Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

In respect to the enhanced incidence rate of cancer worldwide, studies have focused on cancer therapy using novel strategies. Chemotherapy is a common strategy in cancer therapy, but its adverse effects and chemoresistance have limited its efficacy. So, attempts have been directed towards minimally invasive cancer therapy using plant derived‐natural compounds. Cryptotanshinone (CT) is a component of salvia miltiorrihiza Bunge, well‐known as Danshen and has a variety of therapeutic and biological activities such as antioxidant, anti‐inflammatory, anti‐diabetic and neuroprotective. Recently, studies have focused on anti‐tumor activity of CT against different cancers. Notably, this herbal compound is efficient in cancer therapy by targeting various molecular signaling pathways. In the present review, we mechanistically describe the anti‐tumor activity of CT with an emphasis on molecular signaling pathways. Then, we evaluate the potential of CT in cancer immunotherapy and enhancing the efficacy of chemotherapy by sensitizing cancer cells into anti‐tumor activity of chemotherapeutic agents, and elevating accumulation of anti‐tumor drugs in cancer cells. Finally, we mention strategies to enhance the anti‐tumor activity of CT, for instance, using nanoparticles to provide targeted drug delivery.     

黄酮类化合物肠道细菌生物转化的研究进展

黄酮类化合物是一类在自然界分布广泛的天然产物,具有多方面的生物活性.黄酮类化合物在肠道细菌的作用下发生降解,进而影响其在体内的生物利用度.肠道细菌对黄酮类化合物的代谢研究能为筛选黄酮生物转化相关菌、阐明黄酮体内代谢过程提供依据.以黄酮类化合物为先导化合物,肠道细菌通过结构修饰可以产生高效、高生物利用度和吸收性良好的化合物,为新药研发、药物剂型选择和药物生产奠定基础.该文归纳总结了肠道细菌对黄酮类化合物生物转化的主要反应类型与影响因素,供生物转化研究借鉴.     

Molecular mechanisms of natural compounds in cell death induction and sensitization to chemotherapeutic drugs in lung cancer

Cancer remains one of the leading causes of death worldwide, especially lung cancer. Chemotherapeutic drugs are commonly used for lung cancer treatment; nonetheless, undesirable side effects and drug resistance remain major challenges for therapeutic success. Therefore, harmless and effective treatments against lung cancer are urgently required. The use of natural phytochemical products, in single or combinatorial therapy, is an emerging strategy for prevention and cure of cancer because of the various remarkable anticancer properties of these compounds. Cell death, which primarily occurs via apoptosis and nonapoptotic mechanisms (necrosis, autophagy, and cellular senescence), is one of the antineoplastic effects of natural compounds. In this review, we highlight representative plant‐derived compounds with cancer chemopreventive and sensitizing effects in combination with chemotherapeutic drugs with various cell death‐inducing mechanisms. Relevant molecular mechanisms implicated in the pharmacological effects of these natural compounds are discussed. Overall, this review provides a reference and new perspective for application of phytochemical agents as potential anti‐lung cancer drugs for further cancer drug research and development.     

Efficacy and Safety of White Willow Bark (Salix alba) Extracts

Willow bark extract has been used for thousands of years as an anti‐inflammatory, antipyretic, and analgesic. In spite of its long history of use, relatively few human and animal studies have been published that confirm anecdotal observations. A small number of clinical studies have been conducted that support the use of willow bark extracts in chronic lower back and joint pain and osteoarthritis. Willow bark extracts also are widely used in sports performance and weight loss products presumably because of anti‐inflammatory and analgesic activities, although no human studies have been published that specifically and directly document beneficial effects. In recent years, various in vitro and animal studies have demonstrated that the anti‐inflammatory activity of willow bark extract is associated with down regulation of the inflammatory mediators tumor necrosis factor‐α and nuclear factor‐kappa B. Although willow bark extracts are generally standardized to salicin, other ingredients in the extracts including other salicylates as well as polyphenols, and flavonoids may also play prominent roles in the therapeutic actions. Adverse effects appear to be minimal as compared to non‐steroidal anti‐inflammatory drugs including aspirin. The primary cause for concern may relate to allergic reactions in salicylate‐sensitive individuals. Copyright © 2015 John Wiley & Sons, Ltd.     

5,7‐Dihydroxy‐6‐Methoxy‐Flavonoids Eliminate HIV‐1 D3‐transfected Cytoprotective Macrophages by Inhibiting the PI3K/Akt Signaling Pathway

Flavonoids, well‐documented secondary metabolites in many vegetables and plants, exhibit antiinflammatory, anti‐oxidant, anti‐microbial, and anticancer activities. However, their cytotoxic effects against human immunodeficiency virus type 1 (HIV‐1)‐infected cytoprotective macrophages have not been studied. In the present study, we investigated their effects and their molecular mechanisms. Treatment with flavonoids in the presence of lipopolysaccharide (LPS)/cycloheximide (CHX) potently eliminated HIV‐1 Tat‐transduced cytoprotective human microglial CHME5 cells; the 5,7‐dihydroxy‐6‐methoxy‐flavonoids oroxylin A and tectorigenin, at a concentration of 10 μM, most potently eliminated the cytoprotective phenotype. These flavonoids eliminated Tat‐transduced CHME5 cells, D3‐transfected CHME5 cells, and HIV‐1 D3‐infected human primary macrophages, in a dose‐dependent manner. Furthermore, oroxylin A and tectorigenin potently inhibited LPS/CHX‐induced phosphorylation of phosphoinositide 3‐kinase (PI3K), pyruvate dehydrogenase lipoamide kinase isozyme 1, Akt, and glycogen synthase kinase‐3β in the Tat‐transduced cells, D3‐transfected CHME5 cells, and D3‐infected human primary macrophages. Based on these findings, 5,7‐dihydroxy‐6‐methoxy‐flavonoids may eliminate HIV‐1 infected cytoprotective macrophages by inhibiting the PI3K/Akt signaling pathway and deliver anti‐HIV‐1 effects in vivo by shortening the lifespan of infected macrophages. Copyright © 2015 John Wiley & Sons, Ltd.     

Anti‐inflammatory activity of Rhodiola rosea – “a second‐generation adaptogen”

Rhodiola rosea (golden root), a unique phytoadaptogen grown in high‐altitude regions has gained attention for its various therapeutic properties. In India, this plant is found in the Himalayan belt and has not been completely explored for its beneficial health effects. The present study was undertaken to evaluate the anti‐inflammatory efficacy of the tincture extract of Rhodiola rosea roots (RTE). The anti‐inflammatory activity was determined through carrageenan‐induced paw oedema, formaldehyde‐induced arthritis and nystatin‐induced paw oedema in rat model. The tincture extract exhibited inhibitory effect against acute and subacute inflammation at a dose of 250 mg/kg body weight. Inhibition of nystatin‐induced oedema was also observed in a dose‐dependent manner. The in vitro inhibitory effects of the tincture extract from R. rosea roots was evaluated against the enzymes relating to inflammation. The enzymes include cyclooxygenase‐1 (COX‐1), cyclooxygenase‐2 (COX‐2) and Phospholipase A₂ (PLA₂). The extract showed varying inhibitory activities against these enzymes depending on the concentrations. A potent inhibition was observed against Cox‐2 and PLA₂. Inhibition of nystatin induced oedema and phospholipase A₂ suggested that membrane stabilization could be the most probable mechanism of action of RTE in anti‐inflammation. The findings in this study may provide the use of R. rosea root extract in the treatment of inflammatory conditions. Copyright © 2009 John Wiley & Sons, Ltd.     

A systematic review on ethnomedicines of anti‐cancer plants

Cancer is a serious health problem and the second leading cause of death around the globe. Present review is an attempt to provide utmost information based on ethno‐pharmacological and toxicological aspects of anti‐cancer plants of the world. A total of 276 articles published in English journals and containing maximum ethnomedicinal information were reviewed using several data sources such as; Google scholar, Web of Science, Scopus, PubMed and floras of different countries. A total of 199 anti‐cancer plants were recorded in present review and results indicated that traditional medicines are mostly being use in developing countries for cancer treatment. Traditionally and scientifically skin and breast cancer types gained more focus. Seventy plants were reportedly analyzed for in‐vitro activities while 32 plants were having in‐vivo reports. Twenty nine pure compounds (mostly phenolic) were reportedly isolated from anti‐cancer plants and tested against different cancer cell lines. Inspite having better efficiency of ethnomedicines as compared to synthetic drugs, several plants have also shown toxic effects on living system. Therefore, we invite researchers attention to carry out detailed ethno‐pharmacological and toxicological studies on un‐explored anti‐cancer plants in order to provide reliable knowledge to the patients and develop novel anti‐cancer drugs. Copyright © 2017 John Wiley & Sons, Ltd.     

Anti‐microbial activity of curcumin nanoformulations: New trends and future perspectives

Curcumin has been used in numerous anti‐microbial research because of its low side effects and extensive traditional applications. Despite having a wide range of effects, the intrinsic physicochemical characteristics such as low bioavailability, poor water solubility, photodegradation, chemical instability, short half‐life and fast metabolism of curcumin derivatives limit their pharmaceutical importance. To overcome these drawbacks and improve the therapeutic ability of curcuminoids, novel approaches have been attempted recently. Nanoparticulate drug delivery systems can increase the efficiency of curcumin in several diseases, especially infectious diseases. These innovative strategies include polymeric nanoparticles, hydrogels, nanoemulsion, nanocomposite, nanofibers, liposome, nanostructured lipid carriers (NLCs), polymeric micelles, quantum dots, polymeric blend films and nanomaterial‐based combination of curcumin with other anti‐bacterial agents. Integration of curcumin in these delivery systems has displayed to improve their solubility, bioavailability, transmembrane permeability, prolong plasma half‐life, long‐term stability, target‐specific delivery and upgraded the therapeutic effects. In this review paper, a range of in vitro and in vivo studies have been critically discussed to explore the therapeutic viability and pharmaceutical significance of the nano‐formulated delivery systems to elevate the anti‐bacterial activities of curcumin and its derivatives.     

Anticancer Activity of Punica granatum (Pomegranate): A Review

Cancer is a pathological condition where excessive and abnormal cell growth leads to widespread invasion within the body to affect various organ functions. It is known that chemotherapeutic agents are themselves possible candidate of cancer generation as they can kill normal cells. So, therapeutic approach for cancer treatment and prevention is weighed in terms of benefit to risk ratio. Nowadays, there is an immense interest for the search herbal formulation with cancer preventive effect because of the problems, generated with existing chemotherapeutic regimens. Research interest in fruits rich in polyphenols is increasing because of their anticancer potential. In this review, we highlight the potential health benefits of pomegranate (Punica granatum) fruit and the underlying mechanism of its inhibition of cancer progression. Pomegranate has demonstrated anti‐proliferative, anti‐metastatic and anti‐invasive effects on various cancer cell line in vitro as well as in vivo animal model or human clinical trial. Although several clinical trials are in progress for identifying the pomegranate as a candidate for various cancer treatment. It is necessary to replicate and validate its therapeutic efficacy by multiple clinical studies in order to formulate pomegranate products as an integral part of the dietary and pharmacological intervention in anticancer therapy. Copyright © 2017 John Wiley & Sons, Ltd.     

甘草酸、甘草次酸的抗肿瘤机制及其作为药物递送载体的研究进展

甘草Glycyrrhizae Radix et Rhizoma是中医临床常用中药之一,具有补脾益气、清热解毒、祛痰止咳、缓急止痛、调和诸药等功能。其主要活性成分为皂苷、黄酮、多糖等。其中,皂苷类成分甘草酸、甘草次酸不仅对肝癌、肺癌、乳腺癌等多种癌症具有抑制作用,还能与化疗药物联用增加药效,同时可被开发用作药物递送的载体材料以解决药物低水溶性、低生物利用度、高毒副作用等问题。研究发现,甘草酸、甘草次酸的增溶作用可能与其两亲性结构有关,有望进一步探索它们作为药物跨膜运输载体的特性。基于甘草的抗肿瘤机制,系统地对甘草酸、甘草次酸在药物递送系统方面的应用进行综述,为开发甘草酸、甘草次酸作为药物递送系统辅料的深入研究提供参考。     

Synergistic Effect of SH003 and Doxorubicin in Triple‐negative Breast Cancer

Triple‐negative breast cancer (TNBC) is highly aggressive, resulting in poor prognosis. Chemotherapy of TNBC relies on anti‐cancer agents with strong cytotoxicity, but it causes several side effects with recurrence. While combinational approaches of chemotherapeutics have been highlighted as a new treatment strategy for TNBC to reduce side effects, combinations of anti‐cancer agents with herbal medicines have not been reported. We recently reported that newly modified traditional Chinese medicine named SH003 inhibited TNBC growth. Considering a combinational strategy for TNBC treatment, we further studied synergistic effects of SH003 with various anti‐cancer drugs in TNBC treatment. Here, we demonstrate that SH003 shows a synergistic effect with doxorubicin on TNBC treatment. Our in vitro cell viability assays revealed that SH003 and doxorubicin showed a synergistic effect in the well‐defined TNBC cell line, MDA‐MB‐231. Moreover, we found that the combinational treatment caused Caspase‐dependent apoptotic cell death. Our in vivo mouse xenograft tumor growth assays confirmed that combinational treatment of SH003 with doxorubicin repressed MDA‐MB‐231 tumor growth with no weight loss. Therefore, we conclude that the combinational treatment of SH003 with doxorubicin shows the synergism in TNBC treatment, and suggest that SH003 can be used together with conventional anti‐cancer drugs in chemotherapeutic approaches. Copyright © 2016 John Wiley & Sons, Ltd.     

Chemistry,Pharmacology and Health Benefits of Anthocyanins

Anthocyanins are naturally occurring molecules belonging to the flavonoid class characterized by the presence of chromophores. Apart from their well‐known antioxidant activity, they show a wide variety of health‐promoting properties for human health, ranging from cytoprotective, antimicrobial and antitumour activities to neuroprotective, anti‐obesity and lipidomic potential, properties for which anthocyanins have been prescribed as medicines in several countries for thousands of years. Despite this, these phytochemicals have received less attention than other flavonoids, and there is still a gap in the literature, particularly regarding pharmacological and toxicological aspects. Moreover, epidemiological evidence suggests a direct correlation between anthocyanin intake and a lower incidence of chronic and degenerative diseases. In light of this, the aim of this review is to cover the current literature on anthocyanins, their biological in vitro and in vivo effects and their potential therapeutic applications, as well as their bioavailability and pharmacokinetics, all of which are essential to gain a better understanding of their biological effectiveness and potential toxicity. Copyright © 2016 John Wiley & Sons, Ltd.     

Safety and toxicity of silymarin,the major constituent of milk thistle extract: An updated review

Milk thistle (Silybum marianum) is a medicinal plant from the Asteraceae family. Silymarin is the major constituent of milk thistle extract and is a mixture of some flavonolignans such as silybin, which is the most active component of silymarin. It is most commonly known for its hepatoprotective effect. Also, studies have shown other therapeutic effects such as anticancer, anti‐Alzheimer, anti‐Parkinson, and anti‐diabetic, so its safety is very important. It has no major toxicity in animals. Silymarin was mutagen in Salmonella typhimurium strains in the presence of metabolic enzymes. Silybin, silydianin, and silychristin were not cytotoxic and genotoxic at concentration of 100 μM. Silymarin is safe in humans at therapeutic doses and is well tolerated even at a high dose of 700 mg three times a day for 24 weeks. Some gastrointestinal discomforts occurred like nausea and diarrhea. One clinical trial showed silymarin is safe in pregnancy, and there were no anomalies. Consequently, caution should be exercised during pregnancy, and more studies are needed especially in humans. Silymarin has low‐drug interactions, and it does not have major effects on cytochromes P‐450. Some studies demonstrated that the use of silymarin must be with caution when co‐administered with narrow therapeutic window drugs.     

Biologically active prenylated flavonoids from the genus Sophora and their structure–activity relationship—A review

The genus Sophora (Fabaceae) has been used in traditional medicine for years. Prenylated flavonoids are one of the constituents of Sophora species that play important roles in their biological properties. Different classes of prenylated flavonoids are produced by Sophora spp. including prenylated flavonol (e.g., sophoflavescenol), prenylated flavanone (e.g., sophoraflavanone G), prenylated flavonostilbene (e.g., alopecurones A and B), and prenylated chalcone (kuraridin). Prenylated flavonoids have a more lipophilic structure, which leads to its high affinity to the cell membranes and enhancement of the biological activity, which includes cytotoxicity, antibacterial, anti‐inflammatory, and estrogenic activities. However, it is reported that prenylation decreases the plasma absorption but increases the tissue accumulation. The presence of the prenyl or lavandulyl groups on C8 position of flavonoids plays an important role in the biological activity. It seems that prenylated flavonoids have the potential to be developed as new drugs or supplements for human health.     

Genome wide expression analysis of the effect of the Chinese patent medicine Zilongjin tablet on four human lung carcinoma cell lines

Zilongjin (ZLJ) tablet, which is a traditional Chinese medicine, has been approved as a new anti‐tumor drug by the State Food and Drug Administration of China; however, its anti‐cancer mechanisms remain elusive. The goal of this study was to investigate the underlying anti‐cancer activities of ZLJ tablet in vitro. In this study, four lung cancer cell lines, A549, H446, H460 and H520, were treated with 2.2 mg/mL of ZLJ solution for 24 h at 37 °C under 5% CO₂. RNA was isolated and a microarray experiment using the Affymetrix Human Genome U133 plus 2.0 Array was employed to differentiate the expression patterns of cancer‐related genes after drug treatment. Of 483 genes in 63 functional categories and 25 different pathways that showed at least a 2‐fold change of expression level in the four cancer cell lines, 170 genes were upregulated, and 313 genes were downregulated. Eleven of the 483 genes were cancer‐related and belong to the three known pathways: apoptosis, cell cycle regulation and mitogen‐activated protein kinase (MAPK) cascade. The microarray data were validated by real‐time RT‐PCR. The results of this investigation suggest possible anti‐cancer mechanisms of the ZLJ tablet, and lay a foundation to further analyse its therapeutic roles. Copyright © 2011 John Wiley & Sons, Ltd.     

Pharmacokinetic and pharmacodynamic studies on interaction of "Trikatu" with diclofenac sodium

"Trikatu"-an Ayurvedic formulation comprising of a 1:1:1 ratio of dried fruits of Piper nigrum, Piper longum and dried rhizomes of Zingiber officinale is widely used to enhance the bioavailability of drugs, like vasicine, indomethacin, etc. The enhanced biological response might lead to alteration of therapeutic regimens of commonly prescribed drugs. The present work was aimed to study the effect of concomitant administration of Trikatu on the pharmacokinetics and pharmacodynamics of diclofenac sodium, a frequently prescribed non-steroidal anti-inflammatory drug, having a poor oral bioavailability (54 +/- 2%). The effect of Trikatu on the bioavailability profile of diclofenac sodium was studied in rabbits. It was observed that Trikatu significantly decreased the serum levels of diclofenac sodium. The pharmacodynamic study was carried out to evaluate the effect of Trikatu on the anti-inflammatory activity of diclofenac sodium using carragenin-induced rat paw edema model. It was observed that the mean percent edema inhibition shown by the combination of Trikatu and diclofenac was similar to that shown by Trikatu alone but significantly less than that shown by diclofenac alone. Thus, the experimental findings indicated that Trikatu pretreatment might decrease the bioavailability of certain drugs probably through a drug-herb interaction thereby adversely affecting the therapeutic efficacy of these drugs.     

In Vitro Inhibition of the Transcription Factor NF‐κB and Cyclooxygenase by Bamboo Extracts

Several bamboo species have been used in traditional medicine for the treatment of inflammatory conditions. The present study evaluates the in vitro anti‐inflammatory properties of the traditionally used bamboo species Phyllostachys nigra (Lodd.) Munro and Sasa veitchii (Carr.) Rehder to explore their future research opportunities and therapeutic potential as anti‐inflammatory agents. The extracts were evaluated for their potential inhibitory activity at the level of NF‐κB‐induced gene expression and suppression of cyclooxygenase (COX)‐1 and COX‐2 enzyme activities, representative pharmacological targets for the anti‐inflammatory action of glucocorticoids and non‐steroidal anti‐inflammatory drugs, respectively. The activity of P. nigra (Lodd.) Munro and S. veitchii (Carr.) Rehder was compared with bamboo species without traditional anti‐inflammatory indications. High‐performance liquid chromatography with diode‐array detection and liquid chromatography–tandem mass spectrometry analyses were performed to phytochemically characterize the extracts. P. nigra (Lodd.) Munro leaf extract potently inhibited NF‐κB‐induced gene expression, while S. veitchii (Carr.) Rehder leaf extract exerted a selective COX‐2 inhibition. The crude extracts consistently showed a more potent bioactivity than the solid phase extraction fractions. P. nigra (Lodd.) Munro and S. veitchii (Carr.) Rehder both exert anti‐inflammatory properties, but act via a different molecular mechanism. Copyright © 2013 John Wiley & Sons, Ltd.     

Effect of Grapefruit Juice and Ritonavir on Pharmacokinetics of Lopinavir in Wistar Rats

Lopinavir (LPV), a newer HIV protease inhibitor, has poor bioavailability being a substrate of both cytochrome P450 3A enzyme system (CYP3A) and permeability‐glycoprotein (P‐gp). Ritonavir (RTV) is a known inhibitor of both P‐gp and CYP3A and is co‐administered with LPV in anti‐HIV therapy. Grapefruit juice (GFJ) is known to inhibit CYP3A and has conflicting effects, ranging from activation to inhibition, on P‐gp. In this research work, the effects of GFJ and RTV on the pharmacokinetics of LPV were compared in rats. A mechanistic evaluation was undertaken using various in vitro and ex vivo studies to support the in vivo pharmacokinetic data. The plasma levels of LPV were found to increase significantly upon co‐administration with GFJ in single dose as well as multidose pretreatment studies. Similar, but marginally higher, results were observed upon co‐administration of LPV with RTV. No significant change in t_max was observed in the various treatment groups. The apparent permeability of LPV in the ileum increased significantly after the pre‐incubation with GFJ and RTV compared with no pre‐incubation. The GFJ and RTV showed a significant and similar inhibitory effect on rat intestinal microsomes in the metabolism of LPV. The GFJ was equally effective as RTV in increasing the bioavailability of LPV. Copyright © 2012 John Wiley & Sons, Ltd.     

Phytochemical constituents,biological activities,and health‐promoting effects of the genus Origanum

Origanum species are mostly distributed around the Mediterranean, Euro‐Siberian, and Iran‐Siberian regions. Since time immemorial, the genus has popularly been used in Southern Europe, as well as on the American continent as a spice now known all over the world under the name “oregano” or “pizza‐spice.” Origanum plants are also employed to prepare bitter tinctures, wines, vermouths, beer, and kvass. The major components of Origanum essential oil are various terpenes, phenols, phenolic acids, and flavonoids with predominant occurrence of carvacrol and thymol (with reasonable amounts of p‐cymen and ‐terpinene) or of terpinene‐4‐ol, linalool, and sabinene hydrate. Many species of Origanum genus are used to treat kidney, digestive, nervous, and respiratory disorders, spasms, sore throat, diabetes, lean menstruation, hypertension, cold, insomnia, toothache, headache, epilepsy, urinary tract infections, etc. Origanum essential oil showed potent bioactivities owing to its major constituents' carvacrol, thymol, and monoterpenes. Several preclinical studies evidenced its pharmacological potential as antiproliferative or anticancer, antidiabetic, antihyperlipidemic, anti‐obesity, renoprotective, antiinflammatory, vasoprotective, cardioprotective, antinociceptive, insecticidal, and hepatoprotective properties. Its nanotechnological applications as a promising pharmaceutical in order to enhance the solubility, physicochemical stability, and the accumulation rate of its essential oils have been investigated. However, Origanum has been reported causing angioedema, perioral dermatitis, allergic reaction, inhibition of platelet aggregation, hypoglycemia, and abortion. Conclusive evidences are still required for its clinical applications against human medical conditions. Toxicity analyses and risk assessment will aid to its safe and efficacious application. In addition, elaborate structure–activity studies are needed to explore the potential use of Origanum‐derived phytochemicals as promising drug candidates.