Grape seed proanthocyanidin extract alleviates inflammation in experimental colitis mice by inhibiting NF-κB signaling pathway.

Ulcerative colitis (UC) is a complex inflammatory disease of colorectum that induces abnormal immune responses and severely affects the quality of life of the patients. Grape seed proanthocyanidin extract (GSPE) exerts anti-inflammatory and antioxidant functions in many inflammatory diseases. The objective of this study was to investigate the potential therapeutic effects and underlying mechanisms of GSPE in UC using a dextran sodium sulfate (DSS)-induced mouse UC model and a lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage model. In this study, we found that the GSPE markedly prevented DSS-induced weight loss and colon length shortening in UC mice. Further investigations showed that GSPE significantly attenuated the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß, and elevated the expression of anti-inflammatory cytokine IL-10 in the colon tissues and serum of DSS-induced colitis mice by suppressing NF-κB signaling pathway. Furthermore, LPS-induced inflammation in RAW264.7 cells was also reversed by GSPE. Taken together, our results confirm that GSPE can ameliorate inflammatory response in experimental colitis via inhibiting NF-κB signaling pathway. This study advances the research progress on a potentially effective therapeutic strategy for inflammatory bowel diseases.

A comparative study of in vivo toxicity in zebrafish embryos synthesized CuO nanoparticles characterized from Salacia reticulata.

The Salacia reticulata, a medicinal woody climbing shrub, was utilized for our study, the green synthesis of CuO nanoparticles, which were analyzed through SEM, EDX, FTIR, XRD, and UV‒Vis spectroscopy. This study assessed the toxicity to zebrafish embryos and explored the antibacterial, cytotoxic, antidiabetic, and anti-inflammatory properties of the synthesized nanoparticles. In results, the UV absorption of the CuO NPs showed that the intensity of nanoparticle green colloidal suspension changed from blue to green, which also confirmed that the spectrum of the green CuO NPs changed from colorless to black. in FT-IR and XRD spectral analysis to identify functional groups and determine the particle size of CuO NPs prepared by green and chemical methods. Its showed that CuO NPs (green) had a size of approximately 42.2 nm, while CuO NPs (chemical) had a size of approximately 84 nm. The morphology of these NPs was analyzed using SEM-EDX. Compared with their chemically prepared counterparts, the green-synthesized CuO nanoparticles demonstrated superior dispersion. Additionally, both green and chemical CuO nanoparticles at a concentration of 200 µL/mL caused developmental anomalies and increased mortality in zebrafish embryos and larvae. The green and chemical CuO NPs inhibited α-glucosidase enzyme activity at concentrations between 10 and 50 µL/mL, with IC50 values of 22 µL/mL and 26 µL/mL, respectively. The extract exhibited anti-inflammatory activity, with IC50 values of 274 and 109 µL/mL. The authors concluded that this green nanoparticle method has potential as a more eco-friendly and cost-effective alternative to traditional synthetic methods. NPs are widely used in human contact fields (medicine and agriculture), hence synthesis methods that do not involve toxic substances are becoming increasingly important.

Alkaloids in Withania somnifera (L.) Dunal Root Extract Contribute to Its Anti-Inflammatory Activity.

The anti-inflammatory properties of the medicinal plant Withania somnifera (L.) Dunal (WS) are generally related to withanolides; consistently, several strategies are under investigation to increase the concentration of these compounds in WS extracts. However, a potential toxicity of withanolides has been highlighted, thus questioning the safety of such preparations. At variance, the relative contribution of alkaloids is underrated, in spite of preliminary evidence underlining a possible pharmacological relevance. Starting from these considerations, the efficacy/safety profile of WS root extract (WSE) was compared with those of WS extracts which are enriched in alkaloids (WSA) and withanolides (WSW), respectively. MTT assay was used to evaluate cell viability. The anti-inflammatory activities of the different extracts were estimated throughout the assessment of the inhibition of lipopolysaccharide (LPS)-activated release of nitric oxide (NO) and the upregulation of iNOS and COX-2 protein in RAW 264.7 cells. Both WSA and WSW were able to reduce LPS-mediated effects in RAW 264.7 cells, suggesting that alkaloids and withanolides may contribute to the anti-inflammatory activity of WSE. A significant higher anti-inflammatory activity and a lower toxicity were observed when WSA was compared to WSW. The present results highlighted that the contribution of alkaloids to WS pharmacological effects should not be neglected. Particularly, these compounds may concur to reach a more advantageous efficacy/safety profile when WS is used for anti-inflammatory purposes.

Intramuscular compatibility of an injectable anti-inflammatory nanodispersion from a standardized Bixa orellana oil (Chronic®): a toxicological study in Wistar rats.

Bixa orellana L. is a plant popularly known as "ucurum", "annatto", and "achiote". It is native to South America, and its seeds are an abundant source of geranylgeraniol and tocotrienols. Nanoencapsulation is a valuable technique that can decrease the drug needed to achieve an effect, decreasing potential toxicity, side effects and potentiate the anti-inflammatory effect. This study aimed to evaluate the acute toxicity of an intramuscular application of a nanodispersion containing a standardized extract from the seeds of Bixa orellana (NBO) in Wistar rats. The chemical evaluation showed δ-tocotrienol at 0.725 ± 0.062 mg/mL (72.6 ± 0.9%). The stability study showed the nanoparticles had an average size from 53.15 ± 0.64 to 59.9 ± 3.63 nm, with a polydispersity index ranging from 0.574 ± 0.032 to 0.574 ± 0.32, Zeta potential from 18.26 ± 0.59 to 19.66 ± 1.45 mV. After testing the intramuscular application of NBO with doses from 1 to 5 mg/kg in animals, it was observed that the acute treatment did not elicit any toxic effects within this range. The dose of 10 mg/kg, although not affecting hematological and biochemical parameters (CPK, LDH, myoglobin, AST, ALT, TC, TG, glucose levels, creatinine, and urea), could induce some muscle tissue changes, including leukocyte infiltration, morphological chances, and potentially necrosis. In conclusion, the results showed that the treatments devoided toxicity between 1 and 5 mg/kg.

Neuron-derived neurotrophic factor protects against dexamethasone-induced skeletal muscle atrophy.

Skeletal muscle atrophy caused by various conditions including aging, nerve damage, and steroid administration, is a serious health problem worldwide. We recently reported that neuron-derived neurotrophic factor (NDNF) functions as a muscle-derived secreted factor, also known as myokine, which exerts protective actions on endothelial cell and cardiomyocyte function. Here, we investigated whether NDNF regulates skeletal muscle atrophy induced by steroid administration and sciatic denervation. NDNF-knockout (KO) mice and age-matched wild-type (WT) mice were subjected to continuous dexamethasone (DEX) treatment or sciatic denervation. NDNF-KO mice exhibited decreased gastrocnemius muscle weight and reduced cross sectional area of myocyte fiber after DEX treatment or sciatic denervation compared with WT mice. Administration of an adenoviral vector expressing NDNF (Ad-NDNF) or recombinant NDNF protein to gastrocnemius muscle of WT mice increased gastrocnemius muscle weight after DEX treatment. NDNF-KO mice showed increased expression of ubiquitin E3-ligases, including atrogin-1 and MuRF-1, in gastrocnemius muscle after DEX treatment, whereas Ad-NDNF reduced expression of atrogin-1 and MuRF-1 in gastrocnemius muscle of WT mice after DEX treatment. Pretreatment of cultured C2C12 myocytes with NDNF protein reversed reduced myotube diameter and increased expression of atrogin-1 and MuRF-1 after DEX stimulation. Treatment of C2C12 myocytes increased Akt phosphorylation. Pretreatment of C2C12 myotubes with the PI3-kinase/Akt inhibitor reversed NDNF-induced increase in myotube fiber diameter after DEX treatment. In conclusion, our findings indicated that NDNF prevents skeletal muscle atrophy in vivo and in vitro through reduction of ubiquitin E3-ligases expression, suggesting that NDNF could be a novel therapeutic target of muscle atrophy.

Protective effect of lupeol on arthritis induced by type II collagen via the suppression of P13K/AKT signaling pathway in Sprague dawley rats.

To explore the therapeutic value of lupeol on collagen-induced arthritis (CIA) in rats, a rheumatoid arthritis model. Lupeol is well known pentacyclic triterpene found in various plant sources, which possess anti-inflammatory and antioxidant actions. The current study was assessed the anti-arthritic potential of lupeol and its molecular mechanisms as compared with indomethacin (Indo) in collagen-induced arthritis CIA rats. The rats were randomly alienated into five groups: Control, CIA alone, CIA + lupeol (10 mg/kg bw), CIA + Indomethacin (3 mg/kg bw), and lupeol (10 mg/kg bw) alone. The paw volume, biochemical, hematological parameters, inflammatory enzymes, and cytokines were measured. As well protein expression of apoptotic proteins, and histopathological of ankle joint were examined. Inflammatory markers, cytokines, histological changes, paw volume, and inflammation were intensely reduced and enhanced apoptosis by lupeol. Alterations in hematological parameters, rheumatoid factor, C-reactive protein, and ceruloplasmin in arthritis were reverted by lupeol. Protein expressions of Bcl-2, and P13K/Akt signaling were declined, whereas the Bax, caspssae-3, and caspase-9 were elevated. These results highlighted that lupeol suppresses P13K/Akt signaling and has a promising anti-arthritic potential for collagen-induced rheumatic arthritis treatment. Hence lupeol would be suggested as an alternative natural source with potent anti-inflammatory and apoptotic actions for chronic inflammatory disorders.

A novel peptide identified from skin secretions of Bombina maxima possesses LPS-neutralizing activity.

Lipopolysaccharide (LPS) is a major pathogenic factor in endotoxin shock or sepsis. Most antibiotics have little clinical anti-endotoxin activity, but some antimicrobial peptides (AMPs) have been shown to be effective in blocking LPS. We identified a novel peptide from the skin secretions of Bombina maxima (B. _maxima) by challenging the skin of frogs with an LPS solution. Peptide 2 has an amino acid sequence of LVGKLLKGAVGDVCGLLPIC. Peptide 2 possesses low hemolytic activity, low cytotoxicity against RAW 264.7 cells, and strong anti-inflammatory activity. Moreover, peptide 2 plays an anti-inflammatory role by inhibiting inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). A biolayer interferometry (BLI) assay indicated that peptide 2 binds to LPS with strong affinity and that this interaction has an affinity constant (KD) value of 1.05 × 10-9 M. A survival study showed that peptide 2 possesses potent LPS-neutralizing activity to protect LPS-treated mice from death. In conclusion, we have identified a potent peptide with LPS neutralizing activity, which lays a foundation for future research and development.

The detrimental effects of stress-induced glucocorticoid exposure on mouse uterine receptivity and decidualization.

Glucocorticoids (GCs), stress-induced steroid hormones, are released by adrenal cortex and essential for stress adaptation. Recently, there has been renewed interest in the relationship between GCs and pregnancy following the discovery that glucocorticoid receptor is necessary for implantation. It has been widely recognized that stress is detrimental to pregnancy. However, effects of stress-induced GC exposure on uterine receptivity and decidualization are still poorly understood. This study aims to explore the effects of GCs exposure on uterine receptivity, decidualization, and their underlying mechanisms in mice. Single prolonged stress (SPS) and corticosterone (Cort) injection models were used to analyze effects of GC exposure on early pregnancy, respectively. SPS or Cort injection inhibits embryo implantation by interfering Lif signaling and stimulating the uterine deposition of collagen types I, III, and IV on day 4 of pregnancy. Uterine decidualization is also attenuated by SPS or Cort injection through suppressing Cox-2 expression. Cort-induced collagen disorder also suppresses decidualization through regulating mesenchymal-epithelial transition. Our data should shed lights for a better understanding for the effects of GCs on embryo implantation for clinical research.

Liver X receptors conserve the therapeutic target potential for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic multi-system autoimmune disease with extremely complex pathogenesis. Significantly altered lipid paradox related to the inflammatory burden is reported in RA patients, inducing 50% higher cardiovascular risks. Recent studies have also demonstrated that lipid metabolism can regulate many functions of immune cells in which metabolic pathways have altered. The nuclear liver X receptors (LXRs), including LXRα and LXRß, play a central role in regulating lipid homeostasis and inflammatory responses. Undoubtedly, LXRs have been considered as an attractive therapeutic target for the treatment of RA. However, there are some contradictory effects of LXRs agonists observed in previous animal studies where both pro-inflammatory role and anti-inflammatory role were revealed for LXRs activation in RA. Therefore, in addition to updating the knowledge of LXRs as the prominent regulators of lipid homeostasis, the purpose of this review is to summarize the effects of LXRs agonists in RA-associated immune cells, to explore the underlying reasons for the contradictory therapeutic effects of LXRs agonists observed in RA animal models, and to discuss future strategy for the treatment of RA with LXRs modulators.

Structure-based design of glycyrrhetinic acid derivatives as potent anti-sepsis agents targeting high-mobility group box-1.

Novel Glycyrrhetinic Acid (GA) derivatives with fused heterocycles on A ring were structure-based designed and synthesized. Their potential anti-inflammatory effects were investigated by a classical LPS stimulated macrophage model. Surface plasmon resonance (SPR) was used to verify the binding of GA analogues with HMGB1. A preliminary structure-activity relationship was summarized and an analogue GA-60 with ortho-methoxybenzyl pyrozole showed stronger anti-inflammatory effect and higher affinity for HMGB1 with a Kd value of 12.5 µM. In addition, this compound exhibited excellent inhibitory functions on NO (96%), TNF-α (94%), and IL-6 (100%), by interfering with phosphorylation of p38, ERK, JNK MAPKs, as well as that of NF-κB p65 and IKKα/ß. Moreover, GA-60 extended the survival of either the classic CLP-induced or LPS-induced sepsis mouse models. Molecular modeling predictions further supported these findings, clearly indicating that inhibiting HMGB1 release, using fused heterocyclic GA derivatives, is a promising strategy for treatment of sepsis.

Melittin ameliorates inflammation in mouse acute liver failure via inhibition of PKM2-mediated Warburg effect.

Acute liver failure (ALF) is a fatal clinical syndrome with no special drug. Recent evidence shows that modulation of macrophage to inhibit inflammation may be a promising strategy for ALF treatment. In this study we investigated the potential therapeutic effects of melittin, a major peptide component of bee venom both in mice model of ALF and in LPS-stimulated macrophages in vitro, and elucidated the underlying mechanisms. ALF was induced in mice by intraperitoneal injection of D-galactosamine/LPS. Then the mice were treated with melittin (2, 4, and 8 mg/kg, ip). We showed that melittin treatment markedly improved mortality, attenuated severe symptoms and signs, and alleviated hepatic inflammation in D-galactosamine/LPS-induced ALF mice with the optimal dose being 4 mg/kg. In addition, melittin within the effective doses did not cause significant in vivo toxicity. In LPS-stimulated RAW264.7 macrophages, melittin (0.7 µM) exerted anti-oxidation and anti-inflammation effects. We showed that LPS stimulation promoted aerobic glycolysis of macrophages through increasing glycolytic rate, upregulated the levels of Warburg effect-related enzymes and metabolites including lactate, LDHA, LDH, and GLUT-1, and activated Akt/mTOR/PKM2/HIF-1α signaling. Melittin treatment suppressed M2 isoform of pyruvate kinase (PKM2), thus disrupted the Warburg effect to alleviate inflammation. Molecular docking analysis confirmed that melittin targeted PKM2. In LPS-stimulated RAW264.7 macrophages, knockdown of PKM2 caused similar anti-inflammation effects as melittin did. In D-galactosamine/LPS-induced ALF mice, melittin treatment markedly decreased the expression levels of PKM2 and HIF-1α in liver. This work demonstrates that melittin inhibits macrophage activation-mediated inflammation via inhibition of aerobic glycolysis by targeting PKM2, which highlights a novel strategy of using melittin for ALF treatment.

Nonclinical toxicology studies with sodium taurodeoxycholate: acute and subacute toxicity in dogs.

Sodium taurodeoxycholate (TDCA) has been investigated for various inflammatory disorders such as sepsis. We recently evaluated nonclinical safety profile of TDCA using rats infused intravenously. As a series of preclinical safety investigations, we further conducted toxicity studies with TDCA delivered to dogs via intravenous administration under Good Laboratory Practice regulation in this study. In dose range-finding study (dose escalation study), dogs given with TDCA at a dose of 150 mg/kg showed marked changes in clinical signs, hematology, and serum biochemistry. And biochemical markers of liver damage and local skin lesions were observed following intravenous infusion of 100 mg/kg TDCA, suggesting that 100 mg/kg was chosen as the highest dose of TDCA for 4-week repeated-dose toxicity study using dogs. Despite no treatment-related significant changes in body weight, food consumption, ophthalmoscopy, and urinalysis, skin lesions were observed at the injection site of animals administered with higher than 50 mg/kg of TDCA along with biochemical and histopathological changes associated with liver injury. However, most of off-target effects were found to be reversible since these were recovered after stopping TDCA infusion. These findings indicate that the no-observed-adverse-effect-level (NOAEL) for TDCA in dogs was considered to be 5 mg/kg/d. Taken together, our results provide important toxicological profiles regarding the safe dose of TDCA for drug development or clinical application.

Inflammatory and Cytotoxic Activities of Abietane Terpenoids from Nepeta bracteata Benth.

Nepeta bracteata Benth. is used clinically to treat tracheal inflammation, coughs, asthma, colds, fevers, adverse urination, and other symptoms, along with functions in clearing heat and removing dampness. However, there have been few studies characterizing the material basis of its efficacy. Therefore, the aim of this study was to screen for compounds with anti-inflammatory activities in N. bracteata Benth. Using silica gel, ODS C18, and Sephadex LH-20 column chromatography, as well as semipreparative HPLC, 10 compounds were separated from N. bracteata Benth. extract, including four new diterpenoids (1-4), one amide alkaloid (5), and five known diterpenoids (6-10). The structures of all the isolates were elucidated by HR-ESI-MS, NMR, and CD analyses. Using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, we investigated the anti-inflammatory activities of compounds 1-10. It is worth noting that all were able to inhibit nitric oxide (NO) production with IC50 values < 50 µM and little effect on RAW 264.7 macrophage viability. Compounds 2 and 4 displayed remarkable inhibition with IC50 values of 19.2 and 18.8 µM, respectively. Meanwhile, screening on HCT-8 cells demonstrated that compounds 2 and 4 also had moderate cytotoxic activities with IC50 values of 36.3 and 41.4 µM, respectively, which is related to their anti-inflammatory effects.

Suppression of inflammatory cascades via novel cinnamic acid nanoparticles in acute hepatitis rat model.

Hepatitis was characterized by extreme inflammation and hepatocellular damage. Therefore, the current study aimed to gain insights into the modulation role of Cinnamic acid nanoparticles (CANPs) against acute hepatitis induced by d-Galactosamine and gamma radiation exposure (D-Gal/radiation) in the rat model and to suggest the implied molecular mechanism of CANPs. Acute hepatitis seriousness and the serum enzyme activities of ALT, AST, and ALP have been diminished upon oral administration of CANPs. Besides, the hepatic tissue levels of malondialdehyde (MDA) and nitric oxide (NO) have been significantly decreased, and the total antioxidant activity (TAO) depletion was extremely restored. Furthermore, the reduction of hepatic damage caused by pretreatment with CANPs was accompanied by significant suppression in the levels of hepatic proinflammatory cytokines (TNF-α, IL-1ß, and IL-18), NF-κB, NLRP3, caspase-1 and proapoptotic protein BAX whereas anti-apoptotic protein Bcl-2 level significantly elevated as compared with D-Gal/radiation-induced acute hepatitis (AH) group. Also, CANPs suppress the D-Gal/radiation-induced IL-1ß, IL-18, and ASK1 mRNA gene expression and the protein expression of TLR4 and MyD88 in the hepatic tissue. These biochemical parameters are confirmed by histological examination of the liver tissues. The present results indicated that CANPs can protect the hepatic cells from damage by both its anti-inflammatory and antioxidant influence as well as by modulating oxidation cellular pathways that have contributed to the acute severity of hepatitis. Also, CANPs is capable of suppressing apoptosis. Consequently, Nanoparticles of Cinnamic acid have the medicinal ability to protect the liver from acute hepatitis.

Dexmedetomidine Inhibits Neuroinflammation by Altering Microglial M1/M2 Polarization Through MAPK/ERK Pathway.

Neuroinflammation is critical in the pathogenesis of neurological diseases. Microglial pro-inflammatory (M1) and anti-inflammatory (M2) status determines the outcome of neuroinflammation. Dexmedetomidine exerts anti-inflammatory effects in many neurological conditions. Whether dexmedetomidine functions via modulation of microglia M1/M2 polarization remains to be fully elucidated. In the present study, we investigated the anti-inflammatory effects of dexmedetomidine on the neuroinflammatory cell model and explored the potential mechanism. BV2 cells were stimulated with LPS to establish a neuroinflammatory model. The cell viability was determined with MTT assay. NO levels were assessed using a NO detection kit. The protein levels of IL-10, TNF-α, iNOS, CD206, ERK1/2, and pERK1/2 were quantified using Western blotting. LPS significantly increased pro-inflammatory factors TNF-α and NO, and M1 phenotypic marker iNOS, and decreased anti-inflammatory factor IL-10 and M2 phenotypic marker CD206 in BV2 cells. Furthermore, exposure of BV2 cells to LPS significantly raised pERK1/2 expression. Pretreatment with dexmedetomidine attenuated LPS-elicited changes in p-ERK, iNOS, TNF-α, NO, CD206 and IL-10 levels in BV2 cells. However, co-treatment with dexmedetomidine and LM22B-10, an agonist of ERK, reversed dexmedetomidine-elicited changes in p-ERK, iNOS, TNF-α, NO, CD206 and IL-10 levels in LPS-exposed BV2 cells. We, for the first time, showed that dexmedetomidine increases microglial M2 polarization by inhibiting phosphorylation of ERK1/2, by which it exerts anti-inflammatory effects in BV2 cells.

A review of pharmacological and pharmacokinetic properties of stachydrine.

Stachydrine is extracted from the leaves of Leonurus japonicus Houtt (or Motherwort, "Yi Mu Cao" in Traditional Chinese Medicine) and is the major bioactive ingredient. So far, stachydrine has demonstrated various bioactivities for the treatment of fibrosis, cardiovascular diseases, cancers, uterine diseases, brain injuries, and inflammation. The pharmacological and pharmacokinetic properties of stachydrine up to 2019 have been comprehensively searched and summarized. This review provides an updated summary of recent studies on the pharmacological activities of stachydrine. Many studies have demonstrated that stachydrine has strong anti-fibrotic properties (on various types of fibrosis) by inhibiting ECM deposition and decreasing inflammatory and oxidative stress through multiple molecular mechanisms (including TGF-ß, ERS-mediated apoptosis, MMPs/TIMPs, NF-κB, and JAK/STAT). The cardioprotective and vasoprotective activities of stachydrine are related to its inhibition of ß-MHC, excessive autophagy, SIRT1, eNOS uncoupling and TF, promotion of SERCA, and angiogenesis. In addition to its anticancer action, regulation of the uterus, neuroprotective effects, etc. the pharmacokinetic properties of stachydrine are also discussed.

Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe.

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.

Glabridin Alleviates Inflammation and Nociception in Rodents by Activating BKCa Channels and Reducing NO Levels.

Inflammation, and the pain that accompanies it, is a natural response of the body. The licorice plant (Glycyrrhiza glabra) have demonstrated anti-inflammatory, anti-edematous, and anti-nociceptive effects of its extracts. The effective ingredient remains unidentified; however, one possibility is the unique isoflavone glabridin. The anti-nociceptive, and anti-inflammatory effects of glabridin and its possible mechanism with focus on the large conductance Ca2+-activated K+ (BKCa) channels and L-arginine-nitric oxide (NO) pathway were examined by using different tests. In order to determine the anti-edematous, anti-nociceptive, and anti-oxidative effects of glabradin, some tests such as the tail flick, hotplate, carrageenan-induced paw edema, air pouch, acetic-acid-induced writhing, formalin, and capsaicin tests, as well as toxicity and open field tests were made. Glabridin was administered to rats (n = 8) or mice (n = 8) for 3 d at 3 doses (10, 20, and 40 mg/kg). Glabridin inhibited cytokine production and showed an anti-nociceptive response via the activating of BKCa channels and downregulating NO level and partially transient receptor potential vanilloid-1 pathways. It also demonstrated anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity, while showing no cytotoxicity. Glabridin, however, showed no anti-nociceptive effect in the neurogenic phase. Glabridin is a promising substance in terms of its anti-nociceptive and anti-inflammatory effects by disrupting peripheral NO production, inhibiting cyclic guanosine monophosphate (cGMP) activation and activating BKCa channels and its lack of acute and subacute toxic effects.

Gallic acid prevents 1, 2-Dimethylhydrazine induced colon inflammation, toxicity, mucin depletion, and goblet cell disintegration.

1,2-Dimethylhydrazine (DMH), an environmental toxicant specifically targets the colon. The present study was aimed to evaluate the efficacy of gallic acid (GA) against colon toxicity induced by DMH in Wistar rats. GA, a phenolic acid has numerous beneficial properties, which include antiviral, antifungal and antioxidant properties which help cells to overcome oxidative stress and balance the redox homeostasis. GA was administered orally at two doses (25 and 50 mg/kg body weight) once daily for 14 days and a single dose (40 mg/kg body weight) of DMH was administered subcutaneously on 14th day. Animals were sacrificed on the 15th day and we could find that GA at both the doses significantly ameliorates DMH-induced increased toxicity markers and also substantially increases the glutathione content level and activities of detoxifying enzymes. It also ameliorates the expression of proliferation, inflammation, apoptosis, goblet cell disintegration, and mucin depletion in the colon that was elevated upon administration of DMH. Histological alterations provide further confirmation of the protective role of GA against DMH-induced colon toxicity. The results of this study clearly indicate supplementation of GA is beneficial in ameliorating DMH-induced oxidative stress, inflammation, proliferation, apoptosis, mucin depletion, and goblet cell disintegration in colon of Wistar rats.

Novel pyrazole-clubbed thiophene derivatives via Gewald synthesis as antibacterial and anti-inflammatory agents.

The aim of this study was to synthesize newer potent Schiff bases by condensing 2-amino-5-(2,4-dichlorophenyl)thiophene-3-carbonitrile and 1,3-disubstituted-1H-pyrazole-4-carbaldehydes, and to investigate their biological activity. The compounds were synthesized via Gewald synthesis and characterized by spectral data and elemental analyses. They were screened for their in vitro antibacterial and anti-inflammatory activities. The synthesized compounds were also evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv using the microplate Alamar Blue assay. Compounds 8b, 8c, 8f, 8g, 8k, 8n, and 8o showed promising antibacterial activity. The interactions between the substituted pyrazoles and bovine protein showed promising anti-inflammatory activity. The experimental results revealed compound 8a as a promising antitubercular agent. Hemolytic assays confirmed that the compounds are nontoxic, with percentage hemolysis ranging from 3.6 to 20.1, at a concentration of 1 mg/ml. The results suggest that the pyrazole ring and the substitution pattern on the heterocyclic moiety have an effect on the bioactivity.