Antiviral effects of phytochemicals against severe acute respiratory syndrome coronavirus 2 and their mechanisms of action: A review.

The worldwide spreading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to health, economic, environmental, and social aspects of human lives. Currently, there are no approved treatments that can effectively block the virus although several existing antimalarial and antiviral agents have been repurposed and allowed use during the pandemic under the emergency use authorization (EUA) status. This review gives an updated overview of the antiviral effects of phytochemicals including alkaloids, flavonoids, and terpenoids against the COVID-19 virus and their mechanisms of action. Search for natural lead molecules against SARS-CoV-2 has been focusing on virtual screening and in vitro studies on phytochemicals that have shown great promise against other coronaviruses such as SARS-CoV. Until now, there is limited data on in vivo investigations to examine the antiviral activity of plants in SARS-CoV-2-infected animal models and the studies were performed using crude extracts. Further experimental and preclinical investigations on the in vivo effects of phytochemicals have to be performed to provide sufficient efficacy and safety data before clinical studies can be performed to develop them into COVID-19 drugs. Phytochemicals are potential sources of new chemical leads for the development of safe and potent anti-SARS-CoV-2 agents.

Attenuation of CFA-induced chronic inflammation by a bicyclic monoterpene fenchone targeting inducible nitric oxide, prostaglandins, C-reactive protein and urea.

Fenchone (a bicyclic monoterpene) is present in the essential oils of plant species like Foeniculum vulgare and Peumus boldus and is used to treat GIT disorders. Research reports have indicated its strong anti-inflammatory, antioxidant, and anti-nociceptive properties. The present study was designed to investigate fenchone's anti-arthritic effects in a rat model of chronic joint inflammation (Complete Freud's Adjuvant-mediated inflammation [CFA]). Molecular docking analysis revealed a high binding interaction of fenchone with inducible nitric oxide synthase (iNOS), Interleukin-17, Prostaglandin E Receptor EP4, and Cycloxygenase-2 (COX-2), indicating its anti-inflammatory efficacy using computational tests. Fenchone treatment at 100 mg/kg, 200 mg/kg, and 400 mg/kg significantly enhanced the tail-flick latency when compared with the solvent-treated group. Correspondingly, the raised mRNA values of iNOS, IL-17, IL-1ß, IL-6, TNF-α, and COX-2 in solvent-treated group were significantly reduced following treatment with fenchone. Moreover, fenchone significantly lowered spleen and thymus indices, Nitric oxide (NO) and PGE2 values as compared to solvent-treated group. Hence, the results of the present study indicated that fenchone has a potent anti-inflammatory effect by inhibiting pro-inflammatory markers and thus may have therapeutic potential for chronic joint inflammation as well as chronic inflammatory disorders.

Exploring the potential of natural polymers from plants as tablet binder and accessing their release profiles: A comparative analysis.

A tablet is a compact dosage form that includes both the active pharmaceutical ingredient (API) and various excipients, where a binder acts as an excipient, imparting cohesive quality in the powdered material. The present study aimed to extract polysaccharides from plant samples; Plantago ovata seeds, Plantago ovata husk, Lallemantia royleana, Ocimum basilicum and Acacia nilotica and to investigate their efficacy as tablet excipients. The wet granulation method was adopted for tablet formulation. Three different formulations (3%, 5% and 7%) were prepared by varying the binder concentration (hemicellulose extracted from plant samples). The tablets were evaluated by pre-compression tests; Angle of repose, bulk density, tapped density, Carr's Index, Hausner's ratio and post-compression tests; weight variation test, friability test, disintegration test, thickness test and dissolution test. Results were compared with binder commercially used in paracetamol drug. All 5% and 7% formulations showed friability and hardness values within range. Results of all the formulations of disintegration time are within range except 7% Plantago ovata seeds and 7% Plantago ovata husk. All the extracted hemicellulose showed good binding potential but, in all respects, the best formulation was 7% Lallemantia royleana, which has the potential to replace the synthetic binders in the pharmaceutical industry.

Neuropharmacological and Antidiarrheal Potentials of Duabanga grandiflora (DC.) Walp. Stem Bark and Prospective Ligand-Receptor Interactions of Its Bioactive Lead Molecules.

Duabanga grandiflora (DC.) Walp. is an ethnomedicinally significant plant used to treat various illnesses, but there is little scientific evidence to support its use. This study explored the pharmacological activities of methanol extract of D. grandiflora stem barks (MEDG) through in vivo approaches in Swiss albino mice and a computer-aided molecular approach. The forced swimming test (FST), tail suspension test (TST), elevated plus maze (EPM), and hole board test (HBT) were used to determine anti-depressant and anxiolytic activity in experimental mice. In addition, anti-diarrheal studies were performed using castor oil-induced diarrhea, castor oil-induced enter pooling, and the charcoal-induced gastrointestinal motility test. MEDG showed substantial depletions in the immobility times in both FST and TST after treatment with the MEDG extract, whereas moderate anxiolytic activity was manifested at a higher dose (400 mg/kg) compared with the control. Correspondingly, MEDG extract revealed a significant reduction in wet feces and decreased the small intestinal transit of charcoal meal in castor oil-induced diarrhea and charcoal-induced gastrointestinal motility test. In the computer-aided molecular approaches, vanillin displayed a promising binding score for both anxiolytic and anti-diarrheal activities, while duabanganal C showed a promising score for the anti-depressant activity. The present experimental findings along with a computer-aided model conclude that MEDG could be a possible Phyto therapeutic agent with potential anti-depressant, anxiolytic and anti-diarrheal activity.

Pharmacological evaluation of cardioprotective potential of Berberis orthobotrys Bien.ex Aitch.

The resurgence of scrutiny in plant-based medicine is mainly due to the current widespread belief that "green medicine" is safe and more dependable than the expensive synthetic drugs. The current study was focused to evaluate the anti-myocardial ischemic potential of Berberis orthobotrys Bien ex Aitch against chemically induced myocardial ischemia in animal models. Myocardial ischemia was instigated in Sprague Dawley rats of either sex (250-450g) by administration of Isoproterenol (ISO) and doxorubicin (DOX) at doses of 25mg/kg b.w and 15mg/kg b.w. respectively. The protective effect of the plant extract was explored by pretreating a group of animals with aqueous methanolic extract of Berberis orthobotrys roots at a dose of 50mg/kg b.w. (orally) for 10 days in ISO-ischemic model while for doxorubicin ischemic model; the study was conducted for 14 days. The findings of the study revealed that serum levels of cardiac marker enzymes were significantly increased (p<0.0001) followed by the administration of Isoproterenol and doxorubicin whereas the pretreatment with aqueous methanolic plant extract had significantly (p<0.0001) prevented the rise in the same, as compared to both intoxicated groups. The statistical analysis of the study led to the conclusion that Berberis orthobotrys possesses cardio protective potential against chemically induced myocardial ischemia.

Cardioprotective potential of Thymus linearis Benth.

In developing countries, myocardial ischemia and the resulting impairments in heart function are the leading cause of illness and mortality. Thymus linearis Benth has been used as an antibiotic, antioxidant, and antihypertensive agent for centuries. The goal of this investigation was to see if Thymus linearis could protect isoproterenol and doxorubicin-induced myocardial ischemia in vivo at doses of 25 mg/kg s.c. and 15 mg/kg i.p., respectively. The level of cardiac enzymes (CK-MB, LDH, and AST) in the serum isolated from the experimental animal's blood was used to determine myocardial ischemia. The anti-ischemic potential was assessed by comparing the levels of the aforementioned cardiac biomarkers in the intoxicated and treated animal groups. The study found substantial increase (p0.0001) in the serum levels of CK-MB, LDH, AST when compared to intoxicated groups, while pretreatment of animals with crude extract of Thymus linearis significantly reduced the rise in serum cardiac indicators. The findings of the study indicated that the aqueous methanolic Thymus linearis crude extract has cardioprotective potential against Isoproterenol and Doxorubicin-induced cardiac necrosis in rats.

Standardized ethanol extract, essential oil and zerumbone of Zingiber zerumbet rhizome suppress phagocytic activity of human neutrophils.

BACKGROUND: Zingiber zerumbet rhizome and its bioactive metabolites have previously been reported to exhibit innumerable pharmacological properties particularly anti-inflammatory activities. In the present study, the 80% ethanol extract, essential oil and zerumbone of Z. zerumbet rhizomes were explored for their in vitro immunosuppressive properties on chemotaxis, CD11b/CD18 expression, phagocytosis and chemiluminescence of isolated human polymorphonuclear neutrophils (PMNs). METHODS: The extract was analyzed quantitatively by performing a validated reversed phase high performance liquid chromatography (RP-HPLC). Zerumbone was isolated by chromatographic technique while the essential oil was acquired through hydro-distillation of the rhizomes and further analyzed by gas chromatography (GC) and GC-MS. Chemotaxis assay was assessed by using a 24-well cell migration assay kit, while CD18 integrin expression and phagocytic engulfment were measured using flow cytometry. The reactive oxygen species (ROS) production was evaluated by applying lucigenin- and luminol-enhanced chemiluminescence assays. RESULTS: Zerumbone was found to be the most abundant compound in the extract (242.73 mg/g) and the oil (58.44%). Among the samples tested, the oil revealed the highest inhibition on cell migration with an IC50 value of 3.24 µg/mL. The extract, oil and zerumbone showed moderate inhibition of CD18 integrin expression in a dose-dependent trend. Z. zerumbet extract showed the highest inhibitory effect on phagocytic engulfment with percentage of phagocytizing cells of 55.43% for PMN. Zerumbone exhibited strong inhibitory activity on oxidative burst of zymosan- and PMA-stimulated neutrophils. Zerumbone remarkably inhibited extracellular ROS production in PMNs with an IC50 value of 17.36 µM which was comparable to that of aspirin. CONCLUSION: The strong inhibition on the phagocytosis of neutrophils by Z. zerumbet extract and its essential oil might be due the presence of its chemical components particularly zerumbone which was capable of impeding phagocytosis at different stages.

Immunosuppressive effects of the standardized extract of Zingiber zerumbet on innate immune responses in Wistar rats.

Zingiber zerumbet rhizome has been used in traditional medicine mainly for the treatment of various immune-inflammatory related ailments and has been shown to exhibit a wide spectrum of biological effects especially antioxidant and anti-inflammatory activities. The present study was aimed to investigate the immunosuppressive effects of the standardized 80% ethanol extract of Z. zerumbet at 100, 200, and 400 mg/kg on the innate immune responses in male Wistar rats. The immune parameters determined were chemotaxis of neutrophils, Mac-1 expression, engulfment of Escherichia coli by neutrophils, reactive oxygen species production, and plasma lysozyme and ceruloplasmin levels. Zerumbone was qualitatively and quantitatively determined in the extract by using a validated reversed-phase HPLC, whereas liquid chromatography tandem-mass spectrometry (LC -MS/MS) was used to profile the secondary metabolites. Z. zerumbet significantly inhibited the migration of neutrophils, expressions of CD11b/CD18 integrin, phagocytic activity, and production of reactive oxygen species in a dose-dependent manner. The extract also dose-dependently inhibited the expressions of lysozyme and ceruloplasmin in the rat plasma. Z. zerumbet extract possessed strong inhibitory effects on the innate immune responses and has potential to be developed into an effective immunosuppressive agent.

EVALUATION OF ANTI-DIABETIC EFFECTS OF POLY-HERBAL PRODUCT "DIABETIC BAL" IN ALLOXAN-INDUCED DIABETIC RABBITS.

The current study was conducted to evaluate the anti-diabetic effect of polyherbal product "diabetic bal" in normal and alloxan induced diabetic rabbits. Glibenclamide was used as standard drug. Diabetes was induced by single i.v. injection of 150 mg/kg b.w. of alloxan monohydrate in rabbits. "Diabetic bal" (250 and 500 mg/kg) significantly decreased the blood glucose level both in normal and diabetic rabbits in dose dependent manner. In oral glucose tolerance test, "Diabetic bal" demonstrated a significant inhibitory effect on rise of blood glucose level compared to control. "Diabetic bal" showed synergistic anti-hyperglycemic effect with dif- ferent units of insulin in diabetic rabbits. The "diabetic bal" decreased the glucose level and prevented the weight loss of diabetic rabbits as compared to control for an extended period of one month. It caused a significant increase (p < 0.001) in the insulin level of treated diabetic rabbits in 30 days study. In addition AST, ALT, ALP, cholesterol, LDLs, VLDLs and triglyceride level were significantly reduced whereas HDLs level was sig- nificantly elevated in diabetic rabbits with 500 mg/kg dose. The herbal product did not cause any significant change in CBC as compared to normal control in diabetic rabbits for one month. It is conceivable; therefore, that "diabetic bal" is effective in diabetes and its associated complications which support its use in folklore.

Friedelin and Glutinol induce neuroprotection against ethanol induced neurotoxicity in pup's brain through reduction of TNF-α, NF-kB, caspase-3 and PARP-1.

Ethanol administration triggers an inflammatory response that leads to a complex series of immune responses including the release of an excessive amount of inflammatory mediators particularly tumor necrosis factor (TNF-α) and nuclear factor-kB (NF-KB) which produce a large amount of reactive oxygen species. The inflammatory-induced cytotoxicity is increased when the PI3-kinase/Akt pathway is inhibited. Some studies have also shown that ethanol suppresses the PI3-kinase signaling pathway induced by receptor activation. Friedelin and Glutinol belong to pentacyclic triterpenoid class and are known for their anti-inflammatory and antioxidant properties. The present study was aimed to elucidate the effects of these phytoconstituents on one of the key ethanol-induced neuronal damage pathways. The pups having (5-7 g average body weight) were used and randomly divided into groups. The control and ethanol treated pups were administered 0.9% normal saline while treated pups received glutinol and friedelin (30 mg/kg subcutaneously) respectively. After four hours all the experimental animals were sacrificed and their brains were collected carefully for protein expression analysis of p-Akt, TNF-α, NF-KB, caspase-3 and PARP-1 employing immunoblotting technique. Hemolytic, DNA protection, chelating power and ß-carotene assays results revealed that freidelin and glutinol are safe for parenteral administration. Glutinol administration with ethanol significantly abridged the ethanol induced over expression of TNF-α, caspase-3 and PARP-1 in pup's brain. Similarly, freidelin attenuated the neurodegeneration by inhibiting the ethanol induced p-JNK and NF-kB expression in pups' brain. This protection may be attributed to the revival of p-Akt signaling for cell survival. It is concluded that the present study demonstrates the neuro-protective effects of friedelin and glutinol via modulating the capase-3 and PARP-1 expression and modulating the neuronal apoptotic pathways.

Immunosuppressive Effects of Annona muricata L. Leaf Extract on Cellular and Humoral Immune Responses in Male Wistar Rats.

BACKGROUND: Annona muricata L. (Annonaceae) (AM)'s remarkable anti-inflammatory and anti-cancer activities make it a targeted plant to be explored for its immunomodulatory properties. Traditional practitioners have employed various components of AM to cure a variety of ailments, including cancer, diabetes, and inflammation. OBJECTIVE: The present study evaluated the immunosuppressive effects of 80% ethanol extract of of AM leaves in male Wistar rats on different parameters of humoral and cellular immune responses. METHODS: AM leaf extract (AMLE) was analyzed using UHPLC-MS/MS to profile its secondary metabolites. AMLE was rich in polyphenols which include (epi)catechin-(epi)catechin-(epi) catechin, caffeic acid, coumaroylquinic acid, hyperin, kaempferol, quinic acid and rutin. The rats were administered 100, 200 and 400 mg/kg bw of the extract daily for 14 days. The effects of AMLE on innate immune responses were determined by evaluating phagocytosis, neutrophils migration, reactive oxygen species (ROS) release, CD11b/CD18 integrin expression, and ceruloplasmin, lysozyme and myeloperoxidase (MPO) levels. The adaptive immune parameters were evaluated by immunizing the rats with sheep red blood cells (sRBC) on day 0 and administered orally with AMLE for 14 days. RESULTS: AMLE established significant immunosuppressive effects on the innate immune parameters by inhibiting the neutrophil migration, ROS production, phagocytic activity and expression of CD11b/CD18 integrin in a dose-dependent pattern. AMLE also suppressed ceruloplasmin, MPO and lysozyme expressions in the rat plasma dose-dependently. AMLE dose-dependently inhibited T and B lymphocytes proliferation, Th1 and Th2 cytokine production, CD4+ and CD8+ co-expression in splenocytes, immunoglobulins (IgM and IgG) expression and the sRBC-induced swelling rate of rat paw in delayed-type hypersensitivity (DTH). CONCLUSION: The strong inhibitory effects on the different parameters of humoral and cellular responses indicate that AMLE has potential to be an important source of effective immunosuppressive agents.

Pharmacological insights into Merremia vitifolia (Burm.f.) Hallier f. leaf for its antioxidant, thrombolytic, anti-arthritic and anti-nociceptive potential.

Merremia vitifolia (Burm.f.) Hallier f., an ethnomedicinally important plant, used in the tribal areas to treat various ailments including fever, headache, eye inflammation, rheumatism, dysentery, jaundice and urinary diseases. The present study explored the biological efficacy of the aqueous fraction of M. vitifolia leaves (AFMV) through in vitro and in vivo experimental models. The thrombolytic and anti-arthritic effects of AFMV were evaluated by using the clot lysis technique and inhibition of protein denaturation technique, respectively. The anti-nociceptive activity of AFMV was investigated in Swiss Albino mice by acetic acid-induced writhing test and formalin-induced paw licking test. The antioxidant activities of AFMV, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical and total reducing power, were also tested. The qualitative phytochemical assays exhibited AFMV contains secondary metabolites such as alkaloid, carbohydrate, flavonoid, tannin, triterpenoids and phenols. In addition, AFMV showed strong antioxidant effects with the highest scavenging activity (IC50 146.61 µg/mL) and reducing power was increased with a dose-dependent manner. AFMV also revealed notable clot lysis effect and substantial anti-arthritic activity at higher doses (500 µg/mL) as compared with the control. The results demonstrated a promising reduction of the number of writhing and duration of paw licking in acetic acid-induced writhing test and formalin-induced paw licking test in a dose-dependent manner, respectively. In conclusion, AFMV provides the scientific basis of its folkloric usage, suggesting it as the vital source of dietary supplement.

Dietary polyphenols suppress chronic inflammation by modulation of multiple inflammation-associated cell signaling pathways.

The high failure rate of the reductionist approach to discover effective and safe drugs to treat chronic inflammatory diseases has led scientists to seek alternative ways. Recently, targeting cell signaling pathways has been utilized as an innovative approach to discover drug leads from natural products. Cell signaling mechanisms have been identified playing key role in diverse diseases by inducing proliferation, cell survival and apoptosis. Phytochemicals are known to be able to modulate the cellular and molecular networks which are associated to chronic diseases including cancer-associated inflammation. In this review, the roles of dietary polyphenols (apigenin, kaempferol, quercetin, curcumin, genistein, isoliquiritigenin, resveratrol and gallic acid) in modulating multiple inflammation-associated cell signaling networks are deliberated. Scientific databases on suppressive effects of the polyphenols on chronic inflammation via modulation of the pathways especially in the recent five years are gathered and critically analyzed. The polyphenols are able to modulate several inflammation-associated cell signaling pathways, namely nuclear factor-kappa ß, mitogen activated protein kinases, Wnt/ß-catenin and phosphatidylinositol 3-kinase and protein kinase B via selective actions on various components of the networks. The suppressive effects of the polyphenols on the multiple cell signaling pathways reveal their potential use in prevention and treatment of chronic inflammatory disorders. Understanding the mechanistic effects involved in modulation of the signaling pathways by the polyphenols is necessary for lead identification and development of future functional foods for prevention and treatment of chronic inflammatory diseases.

An Insight Into the Modulatory Effects and Mechanisms of Action of Phyllanthus Species and Their Bioactive Metabolites on the Immune System.

Phyllanthus species (family; Euphorbiaceae) have been intensively studied for their immunomodulating effects due to their wide-ranging uses to treat immune-related diseases in indigenous medicine, which are primarily lack of scientific basis. The focuses of this review are on the significance of Phyllanthus species and their bioactive metabolites particularly corilagin (1), geraniin (2), gallic acid (3), phyllanthin (4), hypophyllanthin (5), ellagic acid (6), phyltetralin (7), niranthin (8), catechin (9), quercetin (10), astragalin (11), and chebulagic acid (12) in the modulation of both innate and adaptive immune systems through various mechanisms and their possible therapeutic benefits for treatment of immune-related diseases. We have compiled all significant findings published in the literature, and the data were analyzed critically to provide perspectives and directions for future research for the plants as a prospective source of novel immunomodulating agents. Various Phyllanthus species particularly Phyllanthus amarus, Phyllanthus emblica, Phyllanthus niruri, and Phyllanthus urinaria have been documented to possess significant immunomodulatory effects. However, the possible challenges encountered by the application of extracts of various Phyllanthus species and their bioactive constituents as immunomodulators need to be addressed. Most reports on the biological and pharmacological studies of the plants were based on crude extracts. The extracts were not chemically characterized, and the contributions of their chemical constituents to the bioactivities were not identified. The underlying mechanisms involved in the immunomodulatory effects of the Phyllanthus species were not indepthly studied due to limitations in terms of design, conduct, and interpretation. Extensive experimental and preclinical studies on the immunomodulating potential of Phyllanthus species should be carried out to provide sufficient data to prove that their traditional uses are inherently effective and safe and will allow clinical trials to be pursued for their further development as therapeutic agents to treat immune-related disorders.

Enhanced immunosuppressive effects of 3,5-bis[4(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one, an α, ß-unsaturated carbonyl-based compound as PLGA-b-PEG nanoparticles.

Background: 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one (BBP), a novel synthetic curcumin analogue has been revealed to possess strong in vitro and in vivo immunosuppressive effects. Purpose: The aim of present study was to prepare and characterize BBP-encapsulated polylactic-co-glycolic acid-block-polyethylene glycol (PLGA-b-PEG) nanoparticles and to evaluate its in vivo efficacy against innate and adaptive immune responses. Methods: Male BALB/c mice were orally administered with BBP alone and BBP- encapsulated nanoparticles equivalent to 5, 10 and 20 mg/kg of BBP in distilled water for a period of 14 days. The immunomodulatory potential was appraised by determining its effects on non-specific and specific immune parameters. Results: The results showed that BBP was successfully encapsulated in PLGA-b-PEG polymer with 154.3 nm size and high encapsulation efficiency (79%) while providing a sustained release for 48 hours. BBP nanoparticles showed significant enhanced dose-dependent reduction on the migration of neutrophils, Mac-1 expression, phagocytic activity, reactive oxygen species (ROS) production, serum levels of ceruloplasmin and lysozyme, immunoglobulins and myloperoxidase (MPO) plasma levels when compared to unencapsulated BBP. Enhanced dose-dependent inhibition was also observed on lymphocyte proliferation along with the downregulation of effector cells expression and release of cytokines, and reduction in rat paw oedema in BBP nanoparticles treated mice. At higher doses the suppressive effects of the BBP nanoparticles on various cellular and humoral parameters of immune responses were comparable to that of cyclosporine-A at 20 mg/kg. Conclusion: These findings suggest that the immunosuppressive effects of BBP were enhanced as PLGA-b-PEG nanoparticles.

Zerumbone from Zingiber zerumbet inhibits innate and adaptive immune responses in Balb/C mice.

Zerumbone exhibited various biological properties including in vitro immunosuppressive effects. However, its modulatory activity on the immune responses in experimental animal model is largely unknown. This investigation was conducted to explore the effects of daily treatment of zerumbone (25, 50, and 100 mg/kg) isolated from Zingiber zerumbet rhizomes for 14 days on various cellular and humoral immune responses in Balb/C mice. For measurement of adaptive immunity, sheep red blood cells (sRBC) were used to immunize the mice on day 0 and orally fed with similar doses of zerumbone for 14 days. The effects of zerumbone on phagocytosis, nitric oxide (NO) release, myeloperoxidase (MPO) activity, proliferation of T and B cells, lymphocyte phenotyping, cytokines release in serum by activated T cells, delayed type hypersensitivity (DTH) and immunoglobulins production (IgG and IgM) were investigated. Zerumbone downregulated the engulfment of E. coli by peritoneal macrophages and the release of NO and MPO in a concentration-dependent manner. Zerumbone showed significant and concentration-dependent suppression of T and B lymphocytes proliferation and inhibition of the Th1 and Th2 cytokines release. At higher concentrations of zerumbone, the % expression of CD4+ and CD8+ in splenocytes was significantly inhibited. Zerumbone also concentration-dependently demonstrated strong suppression on sRBC-triggered swelling of mice paw in DTH. Substantial suppression of anti-sRBC immunoglobulins antibody titer was noted in immunized and zerumbone-treated mice in a concentration-dependent manner. The potent suppressive effects of zerumbone on the immune responses suggest that zerumbone can be a potential candidate for development of immunosuppressive agent.

Exploring the Leaves of Annona muricata L. as a Source of Potential Anti-inflammatory and Anticancer Agents.

The use of anti-inflammatory natural products to treat inflammatory disorders for cancer prevention and therapy is an appealing area of interest in the last decades. Annona muricata L. is one of the many plant extracts that have been explored owing to their anti-inflammatory and anticancer effects. Different parts of A. muricata especially the leaves have been used for various ethnomedicinal purposes by traditional healers to treat several diseases including cancer, inflammation, diabetes, liver diseases, and abscesses. Some of these experience-based claims on the use of the plant have been transformed into evidence-based information by scientific investigations. The leaves of the plant have been extensively investigated for its diverse pharmacological aspects and found eminent for anti-inflammatory and anticancer properties. However, most studies were not on the bioactive isolates which were responsible for the activities but were based on crude extracts of the plant. In this comprehensive review, all significant findings from previous investigations till date on the leaves of A. muricata, specifically on their anti-inflammatory and anticancer activities have been compiled. The toxicology of the plant which has been shown to be due to the presence of neurotoxic annaceous acetogenins and benzyltetrahydro-isoquinoline alkaloids has also been updated to provide recent information on its safety aspects. The present knowledge of the plant has been critically assessed, aimed at providing direction toward improving its prospect as a source of potential anti-inflammatory and anticancer agents. The analysis will provide a new path for ensuring research on this plant to discover new agents to treat inflammatory diseases and cancer. Further in vitro and in vivo studies should be carried out to explore the molecular mechanisms underlying their anti-inflammatory responses in relation to anticancer activity and more detail toxicity study to ensure they are safe for human consumption. Sufficient preclinical data and safety data generated will allow clinical trials to be pursued on this plant and its bioactive compounds.

3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one, a Novel Curcumin Analogue, Inhibits Cellular and Humoral Immune Responses in Male Balb/c Mice.

BACKGROUND: 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one (BBP), a novel synthetic curcumin analogue has previously been shown to manifest potent immunosuppressive effects on the in vitro phagocytosis process of human neutrophils. OBJECTIVE: In the present study, BBP was investigated for it's in vivo innate and adaptive immune responses mediated by different humoral and cellular immune factors. METHODS: Male Balb/c mice were orally fed with BBP (5, 10 and 20 mg/kg) for a period of 14 days and immunized with sheep red blood cells (sRBC) on day 0 for the determination of adaptive responses. The effects of BBP on phagocytosis process of neutrophils isolated from blood of treated/untreated animals were determined. The ceruloplasmin and lysozyme serum levels and myeloperoxidase (MPO) plasma level were also monitored. The mechanism was further explored by assessing its effects on the proliferation of T and B lymphocytes, T-lymphocytes subsets CD4+ and CD8+ and on the secretion of Th1/Th2 cytokines as well as serum immunoglobulins (IgG, IgM) and delayed type hypersensitivity (DTH) reaction. RESULTS: BBP showed a significant dose-dependent reduction on the migration of neutrophils, Mac-1 expression, phagocytic activity and reactive oxygen species (ROS) production. In comparison to the sensitized control group, a dose-dependent inhibition was observed on lymphocyte proliferation along with the downregulation of effector cells expression and release of cytokines. Moreover, a statistically significant decrease was perceived in serum levels of ceruloplasmin, lysozyme and immunoglobulins and MPO plasma level of BBP-treated mice. BBP also dose-dependently inhibited sheep red blood cells (sRBC)-induced swelling rate of mice paw in DTH. CONCLUSION: These findings suggest the potential of BBP as a potent immunosuppressive agent.

Immunosuppressive Effects of Natural α,ß-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,ß-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,ß-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,ß-unsaturated carbonyl-based compounds on immune cells to provide useful information for ensuing research to discover new immunomodulating agents.

Exploring the immunomodulatory and anticancer properties of zerumbone.

Plant-derived immunomodulators and anti-cancer agents have attracted a lot of interest from natural product scientists for their efficacy and safety and their significant contribution towards understanding targeted drug action and drug delivery mechanisms. Zerumbone, the main constituent of Zingiber zerumbet rhizomes, has been investigated for its wide-spectrum role in treating multitargeted diseases. The rhizomes have been used as food flavoring agents in various cuisines and in herbal medicine. Many in vivo and in vitro studies have provided evidence of zerumbone as a potent immunomodulator as well as a potential anti-cancer agent. This review is an interesting compilation of all those significant outcomes from investigations carried out to date to explore the immunomodulatory and anticancer properties of zerumbone. The ultimate objective of this comprehensive review is to provide updated information and a critical assessment on zerumbone including its chemistry and immunomodulating and anticancer properties, which may be of paramount importance to provide a new path for ensuing research to discover new agents to treat cancers and immune-related diseases. In addition, updated information on the toxicology of zerumbone has also been summarized to provide its safety profile.