Design, synthesis and evaluation of phenoxyacetic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for type 2 diabetes. Phosphotyrosine (pTyr) mimetics still dominate the currently available PTP1B inhibitors. The phenoxyacetic acid moiety was taken as a pTyr mimetic herein and phenoxyacetic acid-based compounds 2a-2g and 3a-3c were designed. Among them, compounds 2a-2g exhibited potent inhibition against PTP1B, and compound 2g showed an IC50 of 0.42 μmol·L-1 against PTP1B. Compound 2f exhibited pharmacological profiles similar to that of rosiglitazone, and could improve the insulin sensitivity and the serum total cholesterol level. The results suggest that PTP1B inhibitors might be effective in treating type 2 diabetes as well as associated metabolic syndromes.

CD36 gene deletion reduces muscle insulin sensitivity in mice by up-regulating PTP1B expression / 南方医科大学学报

OBJECTIVE@#To investigate the effect CD36 deficiency on muscle insulin signaling in mice fed a normal-fat diet and explore the possible mechanism.@*METHODS@#Wild-type (WT) mice and systemic CD36 knockout (CD36-/-) mice with normal feeding for 14 weeks (n=12) were subjected to insulin tolerance test (ITT) after intraperitoneal injection with insulin (1 U/kg). Real-time PCR was used to detect the mRNA expressions of insulin receptor (IR), insulin receptor substrate 1/2 (IRS1/2) and protein tyrosine phosphatase 1B (PTP1B), and Western blotting was performed to detect the protein expressions of AKT, IR, IRS1/2 and PTP1B in the muscle tissues of the mice. Tyrosine phosphorylation of IR and IRS1 and histone acetylation of PTP1B promoter in muscle tissues were detected using co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP), respectively.@*RESULTS@#CD36-/- mice showed significantly lowered insulin sensitivity with obviously decreased area under the insulin tolerance curve in comparison with the WT mice (P < 0.05). CD36-/- mice also had significantly higher serum insulin concentration and HOMA-IR than WT mice (P < 0.05). Western blotting showed that the p-AKT/AKT ratio in the muscle tissues was significantly decreased in CD36-/- mice as compared with the WT mice (P < 0.01). No significant differences were found in mRNA and protein levels of IR, IRS1 and IRS2 in the muscle tissues between WT and CD36-/- mice (P>0.05). In the muscle tissue of CD36-/- mice, tyrosine phosphorylation levels of IR and IRS1 were significantly decreased (P < 0.05), and the mRNA and protein levels of PTP1B (P < 0.05) and histone acetylation level of PTP1B promoters (P < 0.01) were significantly increased as compared with those in the WT mice. Intraperitoneal injection of claramine, a PTP1B inhibitor, effectively improved the impairment of insulin sensitivity in CD36-/- mice.@*CONCLUSION@#CD36 is essential for maintaining muscle insulin sensitivity under physiological conditions, and CD36 gene deletion in mice causes impaired insulin sensitivity by up-regulating muscle PTP1B expression, which results in detyrosine phosphorylation of IR and IRS1.

PRE-EQC: A Proficiency Testing Program for Pre-Analytical and Analytical Monitoring Using Pooled Samples without Preservatives

Aim: External Quality Assurance (EQA) is basic requirement of a medical laboratory to assess the quality assurance and achieve the accreditation. The available EQA schemes evaluate the analytical performances of the laboratory but neither evaluate pre analytical factors nor mimic actual laboratory process. PRE-EQC has combined both performances in single scheme and assisting the participant laboratories to take appropriate corrective action and interpretations.Design:Pre-Analytical monitoring evaluates transport condition, correlation of the stability of samples and temperature, storage condition and environment of the laboratory of the participants and its effect on the results. A sample is specially preparedto estimate haemolysis, lipemic and icteric index.Clinical Biochemistry:Serum, fluoride and biological fluid (CSF exempted) samples are pooled from the routine collection of specimens. Pooled fractions are homogenized in a rotary shaker for 10 minutes. The clear samples are poured in individual double pack primary containers, which are placed between two gel packs in a “biohazard” labelled plastic bag. Temperature is recorded, kept in insulated thermocol box and sent to the destination.Urine Routine & Microalbumin, Creatinine Examination:Urine sample is stabilized using preservative.

Triterpenoids from Gynostemma pentaphyllum and their inhibition activity to α-glycosidase and protein tyrosine phosphatase 1B / 中草药

Objective: To determine the total saponins from Gynostemma pentaphyllum, the dammarane-type triterpenoids of its hydrolysate, and its hypoglycemic activity. Methods: Compounds from the acid hydrolyzate extracts and total saponins were isolated by silica gel, recrystal and preparative liquid chromatography, and their structures were identified by the NMR spectral analysis. The sensitive screening modles of α-glucosidase and PTP1B inhibitors were established in vitro. The inhibitory kinetics of compounds were also investigated. Using the method of computer aided drug design of active site, PTP1B interact with the strongest active compound for docking simulation. Results: Seven compounds were isolated from the acid hydrolyzate of total saponins, which identified as gpsapogenin A (1), 20(S)-panaxadiol (2), gypensapogenin F (3), 20(R)-protopanaxadiol (4), (23S)-3β- hydroxydama-20,24-diene-21-carboxylic acid 21,23-lactone (5), gypsapogenin A (6), and (20S,24S)-3β,20,21β,23β,25- pentahydroxy-21,24-epoxydammarane (7). Five compounds were isolated from total saponins, including (20R,23R)- 3β,20-dihydroxydammar-24-en-21-oic acid 21,23-lactone 3-O-[α-L-rhamnopyranosyl(1→2)][β-D-xylopyranosyl(1→3)]-6-O- acetyl-β-D-glucopyranoside (8), (20S,23S)-3β,20-dihydroxydammar-24-en-21-oic acid 21,23-lactone 3-O-[α-L-rhamnopyranosyl(1→2)][β-D-xylopyranosyl(1→3)]-6-O-acetyl-β-D-glucopyranoside (9), (20R,23R)-19-oxo-3β,20-dihydroxydammar-24-en-21-oci acid 21,23-lactone3-O-[α-L-rhamnopyranosyl-(1→2)][β-D-xylopyranosyl(1→3)]-α-L-arabinopyranoside (10), (20S)-3β,20,21- trihydroxydammar-23,25-diene 3-O-{[α-L-rhamnopyranosyl(1→2)][β-D-xylopyranosyl(1→3)]-β-D-glucopyranosyl}-21-O-β- D-glucopyranoside (11), and (20S,23S)-3β,20-dihydroxydammar-24-en-21-oic acid and 21,23-lactone 3-O-[α-L-rhamnopyranosyl(1→2)][β-D-xylopyranosyl-(1→3)]-β-D-glucopyranoside (12). Conclusion: Beside compound 4, the other compounds showed inhibitory activity against α-glucosidase and PTP1B. For the α-glucosidase and PTP1B inhibitions assay, compound 9 indicated the strongest inhibitory effect with IC50 2.10 and 1.07 μmol/L, respectively.

Biological evaluation of 2,3-dioxoindolin-N-phenylacetamide derivatives as potent CDC25B and PTP1B phosphatase inhibitors

A series of 2,3-dioxoindolin-N-phenylacetamide derivatives was evaluated for inhibitory activity against CDC25B and PTP1B enzymes. Most of the derivatives showed inhibitory activity against CDC25B (IC50 = 3.2-23.2 µg/mL) and PTP1B (IC50 = 2.9-21.4 µg/mL). Compound 2h showed the most inhibitory activity in vitro with IC50 values of 3.2 and 2.9 µg/mL against CDC25B and PTP1B, respectively, compared with the reference drugs Na3VO4 (IC50 = 2.7 µg/mL) and oleanolic acid (IC50 = 2.3 µg/mL). The results of selectivity experiments showed that the 2,3-dioxoindolin-N-phenylacetamide derivatives were selective inhibitors against CDC25B and PTP1B. Enzyme kinetic experiments demonstrated that compound 2h was a specific inhibitor with the typical characteristics of a mixed inhibitor. In cytotoxic activity assays compound 2h had potent activity against A549, HeLa, and HCT116 cell lines. In addition, compound 2h showed potent tumor inhibitory activity in a colo205 xenograft model in vivo.

Research progress of PTP1B in common tissue inflammation / 中国药理学通报

Protein tyrosine phosphatase 1B (PTP1B) belongs to the protein tyrosine phosphatase superfamily, which can dephosphoiylate protein tyrosine residues and plays an important role in cell life. Excessive inflammation can damage normal tissues, leading to organ dysfunction and irreversible structural damage. In recent years, a large number of scientific studies have found that PTP1B plays an indispensable role in tissue inflammation. On the one hand, it regulates the functions of macrophages and microglia through regulating inflammatory signaling pathways; on the other hand, it can affect the apoptosis of tissue cells, and the two jointly promote the occurrence and development of tissue inflammation. This paper will review the role and mechanism of PTP1B in inflammation of different tissues, and lay a theoretical foundation for subsequent studies and the discovery of effective drug targets.

Significance of high expression of PTP1B in the valuation of progenosis of ovarian cancer / 临床与实验病理学杂志

Purpose To investigate the expressions of PTP1B in epithelial ovarian cancer tissues and to analysis its correlation with clinical pathological and survival significance.Methods The expression of PTP1B in ovarian cancer tissues was detected by Oncomine database and immunohistochemistry.The relationships between PTP1B expression and clinicopathological features, including prognosis significance, were analyzed. Results Oncomine database showed that the mRNA expression of PTP1B in ovarian cancer was significantly higher than that in normal tissues (P<0.001). Immunohistochemical staining showed that PTP1B expression was significantly correlation with FIGO stage (P<0.001), omentum majus metastasis (P=0.002). Kaplan-Meier analyses revealed that ovarian cancer patients with high PTP1B expression tumors had a significantly worse overall survival rate than those with low PTP1B expression tumors (P<0.001). Multivariate analysis showed that FIGO stage, PTP1B expression were independent survival predictors.Conclusion PTP1B expression may be involved in the tumor progression and poor prognosis of patients with ovarian cancer, and it might be used as one of the valuable markers for poor prognosis in patients with ovarian cancer.

Effect of Squeezing Force on the Extraction of Tablets from Press through Packs (PTPs)in the Selection of Commercial Drug Products / 医薬品情報学

Objective: Difficulty in extracting tablets from a press through pack (PTP) is believed to reduce prescription drug compliance.　This is a particularly serious issue for the elderly or for those who have physical disabilities affecting the fingers.　In this study, the squeezing force necessary to extract tablets from PTPs was measured for 33 commercial tablet products using a force gauge (FG).　Additionally, a sensory test was conducted to determine the degree of difficulty in extracting tablets from PTPs by squeezing, and the correlation between the difficulty measure and squeezing force was evaluated.Methods: The squeezing force for 33 products was measured by FG.　The sensory test was conducted with 64 subjects.　Four products, each with a different squeezing force, were used for the sensory test.　In the test, each subject ranked the products in order according to the amount of force required to extract the tablets.　Each product's total score was used in the statistical analysis.Results: The average squeezing force of the 33 products was 33.1 ± 6.9 〔N〕, and significant differences were observed among the products.　The sensory test revealed that each subject could significantly distinguish the amount of force required to extract the tablets from each product.Conclusion: A positive correlation was observed between the squeezing force obtained using FG and the results from the sensory test.　This suggests that squeezing force can be used as an indicator for the usability of the product.　Therefore, the degree of difficulty in extracting tablets from PTPs should be considered when selecting drugs for the elderly.

Novel benzamido derivatives as PTP1B inhibitors with anti-hyperglycemic and lipid-lowering efficacy

Based on a non-competitive and selective PTP1B inhibitor reported by us previously, thirty-nine benzamido derivatives were designed and synthesized as novel PTP1B inhibitors. Among them, twelve compounds exhibited IC values at micromolar level against human recombinant PTP1B, and most of them exhibited significant selectivity to PTP1B over TC-PTP and CD45. Further evaluation of the most potent compound on high-fat diet (HFD)-induced insulin-resistant (IR) obese mice indicated that could modulate glucose metabolism and ameliorate dyslipidemia simultaneously.

Revisiting the roles of VHR/DUSP3 phosphatase in human diseases

Protein tyrosine phosphatases have long been considered key regulators of biological processes and are therefore implicated in the origins of various human diseases. Heterozygosity, mutations, deletions, and the complete loss of some of these enzymes have been reported to cause neurodegenerative diseases, autoimmune syndromes, genetic disorders, metabolic diseases, cancers, and many other physiological imbalances. Vaccinia H1-related phosphatase, also known as dual-specificity phosphatase 3, is a protein tyrosine phosphatase enzyme that regulates the phosphorylation of the mitogen-activated protein kinase signaling pathway, a central mediator of a diversity of biological responses. It has been suggested that vaccinia H1-related phosphatase can act as a tumor suppressor or tumor-promoting phosphatase in different cancers. Furthermore, emerging evidence suggests that this enzyme has many other biological functions, such as roles in immune responses, thrombosis, hemostasis, angiogenesis, and genomic stability, and this broad spectrum of vaccinia H1-related phosphatase activity is likely the result of its diversity of substrates. Hence, fully identifying and characterizing these substrate-phosphatase interactions will facilitate the identification of pharmacological inhibitors of vaccinia H1-related phosphatase that can be evaluated in clinical trials. In this review, we describe the biological processes mediated by vaccinia H1-related phosphatase, especially those related to genomic stability. We also focus on validated substrates and signaling circuitry with clinical relevance in human diseases, particularly oncogenesis.

Protein tyrosine phosphatase 1B and its effects on pancritic ß cell functions: Research advances / 国际药学研究杂志

Tyrosine phosphorylation, a key post-translational mechanism, is necessary for metabolic homeostasis. Protein tyrsine phosphatase 1B(PTP1B), the main negative regulator in insulin signaling pathway, is becoming a potential target for the treatment of type 2 diabetes mellitus and related metabolic diseases. In thin paper, the structural properties of PTP1B and its regulation on the mass, insulin secretion, endoplasmic reticulum ER stress and inflammation in pancreatic ß cells are reviewed. It is indicated that PTP1B inhibition is important for the protection of ß cells and the treatment of type 2 diabetes mellitus.

Chemical constituents from plant of Artemisia frigida / 中草药

Objective: To study the chemical constituents from plant of Artemisia frigida Willd. and its pharmacological activities. Methods: The compounds were isolated and purified by various chromatography methods. All compounds were identified by spectroscopic and chromatographic techniques, and were screening for their PPARγ activating activity and PTP1B inhibitory activity. Results: There were 26 compounds isolated from the plant of A. frigida and identified as pectolinarigenin (1), jaceosidin (2), chrysoeriol (3), tricin (4), 3-oxogermacra-1(10),11(13)-dien-6α,12-olide (5), achillin (6), 1,10β-epoxyachillin (7), scoparone (8), 4-hydroxyacetophenone (9), chrysosplentin (10), jaceidin (11), 11α,13-dihydroyomogin (12), chrysanthemin A (13), eupatilin (14), eupatrin (15), artemorin (16), 6-methoxytricin (17), hanphyllin (18), cirsimaritin (19), ridentin (20), desacetylmatricarin (21), subchrysine (22), luteolin (23), caffeic acid (24), agastachoside (25), and tilianin (26). Conclusion: Compounds 5, 7, 11, 18, 25, and 26 are firstly isolated from the Artemisia. Compounds 10, 12, 13, 16, 17, and 22 are firstly isolated from this plant. Compounds 2 and 15 exhibited weak activity of PPARγ. Compounds 1 and 3 had inhibitory effect on PTP1B.

Effect of PTP4A3 gene on tumor growth and metastasis / 中国病理生理杂志

PTP4A3 is an oncogene,which encodes phosphatase of regenerating liver(PRL)-3 protein that is a metastasis-associated phosphorylase. At present,a number of studies have found that it promotes cell proliferation, cell motility,cell invasion,tumor metastasis and epithelial-mesenchymal transition. Therefore,it is inseparable with the occur-rence and development of cancer. Here,we summarize the relationship between PTP4A3 gene and the occurrence and de-velopment of cancer,the alteration of PTP4A3 gene expression and the functional role of PTP4A3 gene in a variety of canc-ers. This review will help us to understand the correlation between PTP4A3 gene and cancer as well as the mechanism of signaling pathway,providing new insights of PTP4A3 gene targeting strategy for treating cancer.

Effects of lentinan and thymopentin injection combined with PTP chemotherapy on serum TSGF, IgG, IgA, IgM and quality of life in patients with oral squamous cell carcinoma / 中国生化药物杂志

Objective To investigate the clinical effect of lentinan and thymopentin injection combined with PTP chemotherapy in oral squamous cell carcinoma patients, and to observe the effect of lentinan on serum tumor specific growth factor ( TSGF) , IgG, IgA and IgM and quality of life in patients with oral squamous cell carcinoma .Methods The clinical data of 80 cases of oral squamous cell carcinoma ( postoperative lymph node metastasis) confirmed by operation and pathology were analyzed retrospectively, and the diagnosis and treatment were analyzed.The control group were treated with PTP regimen, 80 ~120 mg/m2 of cisplatin, 50 ~80 mg/m2 of teniposide on the first day, the second to fourth day, once daily +pingyangmycin 4~6 mg/m2 , once daily, 3 to 12 days, 3 weeks for a course of treatment, a total of 6 courses.In the control group based on the use of thymopentin injection 20 mg and lentinan 2 mg+5% glucose solution 250 mL intravenous infusion, chemotherapy 2 d before the start, infusion 14 d, 3 weeks for a course of treatment, a total of 6 courses, for the observation group;two groups were 40 cases.The levels of serum TSGF, IgA, IgG, IgM and CD3 +, CD4 +, CD8 +, NK cells and TSGF in the two groups before and after treatment were measured.The quality of life of the patients was investigated by hospital-made questionnaires.The clinical efficacy and side effects were analyzed.Results TSGF levels in the two groups were significantly lower than that before treatment, and the TSGF level in the observation group was (39.1 ±4.9)U/mL, which was significantly lower than that in the control group (52.3 ±5.8) U/mL(P<0.05).After treatment, the TSGF level in observation group was lower than that in control group [(39.1 ±4.9) U/mL vs. (52.3 ±5.8) U/mL](P<0.05).The CD3 +, CD4 +, NK, IgG levels in observation group were higher than those in control group and the CD8 +level in observation group was lower than that in control group (P<0.05).The scores of physical symptoms, sleep quality, mental state and social affection levels in observation group were higher than those in control group(P<0.05).The total efficacy in observation group was lower than that in control group (77.5% vs.45.0%, P<0.05).The adverse reaction rate was 20.0% in the observation group, which was significantly lower than that in the control group (P<0.05).Conclusion The use of lentinan and thymopentin injection combined with PTP chemotherapy in the treatment of oral squamous cell carcinoma has higher clinical efficacy and less adverse reactions.

Potent water extracts of Indonesian medicinal plants against PTP1B

Objective: To examine the potent of water as a solvent agent in the preparation of traditional herbal medicine. Methods: Water extracts of 18 plants were prepared through reflux and examined (25 mg/mL) to evaluate their possibility for inhibiting protein tyrosine phosphatase 1B (PTP1B). The determination of IC50 values was performed for the samples possessing more than 80% inhibition. Meanwhile, those exhibiting IC50 values more than 7.0 mg/mL were further profiled for their chemical constituents through nuclear magnetic resonance (NMR) measurement. Results: About 44% (8) of the examined samples showed more than 80% inhibition against PTP1B. The water extracts of Elephantopus scaber, Helicteres isora aerial parts, Elaeocarpus grandiflorus (E. grandiflorus) fruits, Melaleuca leucadendron leaves, and Quercus infectoria gum had IC50 values ranging from 2.05 to 6.90 mg/mL. Meanwhile, Andropogon nardus and Centella asiatica were at the area of d 3.0–4.0 ppm. Further, the 13C NMR observation of samples possessing the most intensive signals in their proton NMR Cinnamomum burmannii and E. grandiflorus showed the peaks at the area of d 60–90 ppm as the supportive evidence for sugar group signals. Intriguingly, a disaccharide from E. grandiflorus could be an active inhibitor towards PTB1B. Conclusions: In contrast to the mainstream solvents currently used in modern herbal manufactures especially Jamu medicine in Indonesia, pure-water-extracted materials should be reconsidered and could be reemerged for future studies and for the manufacture of herbal medicines. In addition, the activity of Jamu components should be confirmed that their antidiabetes and antiobesity activities could be through the inhibition of PTP1B.

Protein tyrosine phosphatase 1B(PTP1B) inhibitors from Arnebia euchroma / 中国药学杂志

OBJECTIVE: To study the chemical constituents of the extract of Arnebia euchroma (Royle) Johnst. and screen natural protein tyrosine phosphatase 1B (PTP1B) inhibitors. METHODS: Silica gel, MCI gel, ODS gel, and Sephadex LH-20 chromatographic techniques were used to study the chemical constituents of A. euchroma, the chemical structures were elucidated by analysis of physico-chemical and spectral data, and the inhibitory activity on PTP1B enzyme was tested in vitro. RESULTS: Eight compounds were obtained and their structures were identified as deoxyshikonin (1), shikonin (2), acetylshikonin (3), β, β'-dimethylacrylalkannin (4), quercetin (5), kaempferol (6), kaempferide (7), and β-sitosterol (8). Compounds 1-4 exhibited inhibitory activities on PTP1B with IC50 values of (0.80±0.16), (4.42±0.37), (1.02±0.13), and (0.36±0.08) μmol·L-1, respectively. The study of structure-activity relationship showed that the ring of naphthoquinone might be the key skeleton structure for the inhibition activity on PTP1B, and the 2-substituted long lipo-chain of naphthoquinone significantly affected the activity of these compounds: the increase in the polarity of the lipo-chain led to the reduction of activity, while the increase in the terminal double bond of the lipo-chain led to the enhancement of activity. CONCLUSION: Shikonin derivatives with 1, 4-naphthoquinone skeleton is a new type of leading compounds for the treatment of diabetes.

Potent water extracts of Indonesian medicinal plants against PTP1B

Objective: To examine the potent of water as a solvent agent in the preparation of traditional herbal medicine. Methods: Water extracts of 18 plants were prepared through reflux and examined (25 μg/mL) to evaluate their possibility for inhibiting protein tyrosine phosphatase 1B (PTP1B). The determination of IC

Efecto inhibitorio de un extracto acuoso de las hojas de Allophylus cominia (L) Sw sobre las proteínas tirosina fosfatasa 1B y dipeptidil peptidasa IV / Inhibitory effect of Allophylus cominia (L) Sw leaves aqueous extract on tyrosine phosphatase 1B and dipeptidyl peptidase IV proteins

Introducción: Allophylus cominia (L.) Sw es una planta medicinal cubana usada por la medicina tradicional para el tratamiento de la diabetes, cuyo mecanismo de acción es desconocido. Objetivo: evaluar el efecto del extracto acuoso de hojas de A. cominia (L.) Sw y sus fracciones sobre la proteína tirosina fosfatasa 1B (PTP1B) y dipeptidil peptidasa IV (DPPIV) como diana terapéuticas para el tratamiento de la diabetes tipo 2. Métodos: el extracto acuoso de hojas de A. cominia fue fraccionado sucesivamente con mezclas de solventes orgánicos, incrementando la polaridad, para obtener diez fracciones. El extracto y sus fracciones fueron evaluados para su posible actividad antidiabética sobre diana terapéuticas de diabetes tipo 2: PTP1B y DPPIV. Se realizaron ensayos de inhibición enzimática y la actividad inhibitoria se calculó a partir de los valores de fluorescencia, empleando longitudes de onda de excitación y de emisión de 360 nm y 460 nm respectivamente. Resultados: el extracto acuoso de A. cominia inhibió la actividad enzimática de PTP1B y DPPIV de manera dependiente de la concentración, con valores de CI50 de 0,69 µg/mL y 344,3 µg/mL respectivamente. Varias fracciones se detectaron como potentes inhibidores de PTP1B. Las fracciones más polares AcF9 y AcF10 fueron las más activas, y mostraron valores de CI50 de 4,4 µg/mL y 3,8 µg/mL respectivamente. Las fracciones mostraron una ligera inhibición de DPPIV, y las más activas resultaron AcF6, AcF9 y AcF10, con valores de porcentajes de inhibición de 52,0 por ciento, 39,0 por ciento y 40,0 por ciento respectivamente. Conclusiones: el extracto acuoso de A. cominia y sus fracciones polares (AcF9 y AcF10) tienen propiedades antidiabéticas in vitro y son candidatos promisorios para el desarrollo de nuevos medicamentos con actividad inhibidora de PTP1B y DPPIV para el tratamiento de la diabetes tipo 2(AU)

INTRODUCTION: Allophylus cominia (L.) Sw is a Cuban medicinal plant used by traditional medicine for the treatment of diabetes with unknown mechanisms of action. OBJECTIVE: to evaluate the effect of Allophylus cominia (L.) Sw leaves aqueous extract and its fractions on protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase IV (DPPIV) enzymatic activity, as therapeutic targets of type 2 diabetes. METHODS: the aqueous extract of A. cominia leaves was successively partitioned with organic solvents mixtures, thus increasing polarity in order to obtain ten fractions. The extract and its fractions were tested for their possible antidiabetic activity on therapeutic targets of type 2 diabetes: PTP1B and DPPIV. The enzymatic inhibition assays were performed and the inhibitory activity was calculated with the fluorescence values using an excitation wavelength of 360 nm and an emission wavelength of 460 nm. RESULTS: the aqueous extract from A. cominia inhibited the enzymatic activity of PTP1B and DPPIV according to the concentration, being IC50 values equal to 0.69 µg/mL and 344.3 µg/mL, respectively. Several fractions were detected as potent PTP1B inhibitors. The most polar fractions AcF9 and AcF10 were more active, showing IC50values of 4.4 µg/mL and 3.8 µg/mL respectively. The fractions showed a slight DPPIV inhibition, being fractions AcF6, AcF9 and AcF10 the most active, exhibiting inhibition percentages of 52.0 percent, 39.0 percent and 40.0 percent respectively. CONCLUSIONS: A. cominia aqueous extract and its polar fractions (AcF9 and AcF10) have antidiabetic properties in vitro and are promissory candidates for development of new drugs with inhibitory activity of PTP1B and DPPIV for type 2 diabetes treatment(AU)

Inhibitory effect of Persea americana Mill leaf aqueous extract and itsfractions on PTP1B as therapeutic target for type 2 diabetes / Efecto inhibidor del extracto acuoso de hojas de Persea americana Mill y sus fracciones sobre PTP1Bcomo diana terapéutica para la diabetes tipo 2

Persea Americana Mill (Lauraceae), is a popular plant in Cuba due to its nutritional and medicinal properties. The fruit of the plant is commonly known as avocado. The leaves of Persea americana Mill have been popularly used in the treatment of diabetes incountries in Latin America and Africa. The present study is aimed to explore one of the underlying mechanisms that mediate the antidiabeticefficacy of Persea americana Mill. The aqueous extract from the leaves of the plant and its fractions were evaluated on the inhibitory activity of the protein tyrosine phosphatase 1B (PTP1B) as target of type 2 diabetes. The results revealed that aqueous extract from Pamericana inhibited the enzymatic activity of PTP1B in an extract concentration dependent manner, resulting mainly active the most polarfraction. The present research demonstrated that aqueous extract from P americana and polar fraction (PaF10) have promissory antidiabetic properties mediated by PTP1B, which is a relevant mechanism involved on insulin resistance in type 2 diabetes.

Persea americana Mill. (Lauraceae), es una planta popular en Cuba, debido a sus propiedades nutricionales y medicinales. El fruto de la planta se conoce comúnmente como aguacate. En la etnomedicina las hojas de Persea americana Mill. se han utilizadopopularmente en el tratamiento de la diabetes en varios países en Latinoamérica y África. El presente estudio tuvo el objetivo de explorar laeficacia antidiabética y el mecanismo subyacente, de las hojas de Persea americana. El extracto acuoso de las hojas de la planta y sus fracciones, se evaluaron en un blanco terapéutico de interés en la de diabetes tipo 2: actividad enzimática de la proteína tirosina fosfatasa 1B (PTP1B). Los resultados revelaron que el extracto acuoso de P americana inhibe la actividad enzimática de la enzima PTP1B en una manera dependiente de la concentración, resultando más activa la fracción de mayor polaridad. La presente investigación demostró que elextracto acuoso de P americana y su fracción polar (PaF10), poseen efecto antidiabético promisorio, debido al efecto inhibitorio de PTP1B, mecanismo relevante en la insulino resistencia en la diabetes tipo2.

Inhibitory activity of kaurane-type diterpenes isolated from Acanthopanax senticosus Harms on protein tyrosine phosphatase 1B / 中国药学杂志

OBJECTIVE: To study the constituents isolated from Acanthopanax senticosus Harms and their inhibitory activity on protein tyrosine phosphatase 1B(PTP1B). METHODS: Kaurane-type diterpenes with PTP1 B inhibitory activity were obtained by bio-assay-guided fractionation. RESULTS Nine compounds were identified as 17-isobutyryloxy-16αH-kauran-19-oic acid(1), 17-hydrox-y-16αH-kauran-19-oic acid(2), 17-acetoxy-18-isobutyryloxy-16αH-kauran-19-oic acid (3), ent-kaur-16-en-19-oic acid (4), ent-kaur-16-en-19-oic acid (kaurenoic acid 5), 4-epirulopezol(6), 16α-hydroxy-ent-kauran-19-oic acid(7), 16αH, 17-isovaleryloxy-ent-kauran-19-oic acid(8) and 16α-hydroxy-17-isovaleryloxyent-kauran-19-oic acid(9). CONCLUSION: Compounds 1-3, 5 and 6 are obtained from the plant for the first time. Compounds 1,3-6 and 8 exhibite inhibitory effects on PTP1 B with IC50 values ranging from (5.6 ± 0.8) to (22.8 ± 1.2) μmol · L-1.