摘要：
The severe anticancer situation as well as the emergence of multidrug-resistant (MDR) cancer cells has created an urgent need for the development of novel anticancer drugs with different mechanisms of action. A large number of natural alkaloids, such as paclitaxel, vinblastine and camptothecin have already been successfully developed into chemotherapy agents. Following the success of these natural products, in this review, twenty-six types of isoquinoline alkaloids (a total of 379 alkaloids), including benzyltetrahydroisoquinoline, aporphine, oxoaporphine, isooxoaporphine, dimeric aporphine, bisbenzylisoquinoline, tetrahydroprotoberberine, protoberberine, protopine, dihydrobenzophenanthridine, benzophenanthridine, benzophenanthridine dimer, ipecac, simple isoquinoline, pavine, montanine, erythrina, chelidonine, tropoloisoquinoline, azafluoranthene, phthalideisoquinoline, naphthylisoquinoline, lycorine, crinane, narciclasine, and phenanthridone, were summarized based on their cytotoxic and MDR reversing activities against various cancer cells. Additionally, the structure-activity relationships of different types of isoquinoline alkaloid were also discussed. Interestingly, some aporphine, oxoaporphine, isooxoaporphine, bisbenzylisoquinoline, and protoberberine alkaloids display more potent anticancer activities or anti-MDR effects than positive control against the tested cancer cells and are regarded as attractive targets for discovery new anticancer drugs or lead compounds.
摘要：
Heilaohu, the roots of Kadsura coccinea, has a long history of use in Tujia ethnomedicine for the treatment of rheumatoid arthritis and gastroenteric disorders, and a lot of work has been done in order to know the material basis of its pharmacological activities. The chemical investigation led to the isolation and characterization of three new (1(-)3) and twenty known (4(-)23) lignans. Three new heilaohulignans A-C (1(-)3) and seventeen known (4(-)20) lignans possessed dibenzocyclooctadiene skeletons. Similarly, one was a diarylbutane (21) and two were spirobenzofuranoid dibenzocyclooctadiene (22(-)23) lignans. Among the known compounds, 4(-)5, 7, 13(-)15 and 17(-)22 were isolated from this species for the first time. The structures were established, using IR, UV, MS and NMR data. The absolute configurations of the new compounds were determined by circular dichroism (CD) spectra. The isolated lignans were further evaluated for their cytotoxicity and antioxidant activities. Compound 3 demonstrated strong cytotoxic activity with an IC50 value of 9.92 microM, compounds 9 and 13 revealed weak cytotoxicity with IC50 values of 21.72 microM and 18.72 microM, respectively in the HepG-2 human liver cancer cell line. Compound 3 also showed weak cytotoxicity against the BGC-823 human gastric cancer cell line and the HCT-116 human colon cancer cell line with IC50 values of 16.75 microM and 16.59 microM, respectively. A chemiluminescence assay for antioxidant status of isolated compounds implied compounds 11 and 20, which showed weak activity with IC50 values of 25.56 microM and 21.20 microM, respectively.
摘要：
Berberine, a quaternary ammonium protoberberine alkaloid with an isoquinoline scaffold isolated from medicinal herbs, exhibits a wide spectrum of pharmacological activities. Berberine has been used in traditional Chinese medicine and Ayurvedic medicine. However, it has poor bioavailability, which seriously limits its application and development. The chemical transformation of natural products is an effective method to improve pharmacological activities. Researches have been carried out on the modification of berberine to obtain better pharmacological properties. In this paper, the structural modifications of berberine for different biological activities and its underlying mechanisms are reviewed.
摘要：
Polycystic ovary syndrome (PCOS) is a very prevalent endocrine disease affecting reproductive women. Clinically, patients with this disorder are more vulnerable to develop type 2 diabetes mellitus (T2DM), cardiovascular events, as well as metabolic syndrome (MetS). To date, the molecular mechanism underlying PCOS remains largely unknown. Previously, we showed that mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutation was an important cause for PCOS. In the current study, we described the clinical and biochemical features of a three-generation pedigree with maternally transmitted MetS, combined with PCOS. A total of three matrilineal relatives exhibited MetS including obesity, high triglyceride (TG) and Hemoglobin A1c (HbA1c) levels, and hypertension. Whereas one patient from the third generation manifestated PCOS. Mutational analysis of the whole mitochondrial genes from the affected individuals identified a set of genetic variations belonging to East Asia haplogroup B4b1c. Among these variants, the homoplasmic C3275T mutation disrupted a highly evolutionary conserved base-pairing (28A-46C) on the variable region of tRNA(Leu(UUR)), whereas the T4363C mutation created a new base-pairing (31T-37A) in the anticodon stem of tRNA(Gln), furthermore, the A8343G mutation occurred at the very conserved position of tRNA(Lys) and may result the failure in mitochondrial tRNAs (mt-tRNAs) metabolism. Biochemical analysis revealed the deficiency in mitochondrial functions including lower levels of mitochondrial membrane potential (MMP), ATP production and mtDNA copy number, while a significantly increased reactive oxygen species (ROS) generation was observed in polymononuclear leukocytes (PMNs) from the individuals carrying these mt-tRNA mutations, suggesting that these mutations may cause mitochondrial dysfunction that was responsible for the clinical phenotypes. Taken together, our data indicated that mt-tRNA mutations were associated with MetS and PCOS in this family, which shaded additional light into the pathophysiology of PCOS that were manifestated by mitochondrial dysfunction.
摘要：
Melatonin is an endogenous indoleamine with a wide range of biological functions in the various organisms from bacteria to mammals. Evidence indicates that melatonin facilitates apoptosis in cancer cells and enhances the antitumor activity of chemotherapy in animals and clinical studies. However, the melatonin metabolism and the key metabolic targets in cancer cells still remain unknown. In this study, U118 and SH-SY5Y tumor cell lines were used to investigate the metabolic pathways of melatonin in cancer cells. Interestingly, the inhibitory effect of melatonin on proliferation in SH-SY5Y cells is more potent than that in U118 cells. In contrast, this inhibitory effect on the normal cells is absent. The antitumor effects of melatonin are positively associated with its metabolite N-acetylserotonin (NAS). Unexpectedly, CYP1B1 is, for first time, identified to localize in the mitochondria of tumor cells, and it metabolizes melatonin to form NAS in situ, which subsequently triggers mitochondria-dependent apoptosis in cancer cells. In normal cells, NAS does not induce apoptosis. A remarkable individual variation on CYP1B1 expression was also detected in human tumor tissue. These findings provide the novel mechanisms regarding the antitumor effects of melatonin in the level of mitochondria. Thus, we hypothesize that CYP1B1 overexpression in mitochondria would significantly enhance the antitumor effects of melatonin. Mitochondrial CYP1B1 can potentially serve as a specific target to modify the therapeutic and biological effects of melatonin on cancer patients.
摘要：
Hypomotility is a common symptom of gallstone disease, which is accompanied by a loss of interstitial Cajal-like cells (ICLCs) in the gallbladder. Ursodeoxycholic acid (UDCA) is widely used in treating gallstone disease, and has shown anti-apoptotic and anti-inflammatory effects apart from its ability to dissolve gallstones. In this study, we investigated the anti-apoptotic and anti-inflammatory effects of UDCA on ICLCs in guinea pigs with gallstones. Guinea pigs were fed a high-cholesterol diet for 8 weeks to induce the formation of gallstones. A group of animals was administered UDCA (50 mg·kg−1·d−1, ig) simultaneously. At the end of 8 weeks, the animals were euthanized with anesthesia, cholecystectomy was performed immediately and gallbladder was collected for further analysis. We showed that in the model group the contractility of gallbladder muscle strips in response to both acetylcholine (ACh) and CCK-8 was severely impaired, which was significantly improved by UDCA administration. Furthermore, UDCA administration significantly reduced the apoptotic ratio of ICLCs, based on the observation of co-localization imaging of apoptotic cells and c-kit-positive cells. Western blotting analysis and real-time PCR results revealed that the TNF-α/Caspase8/Caspase3 pathway was suppressed in the UDCA-treated animals, confirming the anti-apoptotic effect of UDCA in the gallbladder. The H&E staining showed that UDCA administration significantly attenuated inflammatory cell infiltration in the gallbladder wall. In conclusion, UDCA can protect ICLCs in the gallbladder from undergoing apoptosis by inhibiting the TNF-α/Caspase8/caspase3 pathway.
摘要：
Background: It is well-known that the public still have been facing on a severe issue about the inconsistency of quality and therapeutic efficacy of traditional medicines. Recently, Professor Chang-Xiao Liu has created a new promising concept for identifying relevant quality-markers (Q-marker) from herbs, their formulas and manufacturing products. Therefore, building up a new approach is necessary for us to bridge over quality to efficacy of pharmaceutical products. Study design: In this paper, five candidate Q-markers, astragaloside IV, paeonflorin, amygdalin, tetra-methylpyrazine, ferulic acid in Buyanghuanwu injection (BYHWI) had been designed to carry out in rat by using single and polypharmacokinetic models for total quanta to ascertain adequate Q-marker. Methods: The Q-marker transitivity in vivo was studied with polypharmacokinetic model and its similarity approach, which were modeled with TQSM principle. The Q-marker was ascertained with transitive similarity and bioavailability in polypharmacokinetics. Their concentrations in plasma sample of white rat were determined by RP-HPLC. Data analyses were used by the DAS software for singles and myself-written-program with EXCEL for multiples. Results: In BYHWI, five candidate Q-marker pharmacokinetic profiles were singly fixed to two compartmental models in rat using classical compartmental analysis, but there were tremendous differences among which the candidate parameters were fluctuated from nearly 3552 folds to equivalency. The theoretical value of TQSM polypharmacokinetic parameters such as AUC(T), MRTT, VRTT, CLT, V-T over the mixure of five drugs were 110.8 +/- 51.91 mg min ml(-1), 176.0 +/- 36.5 min, 39,921 +/- 4311 min(2), 0.3116 +/- 0.02347 ml min(-1) kg(-1), 54.83 +/- 7.683 ml kg(-1) respectively. The TQSM polypharmacokinetic parameters in astragaloside IV ordered by AUC(T), MRTT, VRTT, CLT, V-T were 110.8 +/- 51.91 mg min ml(-1), 176.0 +/- 36.5 min, 39,921 +/- 4311 min(2), 0.3116 +/- 0.02347 ml min(-1) kg(-1), 54.83 +/- 7.683 ml kg(-1), respectively, which were closed to the theoretical values. TQSM similarity versus astragaloside IV was 0.9661. Conclusion: The results represented that the optimum Q-marker in BYHWI is astragaloside IV, whose transitivity in vivo similarity was close to the behavior of polypharmacokinetics with maximum bioavailability to the total quanta. It is feasible for Q-marker in CMMs to screen on the comparison of single pharmacokinetic behavior and bioavailability to the total quanta.
摘要：
As an essential phosphate group hydrolase, alkaline phosphatase (ALP), whose level in serum is correlated with bone disease, liver dysfunction, and cancer, could be used as a biomarker for clinical diagnosis and biomedical studies. Hence, developing a convenient and sensitive method for ALP assay has importance in disease diagnosis, drug treatment, and prognosis assessment. In this work, using a hairpin DNA strand as the substrate, we developed an ultrasensitive and simple fluorescence method for quantitative ALP assay based on the binding difference of reduced graphene oxide (rGO) with different DNA strands coupled with λ exonuclease (λ exo) cleavage. Under the optimal conditions, the limit of detection (LOD) of ALP is estimated to be 0.01 U/L with the linear region from 0.5 U/L to 70 U/L. Furthermore, the proposed assay was used to detect ALP in complicated cell-free extracts and evaluate the inhibitory effects of two well-known inhibitors of ALP activity. Finally, the method was used to investigate the effect of natural compounds on ALP activity and five compounds with different inhibitory capability were screened. In summary, we propose that the new method for ALP assay can be applied for therapeutic drug monitoring (TDM) and high-throughput compound screening in combination with multiwell plate technology.
摘要：
Type 2 diabetes mellitus (T2DM) leads to cognitive impairment (CI), but there have been no effective pharmacotherapies or drugs for cognitive dysfunction in T2DM. Dihydromyricetin (DHM) is a natural flavonoid compound extracted from the leaves of Ampelopsis grossedentata and has various pharmacological effects including anti-oxidant and anti-diabetes. Thus, we investigated the effects of DHM on CI in T2DM mouse model and its possible mechanism. To induce T2DM, mice were fed with high-sugar and high-fat diet for 8 weeks, followed by a low dose streptozotocin (STZ) administration. After the successful induction of T2DM mouse model, mice were treated respectively with equal volume of saline (T2DM group), 125 mg/kg/d DHM (L-DHM group), or 250 mg/kg/d DHM (H-DHM group). After 16 weeks of DHM administration, the body weight (BW), fasting blood glucose, blood lipids, intraperitoneal glucose tolerance (IPGT), and cognitive function were determined. Then, alterations in the expressions of oxidative stress markers and brain-derived neurotrophic factor (BDNF) in the hippocampus were investigated. Our findings demonstrated that DHM could significantly ameliorate CI and reverse aberrant glucose and lipid metabolism in T2DM mice, likely through the suppression of oxidative stress and enhancement of BDNF-mediated neuroprotection. In conclusion, our results suggest that DHM is a promising candidate for the treatment of T2DM-induced cognitive dysfunction.
摘要：
The phytochemical study on the leaves of Acanthopanax gracilistylus (Araliaceae) resulted in the discovery of a new lupane-triterpene compound, acangraciligenin S (1), and a new lupane-triterpene glycoside, acangraciliside S (2), as well as two known ones, 3alpha,11alpha-dihydroxy-lup-20(29)-en-23,28-dioic acid (3) and acankoreoside C (4). Their chemical structures were elucidated by mass, 1D- and 2D-nuclear magnetic resonance (NMR) spectroscopy. The chemical structures of the new compounds 1 and 2 were determined to be 1beta,3alpha-dihydroxy-lup-20(29)-en-23, 28-dioic acid and 1beta,3alpha-dihydroxy-lup-20(29)-en-23,28-dioic acid 28-O-[alpha-l-rhamnopyranosyl-(1-->4)-beta-d-glucopyranosyl-(1-->6)-beta-d-glucop yranosyl] ester, respectively. The anti-neuroinflammatory activity of the selective compounds, 1 and 3, were evaluated with lipopolysaccharide (LPS)-induced BV2 microglia. The tested compounds showed moderate inhibitory effect of nitric oxide (NO) production.
摘要：
IMM-H004 [7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin] is a novel derivative of coumarin, which played neuroprotective roles in brain ischemia in rats in previous studies. Although antiapoptosis and improving synapsis structure were proved, the effects and mechanisms of IMM-H004 in brain ischemia need further study. In this paper, the effect of IMM-H004 on H2O2-induced neurotoxicity in pheochromocytoma (PC12) cells was researched. Morphological observation, MTT method and PI/Hoechst staining were used to indicate cell viability and apoptosis. JC-1 and DCFH-DA were used to test mitochondrial membrane potential (MMP) and reactive oxygen species (ROS), respectively. The antioxidative activity was detected by Glutathione (GSH) and Total Antioxidant Capacity (TAC) Assay kits. Western blot was used to test apoptosis related proteins. Our results showed that treatment with 1-10 μM IMM-H004 markedly increased cell viability and decreased cell apoptosis induced by H2O2. Moreover, 1-10 μM IMM-H004 could enhance MMP and protect mitochondrial function. 1-10 μM IMM-H004 also could lower the ROS and raise the GSH and TAC level. Furthermore, 1-10 μM IMM-H004 could decrease the ratio of Bax/Bcl-2 and increase the ratio of p-AKT/AKT, which were related to apoptosis and survival. All these indicated that IMM-H004 protects PC12 cells against H2O2-induced neurotoxicity. Antioxidative and antiapoptosis may be the mechanisms of IMM-H004 in brain ischemia. These studies indicate that IMM-H004 might be a potential drug for treatment brain ischemia.
摘要：
Ample evidence shows that Parkinson's disease (PD) is more than simply a central nervous system (CNS) disorder: the immune system appears to participate in PD pathogenesis. Extracellular misfolded alpha-synuclein (alpha-syn) may trigger an inflammatory response in the brain. Abnormal immune responses are involved in the development of PD, but little is known about the relationship between the thymus malfunction and the pathogenesis of PD. The present study investigated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced impairment in thymus and explored possible mechanisms involved in PD pathogenesis. After subcutaneous injection of MPTP (25mg/kg) every 4days for 40-days, immune responses became unbalanced, with increased IL-1beta concentrations. On histopathology, mice treated with MPTP displayed pathological involution and damaged ultrastructure of the thymus. Both the PD-related oligomeric alpha-synuclein and oxidative stress related nitrated-alpha-synuclein (Tyr125, Tyr133) in mice treated with MPTP were elevated. Correspondingly, oxidative stress damage was detected in the form of increased 8-hydroxyguanosine staining. Moreover, MPTP significantly increased expression of caspase-8, NF-kappaB, NLPR3, and caspase-1 in the thymus. These results suggested that MPTP was toxic to mouse thymus via a mechanism involving the NF-kappaB and NLRP3 inflammasome pathway. These results suggested that environmental factors may lead to pathological changes in the thymus that are similar to those in the central nervous system. A disordered thymus might take part in the development of PD, and its enhanced immune response might promote the degenerative changes in the brain.
