Amomum subulatum fruits protect against radiation-induced esophagitis by regulating antioxidant status and inflammatory responses.

Radiation esophagitis (RE) is an inimical event that requires proper management while carrying out radiotherapy for thoracic cancers. The present study investigates the protective effect of dry fruits of the culinary and folkloric spice Amomum subulatum against experimental thoracic radiation-induced esophagitis. C57BL/6 mice were subjected to 25 Gy whole thorax irradiation and administered with 250 mg/kg body weight of methanolic extract of A. subulatum dry fruits (MEAS) orally for four consecutive weeks. Changes in tissue antioxidant activities, oxidative stress parameters, expression of antioxidant, inflammation, and fibrosis-related genes were observed. Administration of MEAS boosted antioxidant status, thereby reducing radiation-induced oxidative stress in the esophagus. PCR (polymerase chain reaction) results showed decreased expression of apoptosis, inflammation, and fibrosis-associated genes as well as increased expression of vital cytoprotective and antioxidant genes in MEAS-treated mice, manifesting its protective effect against radiation-induced oxidative stress, inflammatory responses, and fibrosis in the esophagus. Further, histopathology, immunohistochemistry (Cyclooxygenase-2), and Masson's Trichrome staining ascertained the protective effect of MEAS in alleviating radiation-induced esophageal injury. The synergistic effect of bioactive phytochemicals in MEAS with potent antioxidant and anti-inflammatory efficacies might have contributed to its mitigating effect against RE. Taken together, our results ascertained the radioprotective potential of MEAS, suggesting its possible nutraceutical application as a radiation countermeasure.

Pathological Implications of Mucin Signaling in Metastasis.

The dynamic mucosal layer provides a selective protective barrier for the epithelial cells lining the body cavities. Diverse human malignancies exploit their intrinsic role to protect and repair epithelia for promoting growth and survival. Aberrant expression of mucin has been known to be associated with poor prognosis of many cancers. However, the emergence of new paradigms in the study of metastasis recognizes the involvement of MUC1, MUC4, MUC5AC, MUC5B, and MUC16 during metastasis initiation and progression. Hence mucins can be used as an attractive target in future diagnostic and therapeutic strategies. In this review, we discuss in detail about mucin family and its domains and the role of different mucins in regulating cancer progression and metastasis. In addition, we briefly discuss insights into mucins as a therapeutic agent.

Amomum subulatum mitigates experimental thoracic radiation-induced lung injury by regulating antioxidant status and inflammatory responses.

Radiation-induced lung injury (RILI) is one of the most prominent complications of thoracic radiotherapy for which effective therapy is still lacking. This study investigates the nutraceutical potential of the culinary spice Amomum subulatum in mitigating thoracic radiation-induced pneumonitis (RP) and pulmonary fibrosis (PF). Mouse models of RP and PF were established by whole thorax irradiation at a dose of 25 gray. C57BL/6 mice were administered with 250 mg per kg body weight of methanolic extract of A. subulatum dry fruits (MEAS) for four consecutive weeks and observed for changes in lung tissue antioxidant activities, oxidative stress parameters, and expression of antioxidant, inflammation, and fibrosis-related genes by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR analysis, and histology analysis. MEAS administration reduced radiation-induced oxidative stress by enhancing the expression of Nrf2 and its target genes. Irradiation increased gene expression of inflammatory mediators and lung histology further confirmed the characteristics of RP, which were reduced by MEAS treatment. Immunohistochemistry analysis revealed the potential of MEAS in reducing the radiation-induced elevation of cyclooxygenase 2 expression in the lungs. The late sequel of RILI was manifested as PF, characterized by the elevated expression of pro-fibrotic genes and increased collagen content. However, MEAS administration markedly reduced radiation-induced fibrotic changes in the lungs. These effects might be attributed to the synergistic effect of bioactive polyphenols in MEAS with antioxidant, anti-inflammatory, and anti-fibrotic efficacies. Taken together, this study demonstrates the potential of MEAS in mitigating RILI, suggesting the possible nutraceutical application of A. subulatum against radiation toxicities.

Pithecellobium dulce inhibits pulmonary metastasis induced by B16F10 melanoma cells in C57BL/6 via regulating EGFR/STAT/ NFκB /AKT signaling axis.

In this present study we analyzed anti-metastatic efficacy of fruit extract of Pithecellobium dulce (FPD) against B16F10 induced pulmonary metastatic model. FPD administration significantly (p < .01) reduced lung fibrosis, as evidenced by histochemical collagen analysis by Masson's trichome staining, total collagen, hexosamine, and uronic acid. Results showed that FPD treatment significantly attenuated the expression of EGFR mediated P38 and STAT1/3 expression, thus reduced NFκB mediated signaling cascade. Further, the expression of PIP3CA mediated activation of the AKT survival signaling pathway has been analyzed. Interestingly, in FPD treated group, the expression of AKT pathway has also downregulated. Further, we analyzed the downstream regulators of NFκB and AKT signaling pathways, which include, inflammatory genes (iNOS, COX2, NFκB, TGFß1, IL5, IL1ß, IFNγ, IL6, IL10, MCP1, GMCSF), anti-apoptotic genes (BCL2 and BCLXL), cell cycle regulators (cyclin D1 and Ki67), fibrosis activator (CT1α1), angiogenesis promoter (VEGF), metastatic promoter (MMP2/9, N CADH), mucin (MUC5AC), pro-apoptotic genes (Bax, CAS3 and CAS9) and metastasis inhibitors (TIMP1/2, E CADH, p53, PTEN). The expression of inflammatory, anti-apoptotic, cell cycle regulators, fibrosis activator, angiogenesis and metastasis promoter, and mucins were markedly reduced by FPD administration. Interestingly, the level of expression of anti-metastatic genes were markedly elevated in FPD administrated group. Lung histopathology further confirmed the anti-metastatic efficacy of FPD. PRACTICAL APPLICATIONS: Different parts of P. dulce has long been used as a folklore medicine against different diseases. This study demonstrated that bioactive constituents present in the fruit extract of P. dulce (FPD) significantly attenuated proliferation via regulating EGFR/STAT/NFκB/AKT signaling axis.

Potential role of cGAS/STING pathway in regulating cancer progression.

The activation of innate immune response after the engagement of dsDNA is an evolutionarily preserved sophisticated strategy against invading microbial pathogens. cGAS has been identified as one of the major dsDNA sensor present in the cytoplasm which catalyzes the synthesis of a cyclic dinucleotide 2'3'cGAMP, as the secondary messenger that binds and activates the downstream stimulator of interferon (IFN) genes (STING) for subsequent production of type 1 IFNs and other inflammatory genes. Recent progress in the mechanical understanding of cGAS/STING signalling has unveiled its intricate role in tumor progression and metastasis. In this review, we specifically focus on new developments concerning the role of cGAS/STING signalling in regulating antitumorigenesis and tumorigenesis.

Amomum subulatum mitigates total body irradiation-induced oxidative stress and its associated inflammatory response by enhancing the antioxidant status and regulating the pro-inflammatory cytokines.

Free radical-induced oxidative damage and associated inflammatory responses play a crucial role in cancer radiotherapy (RT) mediated normal tissue toxicities. Supplementation of antioxidants or inflammation modulators may alleviate RT toxicity, thereby improving clinical outcomes. Amomum subulatum is a dietary spice rich in biologically active phytochemicals. The present study investigates radiation dose-modifying factor (DMF) and radioprotective efficacy of methanolic extract of Amomum subulatum dry fruits (MEAS) in mice exposed to different doses of total body irradiation (TBI). Administration of MEAS resulted in a DMF of 1.25 Gy, ascertaining its radioprotective efficacy. MEAS reversed X-ray-induced redox imbalance by enhancing antioxidant defense mechanisms. MEAS prevented TBI-induced hematopoietic damages by significantly (P<.01) enhancing bone marrow cellularity, total white blood cell count, and hemoglobin level. MEAS prevented p53-mediated apoptotic death of intestinal cells and increased the expression of cytoprotective genes Nrf2 (nuclear factor-erythroid factor 2-related factor 2) and HO-1 (heme oxygenase-1). Expression of apoptosis regulating genes revealed that MEAS reduced radiation-induced apoptotic death of intestinal cells. Treatment with MEAS also reduced inflammatory responses via reversing TBI-induced elevation in serum pro-inflammatory cytokine (TNF-α, IL-1ß, IL-6) levels. Tissue histopathology further confirmed the protective effect of MEAS against TBI-induced inflammatory responses, suggesting the potential of MEAS in modulating inflammation. These effects might perhaps be attributed to the synergistic effect of biologically active polyphenols with antioxidant, anti-inflammatory, and Nrf2 activating potential in MEAS. Our findings demonstrated the radioprotective efficacy of MEAS, suggesting the possible nutraceutical application of Amomum subulatum in modulating oxidative stress and inflammation.

Pithecellobium dulce induces apoptosis and reduce tumor burden in experimental animals via regulating pro-inflammatory cytokines and anti-apoptotic gene expression.

The present study demonstrates the efficacy of fruit extract of Pithecellobium dulce (FPD) against Dalton's lymphoma ascites (DLA) cell lines in vitro and in vivo (DLA induced ascitic and solid tumor). Administration of FPD induced apoptosis in DLA cells via p53 regulation both in vitro and in vivo. Cell viability was quantified by MTT assay. Apoptotic cells were determined by qualitative (staining methods) and quantitative analysis (Annexin-propidium iodide based flow cytometry). Expression of pro-apoptotic markers (Caspase 3, Caspase 9, and Bax) were markedly elevated, while expression of anti-apoptotic proteins (Bcl 2 and Bcl XL) were downregulated in tumor cells. FPD administration effectively reduced tumor burden, increased mean survival time via modulating NF-kB, and reduced the level of proinflammatory cytokines (IL-6, IL-1ß, GM-CSF and TNF-α). Phytochemical screening of FPD by GC/MS analysis divulged the presence of several novel bioactive chemical constituents. Further, bioactive components identified from extract were evaluated for drug-like properties by Lipinski rule of five and properties. Naringenin, nootkatone, and gallic acid showed good drug-like properties and good pharmacokinetic profiles compared to other bioactive constituents in the extract.

Antioxidant-rich fraction of Amomum subulatum fruits mitigates experimental methotrexate-induced oxidative stress by regulating TNF-α, IL-1ß, and IL-6 proinflammatory cytokines.

The culinary spice Amomum subulatum was assessed for its phytochemical composition, in vitro antioxidant potential, and in vivo ameliorating effect against methotrexate (MTX)-induced toxicities. Phytochemical analysis of methanolic extract of A. subulatum dry fruits (MEAS) confirmed the presence of different bioactive secondary metabolites. MEAS scavenged reactive free radicals and inhibited lipid peroxidation in vitro. To confirm the antioxidant efficiency of MEAS, in vivo experiment was carried out in which MTX was administered to induce oxidative stress. Co-administration of MEAS reduced MTX-induced hepatic, renal, and pulmonary toxicities via significantly (p < .01) enhancing antioxidant status and reducing oxidative stress. MTX treatment significantly (p < .01) increased liver and kidney toxicity markers and increased proinflammatory cytokine (TNF-α, IL-1ß, and IL-6) levels. However, co-administration of MEAS significantly (p < .01) reduced their levels, and tissue histopathology confirmed the protective effect of MEAS in maintaining normal tissue architecture following MTX treatment. Protective effect of MEAS is accredited to the antioxidant and anti-inflammatory properties exhibited by bioactive compounds in MEAS. PRACTICAL APPLICATIONS: Amomum subulatum (Black cardamom) is a folkloric and culinary spice used for its organoleptic, nutritional, and medicinal properties. This study demonstrated the phytochemical composition and antioxidant potential of methanolic extract of A. subulatum dry fruits (MEAS). Toxicities associated with MTX therapy limit its clinical application. MEAS attenuated methotrexate-induced oxidative stress, inflammation, and associated organ damages, suggesting the possible therapeutic application of A. subulatum in reducing oxidative stress and associated diseases. Our results showed that A. subulatum is a potential functional food, which may be used for the betterment of health due to its richness in antioxidant and anti-inflammatory phytochemicals.

Traditional knowledge to clinical trials: a review on nutritional and therapeutic potential of Pithecellobium dulce.

The review describes botanical aspects, bioactive phytocompounds and pharmacological properties of different parts of Pithecellobium dulce, with special emphasis on the nutritional status of its fruits. The different parts of plant extract have been reported to possess anti-oxidant, anti-inflammatory, anti-microbial, anti-diabetic, cardio protective, anti-diarrhoeal, anti-ulcerogenic, larvicidal and ovicidal activities. Different parts of plant extracts were reported to contain several bioactive phytocompounds such as flavonoids, saponins, tannins, alkaloids etc. Natural products discovered so far served as a viable source for new drugs. Over the past few years, continued and perpetual attention of people has been paid to medicinal plants in connection with its remarkable importance in drug discovery. Plant products always remains a drug of choice for the identification of novel leads despite facing a tough competition from existing synthetic alternatives derived from combinatorial chemistry, owing to their efficacy, side effects, and safety. P. dulce is a highly acclaimed genus in traditional system of medicine because of its versatile nutraceutical and pharmacological properties. In this review we discuss in detail about nutritional and various therapeutic properties of P. dulce.

Anti-Inflammatory Potential Exhibited by Amomum subulatum Fruits Mitigates Experimentally Induced Acute and Chronic Inflammation in Mice: Evaluation of Antioxidant Parameters, Pro-Inflammatory Mediators and HO-1 Pathway.

OBJECTIVE: Conventional anti-inflammatory drugs are associated with serious adverse effects which bring about an ever-increasing demand to supersede them with natural and safe anti-inflammatory agents. Hence, the prime objective of this study was to evaluate the anti- inflammatory potential of an underutilized culinary spice "Amomum subulatum". METHODS: To assess anti-inflammatory activity of MEAS, acute and chronic inflammation studies were carried out in carrageenan and formalin induced mice paw edema models respectively. Paw volume was measured by vernier caliper. Status of antioxidant enzymes and oxidative stress markers were determined in paw tissue homogenates following standard protocols. Histopathology and immunohistochemistry analysis of paw tissue samples were also performed. Levels of proinflammatory cytokines in serum were quantified by ELISA. Effect of MEAS on vascular permeability was evaluated by evans blue dye extravasation assay. Involvement of heme oxygenase (HO)-1 pathway in anti-inflammatory action of MEAS was investigated by pretreating mice with zinc protoporphyrin (ZnPP) IX, a specific inhibitor of HO-1. RESULTS: MEAS administration significantly reduced paw edema, as evidenced by paw volume measurement and histopathology analysis. Additionally, pretreatment with MEAS markedly reduced vascular permeability, serum proinflammatory cytokine levels, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Further, the anti-inflammatory mechanism of MEAS showed the involvement of HO-1 pathway when HO-1 was inhibited by ZnPPIX. CONCLUSION: Our results manifested strong anti-inflammatory activity of MEAS, suggesting its potential use as a therapeutic alternative for treating inflammatory disorders.

Fruit Extract of Pithecellobium dulce (FPD) ameliorates carrageenan-induced acute inflammatory responses via regulating pro-inflammatory mediators.

Unravelling the precise mechanisms underlying the anti-inflammatory action of fruit extract of Pithecellobium dulce (FPD) is quite complex. Hence the prime approach of this particular study is to unveil intriguing insights to its possible anti-inflammatory mechanisms. Anti-inflammatory effects of FPD were determined against experimentally induced acute and chronic inflammation in mice paw edema models. Administration of FPD significantly reduced the acute and chronic inflammation via regulating pro-inflammatory mediators such as pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), Cycloxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS) compared to control group. The overall results suggest that FPD mitigates inflammation by regulating the inflammatory mediators. PRACTICAL APPLICATIONS: Fruit of Pithecellobium dulce is comestible and has been widely distributed in Asian pacific region. Non-steroidal anti-inflammatory drugs (NSAIDS) are among the most conventional treatment strategy against pain and inflammation. Although, chronic use of NSAIDS are associated with severe side effects such as gastrointestinal irritation, hepatic injury, excessive bleeding, and cardiovascular disorders. Hence identification of more effective complementary and alternative therapeutic approach from natural resources with fewer side effects could improve the quality of life of those receiving NSAIDS. Administration of fruit extract of Pithecellobium dulce ameliorates carrageenan-induced acute inflammatory responses, as evidenced by paw edema measurement, expression of antioxidant enzymes such as glutathionine, super oxide dismutase, pro-inflammatory cytokine analysis (IL-1ß, IL-6, and TNF-α), vascular permeability measurement, expression of COX-2 and iNOS. Further, confirmed the involvement of HO-1 pathway in anti-inflammatory action of FPD. The outcome of this present investigation could have a broad range of applications in alleviating inflammatory disorders.

Pithecellobium dulce fruit extract mitigates cyclophosphamide-mediated toxicity by regulating proinflammatory cytokines.

Pithecellobium dulce (Family: Fabaceae) is an edible fruit widely used in Asian-Pacific region. In the present study, we had investigated the protective effect of P. dulce fruit extract in mitigating harmful effects of the chemotherapeutic drug, cyclophosphamide (CTX). Our results showed that P. dulce treatment could significantly (p < .01) overcome CTX-induced immunosuppression accompanied with urotoxicity, hepatotoxicity, and nephrotoxicity in experimental animals. This was supported by histopathological data which proved that toxic effects of CTX in urinary bladder walls, liver, and kidney were markedly inhibited with P. dulce administration. Further, we observed significant alterations in in situ formation or release of granulocyte-macrophage colony-stimulation factor (GM-CSF) and interferon gamma (IFN ɤ) in the P. dulce treated group compared with cyclophosphamide control group. The outcome of the study could have wide range of applications in combating chemotherapy-associated malnutrition as well as in cancer drug development. PRACTICAL APPLICATIONS: CTX is a commonly used broad spectrum chemotherapeutic drug with severe side effects including immune suppression, malnutrition, urotoxicity, and nephrotoxicity. Identification of a novel immunomodulator from natural sources can resolve these side effects and could improve the quality of life of cancer patients receiving CTX as chemotherapeutic drug. In the present study, we had proved that P. dulce administration could significantly reduce CTX-induced immunotoxicity, urothelial toxicity, and nephrotoxicity. Administration of P. dulce showed a pronounced improvement in total leukocyte count, bone marrow cellularity/α-esterase activity, expression of antioxidant glutathione and cytokines (GM-CSF and INF-ɤ) compared to CTX-treated mice group. Further, histopathological analysis confirmed the protective efficacy of P. dulce against CTX-induced urothelial, hepato and kidney damage. These insights are fostering new combinational therapeutic approaches to cancer treatment.

Mucins: Structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets.

Mucins are the main structural components of mucus that create a selective protective barrier for epithelial surface and also execute wide range of other physiological functions. Mucins can be classified into two types, namely secreted mucins and membrane bounded mucins. Alterations in mucin expression or glycosylation and mislocalization have been seen in various types of pathological conditions such as cancers, inflammatory bowel disease and ocular disease, which highlight the importance of mucin in maintaining homeostasis. Hence mucins can be used as attractive target for therapeutic intervention. In this review, we discuss in detail about the structural diversity of mucins; their biosynthesis; its role in pathogenesis; regulation and as possible therapeutic targets.