A Review of Bioactive Compounds and Antioxidant Activity Properties of Piper Species.

Antioxidants are compounds that are able to inhibit the negative effects that come from free radicals. The phenomenon of imbalanced antioxidant production and the accumulation of free radicals in cells and tissues can cause oxidative stress. Excessive free radicals that enter the body cannot be warded off by endogenous antioxidant compounds so that the required antioxidant compounds can come from the outside, which helps in the performance of endogenous antioxidants. Antioxidants that come from outside consist of synthetic and natural antioxidants; however, synthetic antioxidants are not an option because they have toxic and carcinogenic effects. Therefore, the use of natural ingredients is an alternative method that is needed to create a new natural antioxidant compound. Piper species are being considered as possible medicinal plants for the development of new sources of antioxidants. Several studies have been carried out starting from the extract levels, fractions, and compounds of the Piper species, which showed good antioxidant activity. Currently, some of these plants are being used as ingredients in traditional medicines to treat allergies, toothaches, and coughs. This review examines the distribution, botanical data, pharmacology, especially antioxidant activity, and the compounds contained in five Piper species, namely Piper amalago L., Piper betle L., Piper hispidum Sw., Piper longum L., and Piper umbellatum L.

Inhibitory effects of Piper umbellatum Linn. leaf extracts on α-amylase and α-glucosidase activities

Background@#Alpha-amylase and alpha-glucosidase are essential enzymes in converting food into energy inside the body. However, the proper management of these enzymes is needed to maintain normal blood glucose levels in the body. Thus, inhibiting these carbohydrate-hydrolyzing enzymes is necessary for managing hyperglycemia and alleviating Type 2 Diabetes Mellitus complications. Studies have reported that the Piper species have inhibitory properties on these digestive enzymes. However, the locally cultivated P. umbellatum has not yet been studied. @*Objectives@#The study evaluated the inhibitory potentials of the locally grown P. umbellatum leaf extracts against α-amylase and α-gluiosidase. @*Methodology@#The P. umbellatum leaf extracts were screened for in vitro inhibitory α-amylase and α-glucosidase tests. The most active crude extract was subjected to semi-purification and fractions were subjected to inhibitory enzymatic tests. Qualitative and quantitative phytochemical analyses were conducted. @*Results@#Among all crude extracts, the KMB-HE exhibited the highest activities comparable to that of the acarbose standard (p>0.05). The KMB-HE showed inhibitions of 81.01%±1.66 and 89.51%±3.03 on α-amylase and α-glucosidase at 250 μg/mL, respectively. In addition, it contained the highest phenolic (195.00 ±3.60 GAE mg/gram) and flavonoid (4.55±0.06 QE mg/gram) contents that may be linked to the observed activities. The semi-purification of KMB-HE collected 24 fractions with PF10 demonstrating inhibitions of 68.07%±13.48 and 74.21%±2.22 in α-amylase and α-glucosidase, respectively. Also, the PF10 contained the highest phenolic (204.75±2.42 GAE mg/gram) and flavonoid (4.00±0.07 QE mg/gram) compounds among all the active fractions tested. The PF10 satisfied the recommended criteria for plant natural inhibitors: a moderate-to-low α-amylase and stronger α-glucosidase inhibitory activity. @*Conclusion@#The P. umbellatum exhibited good inhibitory activities on carbohydrate-hydrolyzing enzymes. These may lead to further analysis of the P. umbellatum for future development of a safer, locally available natural remedy in managing Type 2 Diabetes Mellitus.

Anti-inflammatory activity of Piper umbellatum Linn. leaf extracts

Background@#Earlier studies reported the anti-inflammatory activity in several species of Piper, and Piper umbellatum Linn. leaves containing some phytochemicals that are potent anti-inflammatory agents. However, there was no thorough investigation on the anti-inflammatory activity of the locally grown P. umbellatum in the Philippines. @*Objective@#The study aimed to determine the anti-inflammatory activity of Piper umbellatum leaves using in vitro and in vivo assays. @*Methodology@#Crude extracts were obtained from P. umbellatum leaves using polar and non-polar solvents. The anti-inflammatory activities of all crude extracts were determined using the carrageenan-induced paw edema test in mice and phytochemical analysis. The crude extract with the highest activity was partially purified using column chromatography. The fractions with similar TLC profile were pooled and tested for antiinflammatory activity. COX-1 and COX-2 enzyme inhibitory activity were determined in pooled fractions that showed initial activity in animal model. @*Results@#Among the crude extracts of P.umbellatum, the crude ethyl acetate extract exhibited a significant dose-dependent inhibition on paw edema test with doses of 500 mg/kg bw, 1,000 mg/kg bw and 1,500 mg/kg bw (p<0.05). Among the 20 pooled fractions (PF) collected from the ethyl acetate extract, PF58, PF60 and PF64 had the highest COX-2 enzyme inhibitions of 83.12 %, 84.78% and 77.47%, respectively (p<0.05). PF60 also exhibited the highest anti-inflammatory activity on paw edema with inhibitions of 62.45% at low dose (250 mg/kg bw) and 76.10 % at high dose (1,000 mg/kg bw) in mice. @*Conclusion@#The ethyl acetate extract of P. umbellatum leaves and its fraction-PF60 exhibited a significant anti-inflammatory activity in in vitro and in vivo assays and contained high amounts of total phenolic and total flavonoid.

Piper umbellatum L. (Piperaceae): Phytochemical profiles of the hydroethanolic leaf extract and intestinal anti-inflammatory mechanisms on 2,4,6 trinitrobenzene sulfonic acid induced ulcerative colitis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper umbellatum L. leaves, commonly found in the Amazon, Cerrado and Atlantic rain forest regions of Brazil, are widely used as a traditional medicine to treat gastrointestinal disorders and inflammation, among others diseases. Also, previous scientific studies demonstrated that P. umbellatum has gastroprotective and anti-inflammatory activity. AIM: To investigate the phytochemical profiles and the intestinal anti-inflammatory effect of the hydroethanolic extract of P. umbellatum (HEPu) leaf on ulcerative colitis in rats. MATERIALS AND METHODS: In this study, the chemical composition of HEPu was analyzed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography coupled to mass spectrometry (LC/MS). Also, this work studied the effects of HEPu on ulcerative colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS, 30 mg/mL in 20% ethanol) by intrarectal administration in rats. Simultaneously, animals were pre-treated orally with HEPu (30, 100 and 300 mg/kg), mesalazine (500 mg/kg), or vehicle. At the end of the experimental period, clinical signs of ulcerative colitis were evaluated by determination of weight loss, gross appearance, ulcer area and histological changes. Reduced glutathione (GSH), lipoperoxides (MDA) and nitric oxide (NO) levels, and superoxide dismutase (SOD), myeloperoxidase (MPO) and catalase (CAT) activities were determined in colon tissues. Also, pro-inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL- 1ß) were quantified by immunoassay on the surface of fluorescent-coded magnetic beads (Luminex MagPix System). RESULTS: GC-MS analysis showed the presence of 17 different phytochemical compounds in the HEPu. LC/MS analyses revealed the presence of compounds in HEPu as protocatechuic acid, ferulic acid, kaempferol, rosmarinic acid, apigenin and ursolic acid. Treatment with HEPu significantly ameliorated weight loss, macroscopic damage, ulcerated area and histopathological changes such as sub-mucosal edema, cell infiltration, ulceration and necrosis (p < 0.001). Furthermore, HEPu (30, 100, and 300 mg/kg, p.o) inhibited the levels of oxidative parameters, such as MPO (49%, 53%, and 62%, p < 0.001), NO (20%, 19%, 22%, p < 0.01), and MDA (75%, 83%, 70%, p < 0.001), whereas increased the antioxidant activities such as SOD (208%, 192%, 64%, p < 0.001), GSH (94%, 75%, 49%, p < 0.01), and CAT (92%, 69%, 108%, p < 0.01). The extract also inhibited the pro-inflammatory cytokines TNF-α (81%, 85%, 85%, p < 0.001) and IL-1ß (95%, 79%, 89%, p < 0.001) levels. CONCLUSION: Together, these results revealed that P. umbellatum L. is a promising source of metabolites to be used in the treatment of inflammatory bowel disease.

In vitro bioassay guided anti-dermatophyte and cytotoxic activities from Piper umbellatum L. Miq. led to 4-nerolidylcatechol.

Dermatophytosis is a dermic disease caused by fungi. The aim of this study was to search anti-dermatophyte bioactive compounds in Piper umbellatum leaves. Cytotoxicity evaluation was performed against MRC-5 and HepG2 as a selectivity parameter. Crude ethanol extract presented MIC value of 39.1 µg/mL against M. canis and no cytotoxicity to Hep G2 (human liver cancer) and MRC-5 (normal lung fibroblast). 4-nerolydilcatechol was isolated from P. umbellatum ethanolic extract. MIC values for 4-NC were 7.6µM to M. canisand 15.6µM to Trichophyton rubrum. 4-NC presented activity against M. canis14 times lower than to MRC-5 (non-tumoral human cell line), which suggest selective activity for this fungus. Molecular modeling suggests 4-NC could bind to CYP51, present in lanosterol synthesis, blocking fungi development. In conclusion, P. umbellatum crude ethanol extract and 4-NC demonstrated high and selective in vitro antifungal activity.[Formula: see text].

Antidiabetic potential of methanol extracts from leaves of Piper umbellatum L. and Persea americana Mill

Objective: To determine inhibitory activity of methanolic leaf extract of Piper umbellatum and Persea americana (P. americana) (traditionally used in Cameroon against diabetes) on α-glucosidase, β-glucosidase, maltase-glucoamylase, aldose reductase and aldehyde reductase activities, enzymes involved in starch digestion or diabetic complications. Methods: The methanol extracts from Piper umbellatum and P. americana were prepared by maceration. To assess relative efficacy of these extracts, the determination of concentrations that were needed to inhibit 50% of enzyme activity was done, whereas, gas chromatography-mass spectrum was used to identify components from extracts that may be responsible for the activities. Results: The tested extracts strongly inhibited α-glucosidase, maltase-glucoamylase, aldose reductase and aldehyde reductase activities with IC

Antidiabetic potential of methanol extracts from leaves of Piper umbellatum L.and Persea americana Mill

Objective:To determine inhibitory activity of methanolic leaf extract of Piper umbellatum and Persea americana (P.americana) (traditionally used in Cameroon against diabetes) on α-glucosidase,β-glucosidase,maltase-gluconmylase,aldose reductase and aldehyde reductase activities,enzymes involved in starch digestion or diabetic complications.Methods:The methanol extracts from Piper umbellatum and P.americana were prepared by maceration.To assess relative efficacy of these extracts,the determination of concentrations that were needed to inhibit 50％ of enzyme activity was done,whereas,gas chromatography-mass spectrum was used to identify components from extracts that may be responsible for the activities.Resullts The tested extracts strongly inhibited α-glucosidase,maltase-glucoamylase,aldose reductase and aldehyde reductase activities with IC50 ranging from (1.07 ± 0.03) to 01.77 + 1.17) μg/mL.Among the tested extracts,P.americana was the most active against sensitive enzymes (IC50 of 1.07 ± 0.03 to 15.63 ± 1.23).But,none of the extracts showed interesting inhibitory effect against β-glucosidase as their percentage inhibitions were less than 16％.From gas chromatographymass spectrum analysis,10 and 8 compounds were identified in Piper umbellatum and P.americana extracts respectively,using NIST library 2014.Conclusions:Results of this study provide the scientific credential for a prospective usage of these plants to treat diabetes.

Filaricidal activities on Onchocerca ochengi and Loa loa, toxicity and phytochemical screening of extracts of Tragia benthami and Piper umbellatum.

BACKGROUND: Onchocerciasis is the world's second leading infectious cause of blindness. Its control is currently hampered by the lack of a macrofilaricidal drug and by severe adverse events observed when the lone recommended microfilaricide, ivermectin is administered to individuals co-infected with Loa loa. Therefore, there is the need for a safe and effective macrofilaricidal drug that will be able to cure the infection and break transmission cycles, or at least, an alternative microfilaricide that does not kill L. loa microfilariae (mf). METHODS: Fourteen extracts from two medicinal plants, Tragia benthami and Piper umbellatum were screened in vitro against Onchocerca ochengi parasite and L. loa mf. Activities of extracts on male worms and microfilariae were assessed by motility reduction, while MTT/Formazan assay was used to assess biochemically the death of female worms. Cytotoxicity and acute toxicity of active extracts were tested on monkey kidney cells and Balb/c mice, respectively. RESULTS: At 500 µg/mL, all extracts showed 100 % activity on Onchocerca ochengi males and microfilariae, while 9 showed 100 % activity on female worms. The methylene chloride extract of Piper umbellatum leaves was the most active on adult male and female worms (IC50s: 16.63 µg/mL and 35.65 µg/mL, respectively). The three most active extracts on Onchocerca ochengi females were also highly active on Loa loa microfilariae, with IC50s of 35.12 - 13.9 µg/mL. Active extracts were generally more toxic to the worms than to cells and showed no acute toxicity to Balb/c mice. Phytochemical screening revealed the presence of saponins, steroids, tannins and flavanoids in the promising extracts. CONCLUSIONS: These results unfold potential sources of novel anti-Onchocerca lead compounds and validate the traditional use of the plants in onchocerciasis treatment.

Piper umbellatum L.: A medicinal plant with gastric-ulcer protective and ulcer healing effects in experimental rodent models.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper umbellatum L. (Piperaceae) is a shrub found in the Amazon, Savannah and Atlantic Forest region of Brazil. It is widely used in folk medicine in many countries primarily for the treatment of gastric disorders. The aim of this study was to evaluate the gastroprotective and anti-ulcer effects of hydroethanolic extract of P. umbellatum (HEPu) leaves in experimental rodents. In addition, the anti-Helicobacter pylori activity of the extract was assessed. MATERIALS AND METHODS: The leaves of P. umbellatum were macerated in 75% (1:3w/v) hydroethanolic solution to obtain HEPu. The gastroprotective and ulcer healing activities of HEPu were evaluated using acidified ethanol (acute) and acetic acid (chronic) gastric ulcer models in rodents. The anti-H. pylori activity was evaluated by in vitro broth microdilution assay using H. pylori cagA+ and vacA+ strain. The probable mechanism of action of HEPu was evaluated by determining gastric secretory parameters, antioxidant enzyme (catalase), non-protein sulfhydryl (glutathione) and malondialdehyde levels in gastric tissue, including pro-inflammatory (IL-1ß, TNF-a, IL -17, RANTES, IFN-γ and MIP-2) and anti-inflammatory (IL-10) cytokines. RESULTS: HEPu demonstrated potent gastroprotection against acute ulcer induced by acidified ethanol and excellent healing effect of the chronic ulcer induced by acetic acid. The gastroprotective activity in acidified ethanol is partly attributed to the antioxidant mechanisms, while anti-secretory, anti-inflammatory and regeneration of the gastric mucosa are evoked as part of its antiulcer mechanism of action. The gastric ulcer healing of HEPu also involves restoration of the altered cytokines levels to near normal. However, it has no in vitro anti-H. pylori activity. CONCLUSION: The results of this study showed that HEPu possesses preventive and curative effects in experimental models of gastric ulcers in animals. These effects are partially dependent on antioxidant, antisecretory, anti-inflammatory and mucosa regeneration. It is independent of anti-H. pylori activity, with substances probably responsible for the pharmacological activity being flavonoids, quercetin and rutin. These results support the popular use of P. umbellatum leaves in the treatment of peptic ulcers.

Farmacologia e fitoquímica de extratos e formulações de Jacaranda decurrens Cham., Jacaranda caroba (Vell.) DC. e Piper umbellatum L / Pharmacology and phytochemistry of extracts and formulations from Jacaranda decurrens Cham., Jacaranda caroba (Vell.) DC. and Piper umbellatum L

Jacaranda decurrens Cham., Jacaranda caroba (Vell.) DC. e Piper umbellatum L. são plantas nativas do Brasil, presentes no estado de São Paulo, com relatos de uso popular para atividade antiúlcera. Este trabalho teve como objetivo avaliar a atividade antiúlcera de J. caroba, J. decurrens e formulações de nanocápsulas contendo P. umbellatum. Também pretendeu-se caracterizar a fitoquímica de tais formulações e extratos. Adicionalmente, foi avaliada a toxicidade aguda e subaguda de J. caroba. Os extratos de Jacaranda apresentaram compostos fenólicos em seus perfis cromatográficos obtidos por CCD e CLAE, característicos para cada espécie. Os diferentes extratos de J. caroba variaram sua composição química conforme a procedência e idade da planta. As espécies J. decurrens e J. caroba de três diferentes regiões não apresentaram ação antiúlcera aguda em ratos em modelo de indução por etanol acidificado, embora o extrato e as frações de J. caroba apresentaram potencial atividade anti Helicobacter pylori, com CIM variando entre 125 e 1.000 µg/mL. O extrato de J. caroba não promoveu sintomas de toxicidade aguda e subaguda em ratos. A DL50 observada foi maior que 5.000 mg/kg. Não foram relatadas alterações significativas na aparência macroscópica e peso dos órgãos, porém houve indicação de atividade mutagênica em teste de Ames na linhagem TA98 de S. typhimurium, o qual apresentou uma tendência dose-resposta para concentrações entre 7,5 e 15,0 mg/placa após ativação metabólica (S9). A formulação de nanocápsulas de poli-ε- caprolactona com extrato de P. umbellatum apresentou partículas com diâmetro médio de 181,6 ± 0,9 nm e potencial zeta de -31 ± 4 mV. Através de análise por CLAE observou-se maior eficiência de encapsulamento para a porção mais apolar da fração, enquanto que os compostos mais polares ficaram dispersos no meio. As nanocápsulas poliméricas apresentaram atividade gastroprotetora mesmo sem a adição de ativos e tiveram sua atividade aumentada pela fração clorofórmica de P. umbellatum

Jacaranda decurrens Cham., Jacaranda caroba (Vell.) DC. and Piper umbellatum L. are native plants in Brazil, present in the state of São Paulo, with popular usage reports for anti-ulcer activity. This study aimed to evaluate the anti-ulcer activity of J. caroba, J. decurrens and nanocapsules formulations containing P. umbellatum. Also, we intended to characterize the phytochemistry of such formulations and extracts. Additionally, we evaluated the acute and subacute toxicity of J. caroba. Extracts from Jacaranda presented phenolic compounds in their chromatographic profiles obtained by TLC and HPLC, with variations between species. Samples of J. caroba extracts showed different chemical composition according to the origin and age of the plant. The species J. decurrens and J. caroba from three different regions showed no acute anti-ulcer action when tested in rats by acidified ethanol induction model. However, extract and fractions from J. caroba showed potential anti Helicobacter pylori activity, with MIC ranging from 125 and 1,000 ug/mL. J. caroba extract did not cause symptoms of acute and subacute toxicity in rats. The DL50 was determined above 5,000 mg/kg. Also, there were no significant changes to the macroscopic appearance of organs or changes in their weights. Meanwhile, an indication of mutagenic activity was observed in the Ames test. The TA98 strain of S. typhimurium, showed a tendency of dose-response for concentrations between 7.5 and 15.0 mg/plate after metabolic activation (S9). The nanocapsules formulation of poly-ε-caprolactone containing P. umbellatum extract had an average particle diameter of 181.6 ± 0.9 nm and zeta potential of -31 ± 4 mV. HPLC analysis showed better entrapping efficiency for the more apolar portion of the fraction, while the more polar compounds were dispersed in the medium. The polymeric nanocapsules showed gastroprotective activity even without the addition of active molecules and had their activity increased by chloroform fraction of P. umbellatum

Evaluation of acute toxicity, antibacterial activity, and mode of action of the hydroethanolic extract of Piper umbellatum L.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper umbellatum L., Piperaceae, is a shrub that grows up to 3m high. It is commonly known as "capeba" or "pariparoba" in Brazil. Tea prepared using the leaves of this plant is employed in the treatment of infections and inflammatory processes in different countries. Approximately 50 compounds, notably from the flavonoid, alkaloid, terpene, and sterol classes, have been isolated from the leaves of Piper umbellatum. To evaluate the acute toxicity, antibacterial activity, and mode of action of the hydroethanolic extract of Piper umbellatum leaves (HEPu). MATERIALS AND METHODS: Acute toxicity of HEPu against CHO-K1 cells was evaluated using a cytotoxicity assay with Alamar Blue and that against mice was assessed by the Hippocratic test. Antibacterial activity of HEPu was tested using the broth microdilution method using a panel of clinically relevant bacteria, and the effects of HEPu on the bacterial membrane were analyzed in detail. A preliminary phytochemical analysis based on coloration/precipitation was performed according to procedure described in the literature. Secondary metabolites detected were analyzed and confirmed by thin layer chromatography (TLC), spectrophotometry, and high performance liquid chromatography (HPLC). RESULTS: Piper umbellatum did not appear to be toxic in the in vitro (IC50>200 µg/mL) cytotoxicity test. When administered in vivo at doses up to 2000 mg/kg p.o., HEPu did not cause any signs or symptoms of toxicity in mice. It demonstrated a good spectrum of antibacterial activity and its mode of action appeared to be associated with changes in the permeability of bacterial membranes; it led to increased entry of hydrophobic antibiotics, efflux of K(+), and nucleotide leakage. Preliminary phytochemical analysis revealed the presence of flavonoids, alkaloids, terpenes, and sterols in the extract. Spectrophotometric and HPLC analysis revealed the presence of the flavonoids rutin and quercetin. CONCLUSION: In summary, HEPu has antibacterial activity and low acute toxicity in vitro and in vivo. Its mode of action appears to be associated with changes in the permeability of the bacterial cell wall and cytoplasmic membrane, which can at least be partly attributed to the flavonoids present in the extract.