Md. Areeful Haque

Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action

Abstract Natural products with immunomodulatory activity are widely used in treatment of many diseases including autoimmune diseases, inflammatory disorders in addition to cancer. They gained a great interest in the last decades as therapeutic agents since they provide inexpensive and less toxic products than the synthetic chemotherapeutic agents. Immunomodulators are the agents that have the ability to boost or suppress the host defense response that can be used as a prophylaxis as well as in combination with other therapeutic modalities. The anticancer activity of these immunomodulators is due to their anti‐inflammatory, antioxidant, and induction of apoptosis, anti‐angiogenesis, and anti‐metastasis effect. These natural immunomodulators such as genistein, curcumin, and resveratrol can be used as prophylaxis against the initiation of cancer besides the inhibition of tumor growth and proliferation. Whereas, immunostimulants can elicit and activate humoral and cell‐mediated immune responses against the tumor that facilitate the recognition and destruction of the already existing tumor. This review represents the recent studies on various natural immunomodulators with antitumor effects. We have focused on the relationship between their anticancer activity and immunomodulatory mechanisms. The mechanisms of action of various immunomodulators such as polyphenolic compounds, flavonoids, organosulfur compounds, capsaicin, vinca alkaloids, bromelain, betulinic acid and zerumbone, the affected cancerous cell lines in addition to the targeted molecules and transcriptional pathways have been review and critically analyzed. Graphical abstract Figure. No Caption available. HighlightsNatural immunomodulators can be used as prophylaxis against the initiation of cancer.Immunostimulants activate humoral and cell‐mediated immune responses against tumor.Relation between anticancer activity and immunomodulatory mechanisms is analyzed.

An overview of structure–activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents

Curcumin, extracted mainly from Curcuma longa rhizomes, has been reported to possess potent anti-inflammatory and anti-oxidant activities. Although safe at higher doses and exhibiting multiple biological activities, curcumin still has the problem of poor bioavailability which has been an attractive area of research over the last few years. A number of efforts have been made by modifying structural features of curcumin. This review highlights the structurally modified and more stable newly synthesized curcumin analogs that have been screened against antioxidant and anti-inflammatory activities. Also the structure-activity relationship to gain insight into future guidelines for scheming new compounds has been discussed, and further these analogs being more stable may serve as promising agents for use in different pathological conditions.

Zerumbone suppresses the activation of inflammatory mediators in LPS-stimulated U937 macrophages through MyD88-dependent NF-κB/MAPK/PI3K-Akt signaling pathways

ABSTRACT Zerumbone (ZER), isolated mainly from the Zingiber zerumbet (Z. zerumbet) rhizomes was found to be effective against numerous inflammatory and immune disorders, however, the molecular and biochemical mechanisms underlying its anti‐inflammatory and immunosuppressive properties have not been well studied. This study was carried out to examine the profound effects of ZER on inflammatory mediated MyD88‐dependent NF‐&kgr;B/MAPK/PI3K‐Akt signaling pathways in LPS‐stimulated U937 human macrophages. ZER significantly suppressed the up‐regulation pro‐inflammatory mediators, TNF‐&agr;, IL‐1&bgr;, PGE2, and COX‐2 protein in LPS‐induced human macrophages. Moreover, ZER significantly downregulated the phosphorylation of NF‐&kgr;B (p65), I&kgr;B&agr;, and IKK&agr;/&bgr; as well as restored the degradation of I&kgr;B&agr;. ZER correspondingly showed remarkable attenuation of the expression of Akt, JNK, ERK, and p38 MAPKs phosphorylation in a concentration‐dependent manner. ZER also diminished the expression of upstream signaling molecules TLR4 and MyD88, which are prerequisite for the NF‐&kgr;B, MAPK and PI3K‐Akt activation. Additionally, quantification of relative gene expression of TNF‐&agr;, IL‐1&bgr;, and COX‐2 indicated that, at a higher dose (50 &mgr;M), ZER significantly downregulated the elevated mRNA transcription levels of the stated pro‐inflammatory markers in LPS‐stimulated U937 macrophages. The strong suppressive effects of ZER on the activation of inflammatory markers in the macrophages via MyD88‐dependent NF‐&kgr;B/MAPK/PI3K‐Akt signaling pathways suggest that ZER can be a preventive and potent therapeutic candidate for the management of various inflammatory‐mediated immune disorders. Graphical abstract Figure. No Caption available. HighlightsZerumbone suppressed the MyD88‐dependent NF‐&kgr;B, Akt and MAPK signaling activation.Zerumbone significantly suppressed the up‐regulation of pro‐inflammatory mediators.Zerumbone downregulated the phosphorylation of IKK&agr;/&bgr;, I&kgr;B&agr;, and NF‐&kgr;B (p65).Zerumbone attenuated the expression of Akt, JNK, ERK, and p38 MAPKs phosphorylation.

Tinospora species: An overview of their modulating effects on the immune system

ETHNOPHARMACOLOGICAL RELEVANCE Studies on the effects of natural immunomodulators to heal various diseases related to the immune system have been a growing interest in recent years. Amongst the medicinal plants, Tinospora species (family; Menispermaceae) have been one of the widely investigated plants for their modulating effects on the immune system due to their wide use in ethnomedicine to treat various ailments related to immune-related diseases. However, their ethnopharmacological uses are mainly with limited or without scientific basis. AIM OF THIS REVIEW In this article, we have reviewed the literature on the phytochemicals of several Tinospora species, which have shown strong immunomodulatory effects and critically analyzed the reports to provide perspectives and instructions for future research for the plants as a potential source of new immunomodulators for use as medicinal agents or dietary supplements. MATERIALS AND METHODS Electronic search on worldwide accepted scientific databases (Google Scholar, Science Direct, SciFinder, Web of Science, PubMed, Wiley Online Library, ACS Publications Today) was performed to compile the relevant information. Some information was obtained from books, database on medicinal plants used in Ayurveda, MSc dissertations and herbal classics books written in various languages. RESULTS T. cordifolia, T. crispa, T. sinensis, T. smilacina, T. bakis, and T. sagittata have been reported to possess significant immunomodulatory effects. For a few decades, initiatives in molecular research on the effects of these species on the immune system have been carried out. However, most of the biological and pharmacological studies were carried out using the crude extracts of plants. The bioactive compounds contributing to the bioactivities have not been properly identified, and mechanistic studies to understand the immunomodulatory effects of the plants are limited by many considerations with regard to design, conduct, and interpretation. CONCLUSION The plant extracts and their active constituents should be subjected to more detail mechanistic studies, in vivo investigations in various animal models including pharmacokinetic and bioavailability studies, and elaborate toxicity study before submission to clinical trials.

Immunosuppressive Effects of Natural α,β-Unsaturated Carbonyl-Based Compounds, and Their Analogs and Derivatives, on Immune Cells: A Review

The immune system is complex and pervasive as it functions to prevent or limit infections in the human body. In a healthy organism, the immune system and the redox balance of immune cells maintain homeostasis within the body. The failure to maintain the balance may lead to impaired immune response and either over activity or abnormally low activity of the immune cells resulting in autoimmune or immune deficiency diseases. Compounds containing α,β-unsaturated carbonyl-based moieties are often reactive. The reactivity of these groups is responsible for their diverse pharmacological activities, and the most important and widely studied include the natural compounds curcumin, chalcone, and zerumbone. Numerous studies have revealed the mainly immunosuppressive and anti-inflammatory activities of the aforesaid compounds. This review highlights the specific immunosuppressive effects of these natural α,β-unsaturated carbonyl-based compounds, and their analogs and derivatives on different types of immune cells of the innate (granulocytes, monocytes, macrophages, and dendritic cells) and adaptive (T cells, B cells, and natural killer cells) immune systems. The inhibitory effects of these compounds have been comprehensively studied on neutrophils, monocytes and macrophages but their effects on T cells, B cells, natural killer cells, and dendritic cells have not been well investigated. It is of paramount importance to continue generating experimental data on the mechanisms of action of α,β-unsaturated carbonyl-based compounds on immune cells to provide useful information for ensuing research to discover new immunomodulating agents.

Anti-Inflammatory Effects of Hypophyllanthin and Niranthin Through Downregulation of NF-κB/MAPKs/PI3K-Akt Signaling Pathways

Hypophyllanthin (HYP) and niranthin (NIR) are major lignans in Phyllanthus spp. and have been shown to possess strong anti-inflammatory activity. In this study, we investigated the anti-inflammatory effects and the underlying molecular mechanisms of HYP and NIR in in vitro cellular model of LPS-induced U937 macrophages. The effects of HYP and NIR on the production of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were measured by using ELISA, Western blot, and qRT-PCR. The expressions of signaling molecules related to nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), and phosphatidylinositol 3′-kinase-Akt (PI3K-Akt) signaling pathways were examined. The role of NF-κB, MAPKs, and Akt signaling pathways was confirmed by using specific inhibitors (BAY 11-7082, U0126, SB202190, SP600125, and LY294002) mediated suppression of TNF-α and COX-2 production. HYP and NIR significantly inhibited the protein and gene levels of COX-2 as well as the downstream signaling products of PGE2, TNF-α, and IL-1β. HYP and NIR also suppressed the inhibitors of kappa B (IκB), IkB kinases (Ikkα/β), NF-κB phosphorylation, and IκB degradation. HYP suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 while NIR only suppressed JNK and ERK but did not have effect on p38. These results demonstrate that HYP and NIR downregulated COX-2, TNF-α, and IL-1β gene expressions in U937 macrophages by interfering with the activation of NF-κB, MAPKs, and Akt. In conclusion, these lignans have potential to be developed as anti-inflammatory agents targeting the NF-κB, MAPK, and PI3K-Akt pathways.

Magnoflorine Enhances LPS-Activated Pro-Inflammatory Responses via MyD88-Dependent Pathways in U937 Macrophages

Magnoflorine, a major bioactive metabolite isolated from Tinospora crispa, has been reported for its diverse biochemical and pharmacological properties. However, there is little report on its underlying mechanisms of action on immune responses, particularly on macrophage activation. In this study, we aimed to investigate the effects of magnoflorine, isolated from T. crispa on the pro-inflammatory mediators generation induced by LPS and the concomitant NF-κB, MAPKs, and PI3K-Akt signaling pathways in U937 macrophages. Differentiated U937 macrophages were treated with magnoflorine and the release of pro-inflammatory mediators was evaluated through ELISA, while the relative mRNA expression of the respective mediators was quantified through qRT-PCR. Correspondingly, western blotting was executed to observe the modulatory effects of magnoflorine on the expression of various markers related to NF-κB, MAPK and PI3K-Akt signaling activation in LPS-primed U937 macrophages. Magnoflorine significantly enhanced the upregulation of TNF-α, IL-1β, and PGE2 production as well as COX-2 protein expression. Successively, magnoflorine prompted the mRNA transcription level of these pro-inflammatory mediators. Magnoflorine enhanced the NF-κB activation by prompting p65, IκBα, and IKKα/β phosphorylation as well as IκBα degradation. Besides, magnoflorine treatments concentration-dependently augmented the phosphorylation of JNK, ERK, and p38 MAPKs as well as Akt. The immunoaugmenting effects were further confirmed by investigating the effects of magnoflorine on specific inhibitors, where the treatment with specific inhibitors of NF-κB, MAPKs, and PI3K-Akt proficiently blocked the magnoflorine-triggered TNF-α release and COX-2 expression. Magnoflorine furthermore enhanced the MyD88 and TLR4 upregulation. The results suggest that magnoflorine has high potential on augmenting immune responses.

Recent Updates on the Phytochemistry, Pharmacological, and Toxicological Activities of Zingiber zerumbet (L.) Roscoe ex Sm.

BACKGROUND Zingiber zerumbet (L.) Roscoe ex Sm. (family, Zingiberaceae) is a potent medicinal herb widely known as shampoo ginger and its rhizome is used in numerous ethnomedicinal applications including antipyretic, anti-inflammatory, antibacterial, anti-diarrheal, antidiabetics, carminative, and diuretic. The aim of this review was to bring together all the scientific updates on the phytochemistry and pharmacological activities of this herb, including their toxicological studies, and critically analyzed the outcomes to provide directions for future research on the herb as potential source of bioactive metabolites for pharmaceutical and nutraceutical applications. METHODS A structured electronic search on worldwide accepted scientific databases (Web of Science, PubMed, Google Scholar, Science Direct, SciFinder, Wiley Online Library) was carried out to compile the relevant information. Some information was obtained from books and database on medicinal plants used in various countries. RESULTS About 60 metabolites, mainly polyphenols, and terpenoids have been isolated and identified. However, most of the reported pharmacological studies were based on crude extracts, and only a few of those isolated metabolites, particularly zerumbone have been investigated for biological and pharmacological activities. Many of the mechanistic studies to understand the pharmacological effects of the plant are limited by many considerations with regard to design, experimentation and interpretation. CONCLUSION The bioactive metabolites should be further investigated on their safety and more elaborate preclinical studies before clinical trials can be undertaken.

Anti-inflammatory effects of Phyllanthus amarus Schum. & Thonn. Through inhibition of NF-ΚB, MAPK, and PI3K-Akt signaling pathways in LPS-induced human macrophages

BackgroundPhyllanthus amarus has been used widely in various traditional medicines to treat swelling, sores, jaundice, inflammatory diseases, kidney disorders, diabetes and viral hepatitis, while its pharmacological and biochemical mechanisms underlying its anti-inflammatory properties have not been well investigated. The present study was carried out to investigate the effects of 80% ethanolic extract of P. amarus on pro-inflammatory mediators release in nuclear factor-kappa B (NF-кB), mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Akt (PI3K-Akt) signaling activation in lipopolysaccharide (LPS)-induced U937 human macrophages.MethodsThe release of prostaglandin E2 (PGE2) and pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β in a culture supernatant was determined by ELISA. Determination of cyclooxygenase-2 (COX-2) protein and the activation of MAPKs molecules (JNK, ERK and p38 MAPK), NF-κB and Akt in LPS-induced U937 human macrophages were investigated by immunoblot technique. The relative gene expression levels of COX-2 and pro-inflammatory cytokines were measured by using qRT-PCR. The major metabolites of P. amarus were qualitatively and quantitatively analyzed in the extract by using validated reversed-phase high performance liquid chromatography (HPLC) methods.ResultsP. amarus extract significantly inhibited the production of pro-inflammatory mediators (TNF-α, IL-1β, PGE2) and COX-2 protein expression in LPS-induced U937 human macrophages. P. amarus-pretreatment also significantly downregulated the increased mRNA transcription of pro-inflammatory markers (TNF-α, IL-1β, and COX-2) in respective LPS-induced U937 macrophages. It downregulated the phosphorylation of NF-κB (p65), IκBα, and IKKα/β and restored the degradation of IκBα, and attenuated the expression of Akt, JNK, ERK, and p38 MAPKs phosphorylation in a dose-dependent manner. P. amarus extract also downregulated the expression of upstream signaling molecules, TLR4 and MyD88, which play major role in activation of NF-κB, MAPK and PI3K-Akt signaling pathways. The quantitative amounts of lignans, phyllanthin, hypophyllahtin and niranthin, and polyphenols, gallic acid, geraniin, corilagin, and ellagic acid in the extract were determined by HPLC analysis.ConclusionThe study revealed that P. amarus targeted the NF-κB, MAPK and PI3K-Akt signaling pathways to exert its anti- inflammatory effects by downregulating the prospective inflammatory signaling mediators.

Phyllanthin from Phyllanthus amarus inhibits LPS-induced proinflammatory responses in U937 macrophages via downregulation of NF-κB/MAPK/PI3K-Akt signaling pathways: Phyllanthin suppresses NF-κB/MAPK/Akt signaling pathways

Phyllanthin, a lignan from Phyllanthus species, has been reported to possess potent immunosuppressive properties on immune cells and on adaptive and innate immune responses in animal models. Herein, we investigated the inhibitory effects of phyllanthin isolated from Phyllanthus amarus on nuclear factor‐kappa B (NF‐κB), mitogen‐activated protein kinase (MAPK), and PI3K‐Akt signal transducing pathways in LPS‐activated U937 cells. The lipopolysaccharide‐stimulated excess production of prostaglandin was significantly suppressed by phyllanthin via the mechanisms linked to the modulatory effects of cyclooxygenase 2 protein and gene expression. Phyllanthin also significantly inhibited the release and mRNA expression of proinflammatory cytokines (interleukin‐1 beta and tumor necrosis factor‐alpha). Phyllanthin also significantly downregulated the phosphorylation of IκBα, NF‐κB (p65), and IKKα/β and suppressed the activation of JNK, ERK, p38MAPK, and Akt in a concentration‐dependent manner. Additionally, phyllanthin downregulated the expression of upstream signaling molecules including MyD88 and toll‐like receptor 4 that are essential for the activation of NF‐κB, MAPKs, and PI3K‐Akt signal transducing pathways. Based on these observations, phyllanthin may exert their suppressive effects on inflammatory process by mediating the release of inflammatory signaling molecules via the NF‐κB, MAPKs, and PI3K‐Akt signal transducing pathways. Thus, phyllanthin holds a great promise as a potential anti‐inflammatory agent to treat various inflammatory diseases.