molecular targets/pathways, modes of action, and relevant structure-activity relationships (SARs). Meanwhile, the pharmacokinetics (PK) profile and recent toxicological studies of mangostins are also described for further druggability exploration in the future.

Application effects of dexmedetomidine combined with sevoflurane for anesthesia in short operations in children with burn injury / 解放军医学杂志

Objective To evaluate the effectiveness and safety of dexmedetomidine combined with sevoflurane for anesthesia in short operations in pediatric burn patients. Methods Forty hospitalized children undergoing short operation for burn injury were allocated to sevoflurane group (S group) or sevoflurane combined dexmedetomidine group (group D)(20 patients each). Children in group D inhaled 8% sevoflurane in the beginning until loss of eyelash reflex, and then the density of sevoflurane was reduced to 3% for maintenance, 5µg/(kg.h) of dexmedetomidine was pumped for 10 mins, then the density was reduced to 0.5µg/(kg.h). Then operation was started herewith till to the end. Children in group S received sevoflurane anethesia alone, and dexmedetomidine was replaced by the same volume of physiological saline. Additional 3mg/kg propofol was injected when anesthesia was inadequate. During the procedure, HR, MAP, SpO2 and Ramsay scale were recorded at baseline (T1), loss of eyelash reflex (T2), 5min after the start of operation (T4), 10min (T5) and the end of operation (T6). The operation time, anethesia time, propofol consumption, case of respiratory depression and pediatric anesthesia emergence delirium scale (PAED) in pediatric anesthesia care unit (PACU) were recorded. Results There was no significant difference in operation time between the two groups. Intraoperative SpO2 was higher in group D than in group S (P<0.05), respiratory inhibition occurred in 4 cases of group D and 10 cases of group S (P<0.05). Propofol consumption was less and the operation time was longer in group D than in group S (P<0.05). At T3-T6, the MAP and HR were lower, but the Ramsay scale was higher in group D than in group S (P<0.05). In PACU, PAED scale was lower in group D than in group S (P<0.05). Conclusions Dexmedetomidine combined with sevoflurane for anesthesia for short burn surgery in children not only stabilize hemodynamic parameters but also reduce the impact to respiration. Although delaying the recovery time, this combination may improve the recovery quality.

Two new cyclic bisbibenzyl derivatives from Hebertus dicranus / 中国天然药物

In the present study, two new cyclic bisbibenzyls (1, 2) co-occuring with a known compound, isoplagiochins C (3) were isolated from Hebertus dicranus. The structures were determined mainly by extensive 1D and 2D NMR experiments, and the absolute configurations of 1 and 2 were established by the circular dichroism spectrum. Furthermore, all these three rare compounds were tested in vitro for inhibitory activity against the growth of human cancer cell lines (A549, HCT116, MDA-MB-231, and BEL7404) by the MTT assay, and compound 2 exhibited moderately inhibitory activity with IC50 values ranging from 13.89 to 31.62 μmol·L(-1). In conclusion, our results provided a basis for future development and modification of these compounds for cancer therapy.

A new iridoid from Valeriana officinalis var. latiofolia / 中草药

Objective: To investigate the chemical constituents in the roots of Valeriana officinalis var. latiofolia collected from Guizhou province, China. Methods: The compounds 1-6 were separated and purified by column chromatography with silica gel, RP C18, Sephadex LH-20, and preparative TLC. Their structures were elucidated on the basis of spectroscopic (MS, NMR, etc) methods and chemical evidences. Results: Six compounds were isolated from ethyl acetate fractions of 95% ethanol extract of the root of V. officinalis var. latiofolia and identified as iridoids: valeriridoid P (1); dihydroxymaaliane (2), and madolin F (3); madolin A (4), volvalerenal B (5), and kissoone A (6), respectively. Conclusion: Compound 1 is a new iridoid with two oxo-bridges, and compounds 2-6 are known compounds.