Monocrotaline presence in the Crotalaria (Fabaceae) plant genus and its influence on arthropods in agroecosystems / Presença de monocrotalina em plantas do gênero Crotalaria (Fabaceae) e a sua influência sobre artrópodes nos agroecossistemas

Abstract Crotalaria (Fabaceae) occurs abundantly in tropical and subtropical regions and has about 600 known species. These plants are widely used in agriculture, mainly as cover plants and green manures, in addition to their use in the management of phytonematodes. A striking feature of these species is the production of pyrrolizidine alkaloids (PAs), secondary allelochemicals involved in plant defense against herbivores. In Crotalaria species, monocrotaline is the predominant PA, which has many biological activities reported, including cytotoxicity, tumorigenicity, hepatotoxicity and neurotoxicity, with a wide range of ecological interactions. Thus, studies have sought to elucidate the effects of this compound to promote an increase in flora and fauna (mainly insects and nematodes) associated with agroecosystems, favoring the natural biological control. This review summarizes information about the monocrotaline, showing such effects in these environments, both above and below ground, and their potential use in pest management programs.

Resumo Crotalaria (Linnaeus, 1753) (Fabaceae) ocorre abundantemente em regiões tropicais e subtropicais e tem cerca de 600 espécies conhecidas. Estas plantas são amplamente utilizadas na agricultura, principalmente como cobertura e adubos verdes, além da sua utilização no manejo de fitonematoides. Uma característica marcante destas espécies é a produção de alcalóides pirrolizidinicos (APs), aleloquímicos secundários envolvidos na defesa das plantas contra os herbívoros. Nas espécies de Crotalaria, a monocrotalina é a AP predominante, que tem muitas atividades biológicas relatadas, incluindo citotoxicidade, tumorigenicidade, hepatotoxicidade e neurotoxicidade, além de uma vasta gama de interações ecológicas. Assim, estudos têm procurado elucidar os efeitos desse composto para promover um incremento na flora e fauna (principalmente insetos e nematoides) associados aos agroecossistemas, favorecendo o controle biológico natural. Esta revisão compila informações sobre a monocrotalina, mostrando tais efeitos nesses ambientes, tanto acima como abaixo do solo e a sua potencial utilização em programas de manejo de pragas.

Genotoxic and cytotoxic evaluation of venlafaxine in an acute and a subchronic assay in mouse / Avaliação genotóxica e citotóxica da venlafaxina em ensaio agudo e subcrônico em camundongos

Abstract The present research was made to determine the micronuclei and cytotoxic capacity of the antidepressant venlafaxine in an in vivo acute and subchronic assays in mouse. In the first study, we administered once 5, 50, and 250 mg/kg of the drug, and included a negative and a daunorubicin treated group. Observations were daily made during four days. The subchronic assay lasted 5 weeks with daily administration of venlafaxine (1, 5, and 10 mg/kg) plus a negative and an imipramine administered groups. Observations were made each week. In the first assay results showed no micronucleated polychromatic erythrocytes (MNPE) increase, except with the high dose at 72 h. The strongest cytotoxic effect was found with 250 mg/kg at 72 h (a 51% cytotoxic effect in comparison with the mean control level). In the subchronic assay no MNPE increase was found; however, with the highest dose a significant increase of micronucleated normochromatic erythrocytes was observed in the last three weeks (a mean of 51% respect to the mean control value). A cytotoxic effect with the two high doses in the last two weeks was observed (a polychromatic erythrocyte mean decrease of 52% respect to the mean control value). Results suggest caution with venlafaxine.

Resumo A presente pesquisa foi feita para determinar a capacidade micronuclei e citotóxica do antidepressivo venlafaxina em ensaios agudos e subcrônicos in vivo em camundongos. No primeiro estudo, administramos uma vez 5, 50 e 250 mg/kg do medicamento e incluímos um grupo negativo e um grupo tratado com daunorubicina. As observações foram feitas diariamente durante quatro dias. O ensaio subcrônico durou cinco semanas com administração diária de venlafaxina (1, 5, e 10 mg/kg) mais um grupo negativo e um grupo administrado de imipramina. As observações foram feitas a cada semana. No primeiro ensaio, os resultados não mostraram aumento de eritrócitos policromáticos micronucleados (MNPE), exceto com a dose elevada a 72 h. O efeito citotóxico mais forte foi encontrado com 250 mg/kg a 72 h (um efeito citotóxico de 51% em comparação com o nível médio de controle). No ensaio subcrônico não foi encontrado aumento de MNPE; entretanto, com a dose mais alta, um aumento significativo de eritrócitos normocromáticos micronucleados foi observado nas últimas três semanas (média de 51% em relação ao valor médio de controle). Foi observado um efeito citotóxico com as duas altas doses nas últimas duas semanas (uma diminuição média de 52% em relação ao valor médio de controle dos eritrócitos policromáticos). Os resultados sugerem cautela com a venlafaxina.

Chlorophytum borivilianum aqueous root extract prevents deterioration of testicular function in mice and preserves human sperm function in hydrogen peroxide (H2O2)-induced oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Chlorophytum borivilianum (C. borivilianum) (CB) has traditionally been used to treat male sexual dysfunctions and has been claimed to possess aphrodisiac properties. AIM OF THE STUDY: To investigate the ability of CB to ameliorate H2O2-induced oxidative stress in testes and sperm in mice and prevent H2O2-induced oxidative in human sperm. MATERIALS AND METHODS: Oxidative stress was induced in male mice by pre-exposure to 2% H2O2 orally for seven consecutive days, followed by 100 and 200 mg/kg b. w. administration. CB for another seven days. At the end of treatment, mice were sacrificed and testes and epididymal sperm were harvested. Serum FSH, LH and testosterone levels were measured and sperm parameters were obtained. Meanwhile, oxidative stress levels in mice testes and sperm, steroidogenesis and spermatogenesis markers in mice testes were assessed by molecular biological techniques. In another experiment, sperm from thirty-two healthy fertile men were incubated with 200 µM H2O2 and CB (100 and 200 µg/ml) simultaneously and were then evaluated for sperm parameter changes. RESULTS: In mice, CB administration ameliorates persistent increases in oxidative stress and decreases in anti-oxidative enzyme levels in testes and sperm following H2O2 pre-exposure. Additionally, CB also helps to ameliorate deterioration in sperm parameters and testicular steroidogenesis and spermatogenesis and restores the serum FSH, LH and testosterone levels near normal in mice. In humans, CB helps to prevent deterioration in sperm parameters following H2O2 exposure. CONCLUSION: CB is potentially useful to preserve the male reproductive capability and subsequently male fertility in high oxidative stress conditions.

The preventative effect of Baihe Gujin Pill on cisplatin-induced acute kidney injury by activating the PI3K/AKT and suppressing the NF-κB/MAPK pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Baihe Gujin Pill (BHGJP) is a traditional Chinese medicine (TCM) derived from the "Collection of Medical Formulas". BHGJP is applied to treat lung and kidney deficiency by nourishing yin and clearing heat. However, the role and preventative mechanism of BHGJP in cisplatin induced acute kidney injury (CIAKI) are poorly understood. AIM OF THE STUDY: The preventative effect of BHGJP on CIAKI by the in vitro and in vivo experiments based on network pharmacology was investigated. METHODS: Network pharmacology was used to predict the protective effect of BHGJP on CIAKI. The effect and mechanism of BHGJP against CIAKI were detected and verified by the in vitro kidney cells 293T and HK-2 as well as the in vivo mice model established by a single injection of cisplatin. RESULTS: Network pharmacology predicted that BHGJP prevented CIAKI by regulating PI3K/AKT and NF-κB/MAPK signaling pathways. BHGJP could reverse the reduced cell viability of HK-2 and 293T cells caused by cisplatin without decreasing its cytotoxic effects on H460, H1299, and A549 cells. Meanwhile, BHGJP effectively controlled kidney injury in the CIAKI model. Moreover, cisplatin induced cell apoptosis and accumulation of reactive oxygen species (ROS) were downregulated after treatment with BHGJP. The changes of oxidative stress indexes of GSH, MDA, and SOD as well as the inflammatory factors of TNF-α, IL-6, and IL-1ß in the CIAKI model were recovered to normal state when BHGJP treatment. Furthermore, BHGJP activated PI3K/AKT pathway and suppressed the NF-κB/MAPK pathway in the CIAKI model. CONCLUSION: The study found that BHGJP prevented CIAKI by inhibiting apoptosis, oxidative stress, and inflammation via regulating PI3K/AKT and NF-κB/MAPK pathways, providing new efficacy and clinical applications for BHGJP.

Protective action of Cecropia pachystachya extract and enriched flavonoid fraction against memory deficits, inflammation and oxidative damage in lipopolysaccharide challenged mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cecropia pachystachya (CP) Trécul is a medicinal plant native to South and Central America with several pharmacological properties, such as anti-inflammatory and neuroprotective. AIM OF THE STUDY: In this study, we investigated the effect of CP extract (200 mg/kg) and its enriched flavonoid fraction (EFF-CP) (50 and 100 mg/kg) in a model of lipopolysaccharide (LPS)-induced neuroinflammation. MATERIAL AND METHODS: CP and EFF-CP were administered intragastrically for 14 days and LPS (250 µg/kg) was administered intraperitoneally from the 8th to the 14th days. LC/DAD/MS analysis showed the presence of isoorientin, orientin, and isovitexin as major compounds. RESULTS: The results demonstrated that CP extract and EFF-CP gave protection against LPS-induced short-term and long-term memory deficits. The treatment with CP and/or EFF-CP protected against LPS-induced increases in reactive species, nitrites, total thiol and lipoperoxidation in the cerebral cortex, hippocampus and striatum. Moreover, CP and EFF-CP restored superoxide dismutase and catalase activities that had been reduced by LPS in the cerebral cortex, hippocampus and striatum. TNF-α levels were increased in the cortex, striatum and hippocampus in the LPS group, while CP treatment prevented this change in the cerebral cortex. EFF-CP decreased the levels of this cytokine in all structures analyzed at both doses. CONCLUSION: CP extract and its EFF-CP are important therapeutic targets for the management of neuroinflammation observed in neurodegenerative diseases.

Baitouweng decoction repairs the intestinal barrier in DSS-induced colitis mice via regulation of AMPK/mTOR-mediated autophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is one of non-specific inflammatory bowel disease that mainly affects the colon. Recently, UC has become a significant social and economic problem worldwide. Baitouweng decoction (BD), a traditional Chinese medicine described in the "Treatise on Febrile Diseases", has been used for centuries to treat intestinal diseases. However, its underlying mechanism remains largely unexplored. AIM OF STUDY: In this study, we aimed to investigate the effect of BD on autophagy for repairing the colonic barrier in DSS-induced colitis mice and explored its role in regulating the autophagic signaling pathway AMPK/mTOR. MATERIALS AND METHODS: Mice with colitis were treated with 3% dextran sulfate sodium (DSS) for 7 days. The effectiveness of BD in treating DSS-induced colitis was evaluated through body weight, disease activity index (DAI), colon length, pathological changes, organ index, and proportion of blood cells. Moreover, intestinal epithelial permeability was analyzed by examining FITC-dextran leakage, the bacterial load of mesenteric lymph nodes (MLNs), and bacterial infiltration of colon tissues. Barrier function was evaluated by assessing the number and proportion of colonic goblet cells and the expression of tight junction proteins, including ZO-1, claudin-1, and occludin. Furthermore, the levels of autophagy were assessed by examining the number of autophagosomes and the expression of the autophagy-related proteins LC3, Beclin1, and P62. Additionally, network pharmacology research was conducted to analyze the potential mechanisms underlying the medicinal effects, as indicated by the role of AMPK/mTOR in regulating the autophagic signaling pathway. RESULTS: BD improved colitis symptoms in mice by restoring body weight and colon length and reducing inflammatory cell infiltration. Additionally, BD decreased the diffusion of FITC-dextran and bacterial translocation in MLNs, as well as bacterial infiltration of the colonic mucosa. The number and proportion of colonic goblet cells, the expression of ZO-1, Claudin-1, and Occludin, and the levels of autophagy were also increased by BD. Network pharmacology analysis suggested that BD might affect intestinal autophagy through the AMPK signaling pathway, which was confirmed by the activation of AMPK phosphorylation and the downregulation of mTOR expression following BD treatment. CONCLUSION: Our study demonstrated that BD repaired the intestinal epithelial barrier in DSS-induced colitis mice by activating AMPK phosphorylation and inhibiting mTOR expression to promote autophagy.

Ameliorative effect of traditional polyherbal formulation on TNF-α, IL-1ß and Caspase-3 expression in kidneys of wistar rats against sodium fluoride induced oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Sharbat-e-bazoori Motadil (SBM) is a polyherbal formulation that have been used for centuries as a part of the Unani system of medicine for renal disease. AIM OF THE STUDY: The objective of this study was to explore and validate the nephroprotective potential of sugar-free SBM (SF-SBM) and its mechanisms of action against sodium fluoride (NaF)-induced nephrotoxicity in HEK-293 cells. Additionally, the study aimed to assess the quality control of SF-SBM and investigate its effects using an in vivo rat model with pattern recognition following oral administration of SF-SBM. MATERIALS AND METHODS: The nephroprotective effect of SF-SBM was investigated using both an HEK-293 cell line and Wistar rats. Nephrotoxicity was induced in these models by administering NaF at a concentration of 600 ppm (parts per million) for a duration of seven days. The SF-SBM formulation was standardized using high-performance thin-layer chromatography (HPTLC) to assess the presence of marker compounds, namely gallic acid, quercetin, and ferulic acid. Metabolite characterization of SF-SBM was carried out using ultra-high-performance liquid chromatography mass spectrometry (UPLC-MS) with a monolithic capillary silica-based C18 column. This analytical technique allowed for the identification of bioactive substances and verification of the identified markers. Acute toxicity of SF-SBM was evaluated in Wistar rats by administering a single oral dose of 2000 mg/kg of SF-SBM. The nephroprotective efficacy of SF-SBM was further assessed at low (LD), medium (MD) and high (HD) doses of 32.1, 64.2, and 128.4 mg/kg, respectively, administered orally. Nephrotoxicity was induced in Wistar rats by adding NaF to their drinking water for seven days. Biochemical and urine markers were analyzed to evaluate the antioxidant, inflammatory, and apoptotic potential of SF-SBM. Additionally, histopathological analysis and immunohistochemical alterations in the expression of caspase-3 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4 (NOX-4) in kidney tissue were performed to confirm the findings of the in vivo experiments. Furthermore, in vivo pattern recognition of SF-SBM metabolites, identified through GC-MS metabolomics, and in-silico docking analysis of major metabolites in plasma were conducted to gain further insights. RESULT: Phytochemical analysis using HPTLC, TLC-bioautography, and UPLC-MS revealed the presence of several bioactive constituents in SF-SBM, including ferulic acid, gallic acid (GA), ellagic acid, quercetin, and apigenin. These compounds exhibit diverse pharmacological properties. In vitro studies demonstrated the protective effect of SF-SBM on HEK-293 cell line against nephrotoxicity. The acute toxicity study of SF-SBM at a dose of 2000 mg/kg showed no mortality or signs of toxicity throughout the 14-day observation period. In the in vivo studies, administration of NaF resulted in significant elevation (P < 0.001) of biochemical and urine parameters, indicating oxidative, inflammatory, and apoptotic stress. Histopathological examination revealed severe depletion of Bowman's capsule, and immunohistochemistry demonstrated negative immunostaining for caspase-3 and reduced NOX-4 reactions. Pre-treatment with SF-SBM significantly attenuated the elevated biochemical and urine markers, restored the antioxidant enzyme levels (such as SOD, CAT, GSH, GPx and NO), and regulated the expression of inflammatory cytokines (TNF-α, IL-1ß, CASP-3) in kidney tissue at doses of SF-SBM-MD (64.2 mg/kg) and SF-SBM-HD (128.4 mg/kg), showing comparable results to those of α-Ketoanalogue. Histopathological assessment demonstrated improvements in tissue damage. Pattern recognition analysis of SF-SBM identified the presence of 56 metabolites at different time intervals. Additionally, in-silico studies revealed strong interactions of SF-SBM with a binding energy of -6.5 and -5.6 kcal for 4C2N. CONCLUSION: The phytoconstituents present in SF-SBM play a crucial role in its nephroprotective action by acting as potent antioxidants and reducing proinflammatory and apoptotic damage in rat cells. This indicates that SF-SBM has promising potential for the treatment of nephrotoxicity.

Geniposide protects against neurotoxicity in mouse models of rotenone-induced Parkinson's disease involving the mTOR and Nrf2 pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Gardeniae, with the effects of discharging fire, eliminating vexation, reducing fever and causing diuresis, and cooling blood to remove apthogentic heat, could be used to treat Parkinson's disease (PD). Geniposide, as the main active ingredient of Fructus Gardeniae, has been shown to have neuroprotective effects in several rodent models. Rotenone, a commonly used neurotoxin, induced PD model progresses slowly, but simulates the pathological changes of PD's slow progression. AIM OF THE STUDY: Herein, we mainly investigated the neuroprotective effects of geniposide on rotenone-induced mouse model of PD and the underlined mechanism. MATERIALS AND METHODS: C57BL/6 mice were treated with rotenone (30 mg/kg, p. o.) daily for 60 days. Geniposide (25 and 50 mg/kg, p. o.) were administered at alterative day 30 min before rotenone. On day 60, the challenging beam, spontaneous activity, and adhesive removal tests were performed to evaluate the motor activity. Dopamine, DOPAC and HVA levels were detected by UPLC-MS/MS methods. Dopaminergic neurodegeneration was assessed using immunohistochemistry staining. ROS production, MDA level and GSH: GSSG ratio were measured to analyze oxidative stress. Cleavage of PARP and caspase-3 were detected to assess neuronal apoptosis. The expression of Nrf2 and mTOR signaling were detected using Western blot. RESULTS: Geniposide improved motor dysfunction, restored neurotransmitters levels, and attenuated dopaminergic neurodegeneration induced by rotenone in mice. Geniposide suppressed rotenone-induced neuronal oxidative damage associated with Nrf2 signaling, and neuronal apoptosis involving mTOR pathway. CONCLUSIONS: Geniposide may exert a neuroprotective effect in a mouse model of PD by rotenone, and this effect might be relevant to Nrf2 associated antioxidant signaling and mTOR involved anti-apoptosis pathway.

'Pterocephalodes hookeri-Onosma hookeri' decoction protects against LPS-induced pulmonary inflammation via inhibiting TLR4/ NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: As the second-largest traditional medical system in China, Tibetan medicine has a long history and abundant resources. To promote the development of the Tibetan medicine industry, it is essential to study the pharmacological activities of Tibetan medicine based on its traditional usage methods. AIM OF THE STUDY: Pneumonia has been a worldwide health problem with high morbidity and mortality rates, especially in the context of the COVID-19 epidemic. Given the unique advantages of traditional Tibetan medicine in treating pulmonary diseases, further research is warranted to develop potential anti-pneumonia drugs. MATERIALS AND METHODS: In our study, the potential combined decoction from traditional Tibetan medicine was determined by the data mining method. The antioxidant activity in vitro, anti-inflammatory effects on the macrophage cell model, as well as the anti-pulmonary inflammation effects on the LPS-induced mice model, have been explored to investigate the potential anti-pneumonia role of the decoction. Additionally, we conducted network pharmacology analysis to identify the potential targets against pneumonia, which were further confirmed by western blot assays. RESULTS: Following the combination therapy of Pterocephalodes hookeri (C.B.Clarke) V.Mayer & Ehrend. and Onosma hookeri var. longiflora (Duthie) A.V.Duthie ex Stapf ('P-O'), the clearance of DPPH radical and the total reducing power were all improved, as well as alleviated the toxicity. On the in vitro level, 'P-O' pre-treatment reduced the secretion of NO, TNF-α, IL-6, and IL-1ß in LPS-stimulated RAW264.7 cells, while promoting the concentration of IL-10. Meanwhile, on the in vivo level, the 'P-O' pre-treating also could alleviate LPS-induced pulmonary inflammation by reducing the pulmonary edema and leakage of the lung microvascular, improving the pathological change of lung tissue and regulating the cytokines content in bronchoalveolar lavage fluid (BALF). Furthermore, network pharmacology analysis revealed that the mechanism of 'P-O' in treating pneumonia in a multi-component, multi-target, and multi-pathway network, with the TLR4/NF-κB signaling pathway playing a crucial role, as demonstrated by the western blot assay results. CONCLUSION: In summary, the combination therapy of 'P-O' exhibited good antioxidant activity and anti-inflammatory activity in vitro, as well as a therapeutic effect against pulmonary inflammation in vivo. These findings provide evidence for the clinical application of 'P-O' and offer new approaches for treating pneumonia.

Mechanism of Xiaojianzhong decoction in alleviating aspirin-induced gastric mucosal injury revealed by transcriptomics and metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Aspirin, as a first-line drug for the treatment of cardiovascular diseases, currently has high clinical usage. However, reports of aspirin-induced gastric mucosal injury are increasing. Xiaojianzhong decoction (XJZD), a classic traditional Chinese medicine formula, has been shown to alleviate gastric mucosal injury, although its potential mechanism of action requires further study. AIM OF THE STUDY: This study aimed to explore the effect and mechanism of XJZD in preventing aspirin-induced gastric mucosal injury. MATERIALS AND METHODS: Aspirin was used to induce damage in the morning, while XJZD was applied as an intervention in the afternoon. The compounds in the XJZD were analyzed by means of both high-performance liquid chromatography and ultra-performance liquid chromatography-tandem mass spectrometry. The overall condition of the aspirin-related gastric mucosal injury was evaluated. The expressions of inflammatory factors and tight-junction-related proteins and apoptosis were observed via immunohistochemistry and immunofluorescence. The expression levels of the apoptosis-related proteins were detected using Western blot. Transcriptomics was used to perform the integrative analysis of gastric tissues, which was then validated. Molecular dynamics was used to explore the interaction of key compounds within the XJZD with relevant targets. Finally, non-targeted metabolomics was used to observe any metabolic changes and construct a network between the differentially expressed genes and the differential metabolites to elucidate their potential relationship. RESULTS: XJZD can alleviate inflammation response, maintain the gastric mucosal barrier's integrity, reduce apoptosis and necroptosis levels, and promote the proliferation and repair of gastric mucosal tissues. Its mechanism of action may be related to the regulation of TNF-α signaling. Furthermore, molecular docking showed that the cinnamaldehyde within XJZD played an important role in its effects. In addition, XJZD can correct metabolic disorders, mainly regulating amino acid metabolism pathways. Moreover, six differential genes (Cyp1a2, Cyp1a1, Pla2g4c, etc.) were determined to alleviate both gastric mucosal injury and inflammation by regulating arachidonic acid metabolism, Tryptophan metabolism, etc. CONCLUSIONS: This study is the first to report that XJZD can inhibit necroptosis and gastric mucosal injury induced by aspirin, thereby revealing the complex mechanism of XJZD in relation to alleviating gastric mucosal injury from multiple levels and perspectives.

Quality control assessment, toxicity profiling, and experimental validation of network pharmacology-predicted anti-inflammatory potential of Natsiatum herpeticum Buch.-Ham. Ex Arn.

ETHNOPHARMACOLOGICAL RELEVANCE: Natsiatum herpticum Buch.-Ham. Ex Arn., a least-explored plant, is being considered a wild edible plant by the Bankariya community of Nepal and the Mishing, Sonowal Kachari, and several ethnic groups in the north-east region of India. It is also used as a traditional remedy for the treatment of pain and inflammation-associated conditions like cuts and wounds, stomach ache, backache, and headache as a practice of a folkloristic system of medicine. In spite of several previous publications suggesting its use by different tribes, no documentation or scientific approaches have been made hitherto to validate its ethnopharmacological claims. AIM OF STUDY: The study aimed at the botanical quality control assessment, toxicity profiling, and network pharmacology-assisted experimental validation of the anti-inflammatory potential of the aqueous extract of N. herpeticum to fill the lacunae in the current knowledge. MATERIAL AND METHOD: Plant material was authenticated using a classical taxonomical approach and DNA barcoding. The quality control methods, acute toxicity study, and repeated dose 28-day oral toxicity study were performed as per standard guidelines. QToF-MS analysis, drug-likeness properties, network pharmacology-based anti-inflammatory prediction, and in vitro assays were carried out. RESULTS: Quality control assessment was done for the plant. Toxicity studies revealed the aqueous extract to be non-toxic when consumed for short periods at low doses. Alterations in food and water intake, biochemical parameters, and alterations in liver histology (n = 2 female rats) implicate repeated exposure to high doses (2000 mg/kg) that may possess deleterious effects, particularly in hepatic tissues. 21 representative compounds (14 drug-like molecules) were detected by QToF-MS analysis and then subjected to network pharmacology to predict anti-inflammatory effects. It was found that an anti-inflammatory effect may be exerted by modulating inflammatory pathways involving genes such as TNF, PTGS2, EGFR, STAT3, PPARG, PTGER4, PPARA, NOS2, TRPV1, and JAK2. Further, in vitro studies demonstrated plant extract to possess a good anti-inflammatory effect with IC50 values of 98.76, 85.73, and 96.16 µg/ml in protein denaturation, proteinase inhibition, and haemolysis inhibition assays, respectively. CONCLUSION: The plant extract was found to be safer at acute dose but may cause potential liver toxicity on prolonged use. The anti-inflammatory property predicted by network pharmacology was further supported by the positive results of in vitro experiments. In summary, to further establish the toxicity profile of this edible plant and its anti-inflammatory properties, chronic toxicity study and in vivo experiments are required.

Neuroprotective effects of Petiveria alliacea on scopolamine-induced learning and memory impairment mouse model.

ETHNOPHARMACOLOGY RELEVANCE: Petiveria alliacea L., commonly known as macura and gully root, is an important medicinal plant used in the Caribbean and Central America to treat ailments associated to the central nervous system, including poor memory. AIM OF THE STUDY: To assess the effects of the P. alliacea leaves methanol fraction (PMF) on a scopolamine-induced learning and memory impairment mouse model related to acetylcholinesterase activity and oxidative stress. MATERIAL AND METHODS: After PMF administration at doses of 500 or 900 mg/kg, cognitive ability was evaluated using the Morris water maze (MWM), Y-maze (YM) and novel object recognition (NOR) tests. The mouse brain tissue was further assessed for acetylcholinesterase activity and antioxidant activity. Levels of oxidative stress were also evaluated by measuring malondialdehyde (MDA) and glutathione activity. Acute toxicity was also evaluated. RESULTS: PMF led to memory improvement in the behavioral tests in mice with scopolamine-induced cognitive impairment. Moreover, PMF inhibited acetylcholinesterase activity and showed antioxidant potential that in turn attenuated cholinergic degradation. Additionally, PMF increased glutathione levels and glutathione reductase activity and reduced MDA levels in the brain. Moreover, no acute toxicity was detected with the use of PMF. CONCLUSION: In a mouse model of scopolamine-induced cognitive deficit, PMF exhibited protective effects, decreasing oxidative damage and regulating cholinergic function in the brain bearing significant memory enhancing potency. These data suggest that PMF is a promising candidate for developing therapies for neurodegenerative disorders.

Essential oil from leaves of Croton blanchetianus Baill does not present acute oral toxicity, has antigenotoxic action and reduces neurogenic and inflammatory nociception in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Croton blanchetianus Baill., popularly known as "marmeleiro preto", is an endemic plant from Brazil, being found mainly in the Northeast region. In traditional medicine, the use of medicines based on the leaves of this plant has been reported for the treatment of inflammatory processes, pain, urethral pain, gastrointestinal disorders, rheumatism and headache. AIM OF THE STUDY: The present work describes the chemical characterization, as well as toxicological evaluation and antinociceptive activity of an essential oil of C. blanchetianus leaves (EOCb). MATERIALS AND METHODS: The chemical constituents of the oil were identified by gas chromatography coupled to mass spectrometry (GC-MS). In vitro hemolytic activity was tested using mouse blood. Acute toxicity in mice was assessed by the oral or intraperitoneal administration of a single dose of 2000 mg/kg b.w. EOCb (1000 and 2000 mg/kg) was also evaluated for genotoxicity and antigenotoxicity in vivo using the micronucleus test. The antinociceptive activity of EOCb (25, 50 and 100 mg/kg) was evaluated through the abdominal writhing, formalin and tail flick tests. RESULTS: The chemical characterization indicated as major components α-pinene (21.23%), ß-phelandrene (13.92%), terpinolene (13.01%) and germacrene D (10.89%). EOCb did not cause hemolysis and was also neither toxic nor genotoxic, while protected the animals' bone marrow cells from damage caused by cyclophosphamide in oral treatment. However, all animals died after 15 min of intraperitoneal treatment. There was a reduction in the number of abdominal contortions (69.43-89.41%) as well as in licks in the first (38.77-84.47%) and second (59.75-90.74%) phases of the formalin test. In the latter case, the effects were reduced by naloxone and glibenclamide, indicating action via the opioid system and blockage of K+ channels. The latency time in the tail flick test also increased significantly. CONCLUSION: In conclusion, ingestion of EOCb proved to be safe when administered orally; however, it was lethal intraperitoneally. Additionally, EOCb protected mouse blood cell DNA against the action of cyclophosphamide and showed an antinociceptive effect via the opioid system and dependent on K+ channels.

Sijunzi decoction ameliorates gastric precancerous lesions via regulating oxidative phosphorylation based on proteomics and metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Sijunzi decoction (SJZD), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of gastric precancerous lesions (GPL). However, the mechanism of gastric protection is not fully understood. AIMS OF THE STUDY: The purpose of this study was to systematically evaluate the efficacy of SJZD in blocking the development of GPL and to reveal the underlying mechanism. METHODS: First, we established a rat model of GPL, which was induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) combined with an irregular diet and 40% ethanol. The efficacy of SJZD was evaluated based on pathological sections and serum biochemical indices. Then, the pharmacodynamic mechanism of SJZD was revealed by quantitative proteomics based on stable isotope dimethyl labeling. At the same time, the pharmacodynamic mechanism was verified by quantitative metabolomics. In addition, the anti-gastritis effect of SJZD was confirmed by a serum pharmacology method in a cell model, and the functional mechanism was further verified. RESULTS: We demonstrated that SJZD could block the development of GPL in the animal model. Proteomics and metabolomics revealed that SJZD blocks GPL development by regulating oxidative phosphorylation (OXPHOS). In addition, the serum pharmacology results showed that SJZD-containing serum (SJZD-CS) could inhibit apoptosis in MNNG-induced GES-1 cells. OXPHOS inhibitors could significantly reduce the protective effect of SJZD-CS. CONCLUSION: SJZD effectively ameliorates GPL, and proteomics and metabolomics revealed that its protective effects are closely related to OXPHOS.

Pharmacological potential of Jussiaea repens L. against CuSO4 and bacterial lipopolysaccharide O55:B5 induced inflammation using in-vivo zebrafish models.

ETHNOPHARMACOLOGICAL RELEVANCE: The Northeastern state of India is known for its remarkable biodiversity and untapped medicinal resources. Jussiaea repens L., commonly known as water primrose, is a plant found in this region that has been traditionally used by indigenous communities for various purposes. It has been employed to treat skin ulcerations, bone fractures, rheumatism, stomach pain, and intestinal worms. Despite its long-standing ethnopharmacological usage, there is limited scientific research on the bioactivity of Jussiaea repens L. However, preliminary studies have shown its potential antioxidant properties and cytotoxicity against cancer cells. Further exploration of its medicinal properties, particularly its potential as an anti-inflammatory agent, is warranted. AIM OF THE STUDY: This study aimed to investigate the anti-inflammatory properties of Jussiaea repens L., a plant species found in the biodiverse Northeastern region of India. The plant has been traditionally used by indigenous communities for various ailments. By utilizing zebrafish as an animal model and evaluating its effects in different inflammation models, the study aimed to uncover the plant's potential as an anti-inflammatory agent. The research contributes to the scientific understanding of this traditional remedy and its potential therapeutic applications. METHODS: Jussiaea repens L. extract was obtained from the stem and leaves using methanol as the solvent. Zebrafish embryos were used for in vivo assays. The anti-inflammatory study included two models: CuSO4-induced inflammation and tail wounding followed by bacterial lipopolysaccharide-induced inflammation. The activities of catalase (CAT) and superoxide dismutase (SOD) were measured in CuSO4-induced inflammation. Leukocyte migration at the injury site was observed in the tail wounding model. The extract's inhibition of the 15-LOX enzyme was assessed. All procedures followed established protocols and ethical guidelines. RESULTS AND CONCLUSION: Jussiaea repens L. extract exhibited anti-inflammatory activity in two in vivo zebrafish models: CuSO4-induced inflammation and tail wounding combined with bacterial lipopolysaccharide-induced inflammation. The extract reduced mortality rates and showed antioxidant effects by increasing catalase (CAT) and superoxide dismutase (SOD) activities in the CuSO4 model. In the tail wounding model, the extract reduced leukocyte migration in a concentration-dependent manner. Additionally, the extract demonstrated dose-dependent inhibition of the 15-LOX enzyme in the in vitro assay. These results suggest that Jussiaea repens L. extract possesses anti-inflammatory properties and inhibits the 15-LOX enzyme.

Chaiqin chengqi decoction alleviates acute pancreatitis by targeting gasdermin D-mediated pyroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute pancreatitis (AP) is an acute inflammatory condition of pancreas with high morbidity and mortality, which has no effective medical treatment. Chaiqin chengqi decoction (CQCQD) has been clinically used for AP for many years in China. However, the underlying mechanisms are still unknown. AIM OF THE STUDY: To investigate the mechanism of CQCQD on gasdermin D (GSDMD) -mediated pyroptosis in AP. MATERIALS AND METHODS: In this study, network pharmacology was used to screen the potential mechanism of CQCQD protecting against AP and then we focused to investigate the mechanism of CQCQD on GSDMD mediated pyroptosis. Mouse models of AP were conducted by caerulein and L-arginine. In order to clarify the mechanism of CQCQD, two kinds of GSDMD gene knockout mice (Gsdmd-/- and Pdx1creGsdmdfl/fl) were applied. And the potential interaction between the main components of CQCQD and GSDMD was explored by molecular docking. RESULTS: In the caerulein-induced AP model, CQCQD ameliorated pancreatic pathological injury, attenuated systemic inflammation and serum enzymatic levers. Moreover, network pharmacology analysis showed GSDMD mediated pyroptosis was one of the core targets of CQCQD protecting against AP. Additionally, CQCQD appreciably decreased the levels of pyroptosis-related proteins N-terminal GSDMD, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3, and cleaved Caspase-1. Furthermore, the protective effect of CQCQD was neutralized in Gsdmd-/- and Pdx1creGsdmdfl/fl mice in caerulein-induced AP. In addition, we found that CQCQD protects pancreatic tissue from damage and pancreatitis-associated lung injury in the L-arginine-induced mouse model. Moreover, all of the main components of CQCQD possessed binding activity with GSDMD by molecular docking. Seventeen components bound with the human GSDMD Cys191 successfully, which is important for GSDMD pore formation. Among the components, rhein possessed the highest binding activity. CONCLUSION: CQCQD could reduce pancreatic necrosis and inflammatory response via inhibiting GSDMD-mediated pyroptosis in acinar cells of AP. Rhein may be the key active ingredient of CQCQD in suppressing pyroptosis.

Aqueous M. oleifera leaf extract alleviates DSS-induced colitis in mice through suppression of inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Moringa oleifera Lam. (M. oleifera) is a perennial deciduous tree with considerable agricultural and pharmacological value. Nearly all parts of the tree are edible, and nearly all parts are used in traditional medicine. Leaves of M. oleifera have the functions of hypoglycemic (antidiabetic), anti-cancer and anti-oxidant stress, but less research pay attention to the anti-inflammatory effect of M. oleifera leaves. AIM OF THE STUDY: Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gut with no ideal medication. Here, we investigated the anti-inflammatory effects of aqueous extract of M. oleifera leaves. MATERIALS AND METHODS: Intestinal organoids and mice as in vitro and in vivo models to investigate the effects of aqueous extract of M. oleifera leaves on inflammation induced by TNF-α and dextran sulfate sodium (DSS) respectively. The expression of inflammatory cytokines and proliferation-related genes were evaluated by RT-qPCR, respectively. The compounds in the leaf extract were determined by LC/MS, and network pharmacology approach was employed to predict 54 anti-IBD potential targets of quercetin-3-galactoside (QG) and isoquercitrin (IS). RESULTS: We found that the extract protected against damage to intestinal organoids caused by tumor necrosis factor (TNF-α), and significantly down-regulated the expression of inflammatory cytokines. The extract also suppressed the TNF-α-induced expression of Pcna, c-Myc, and c-Jun. Additionally, oral administration of the extract also ameliorated DSS-induced colon damage (colonic shortening, loss of goblet cells and overall abnormal cellularity), and inhibited the expression of inflammatory cytokines and proliferation-related genes in colitis. By LC/MS we identified nearly 2000 of the compounds in the leaf extract, of the flavonoids identified, QG and IS made up the largest percentage; both have been shown to have anti-inflammatory properties. Moreover, network pharmacology approach was employed to predict 54 anti-IBD potential targets of QG and IS. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the overlapping targets participated in response to oxidative stress and PI3K-Akt signaling pathway respectively. CONCLUSIONS: The present study demonstrated the anti-inflammatory capability, in vitro and in vivo, of the aqueous extract of M. oleifera leaves and suggests its potential phytotherapeutic treatment for IBD.

Jingfang Granules () alleviates bleomycin-induced acute lung injury through regulating PI3K/Akt/mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury is a kind of clinical emergency severe syndrome which might trigger acute respiratory distress syndrome. Jingfang Granules () is a traditional Chinese medicine which has been proven to improve acute lung injury induced by bleomycin through inhibiting recruitment and overactive of inflammation. However, the potential mechanisms are still not well evaluated. AIM OF STUDY: The aim of this study was to evaluate the protective function of Jingfang Granules on bleomycin caused acute lung injury and further discuss the potential pharmacological mechanisms. MATERIALS AND METHODS: C57BL/6J mice were intratracheal injected bleomycin to induce model with acute lung injury. The protective impact of Jingfang Granules on acute lung injury and lung fibrosis triggered by bleomycin were evaluated through detecting mice body weight, lung appearance, lung index, and histopathology. The potential pharmacological mechanism of Jingfang Granules in treating acute lung injury was further elucidated by the methods of network pharmacology, proteomics, metabolomics, as well as western blot. Additionally, the network pharmacology analysis and molecular docking technology were integrated to investigate the targets of Jingfang Granules improving acute lung injury. RESULTS: Our results indicated that Jingfang Granules effectively protected mice from acute lung injury induced by bleomycin, which was confirmed by higher body weight, lower pulmonary edema and lung index, and improved pathology and fibrosis of lung tissue compared to model group. Proteomics, western blot, and metabolomics were integrated and the results confirmed that Jingfang Granules regulated the Glycolysis/Gluconogenesis and Pyruvate metabolism through downregulating the PI3K/Akt/mTOR signaling pathway. The network pharmacology analysis and molecular docking technology results showed that the targets of Jingfang Granules for treating acute lung injury were enriched in the PI3K/Akt signaling pathway, which included 7 target proteins such as MAPK1, MAPK3, JAK2, HRAS, EGFR, PIK3R1, and PIK3CA. CONCLUSION: This study indicates that Jingfang Granules displays a markedly protective effect on acute lung injury caused by bleomycin through downregulating PI3K/Akt/mTOR signaling pathway, which in turn regulates Glycolysis/Gluconogenesis and Pyruvate metabolism.

GC-MS analysis and the effect of topical application of essential oils of Pinus canariensis C.Sm., Cupressus lusitanica Mill. and Cupressus arizonica Greene aerial parts in Imiquimod-Induced Psoriasis in Mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, Coniferous plants, in particular Pinus and Cupressus species, have been used in the treatment of burns, skin infections, and immune-mediated inflammatory diseases such as psoriasis. AIM OF THE STUDY: A comparative study between essential oils (EOs) extracted from aerial parts of three coniferous plants: Pinus canariensis C.Sm. (PC), Cupressus lusitanica Mill. (CL) and Cupressus arizonica Greene (CA), cultivated in Egypt, was designed to investigate their composition and their anti-psoriasis mechanism. MATERIALS AND METHODS: The phytochemical profiles were confirmed using Gas Chromatography-Mass Spectrometry (GC-MS) method. In-vivo Imiquimod (IMQ)-induced psoriasis model was performed and EOs were applied topically and compared to mometasone cream as a standard subsequently histopathological analysis and inflammatory biomarkers were measured. RESULTS: In GC-MS analysis, Monoterpene hydrocarbons, sesquiterpene hydrocarbons and oxygenated monoterpenes were the major detected classes in the three plants, except in Pinus canariensis essential oil, oxygenated monoterpenes were absent. A significant attenuation of imiquimod-induced psoriasis symptoms after topical application of P. canariensis C.Sm., and C. lusitanica Mill. essential oils were observed by reducing the psoriasis area severity index (PASI) score, alleviating histopathological alteration, restoring the spleen index, and decreasing serum levels of interleukins 23 and 17A. Indeed, the results of Pinus canariensis essential oil is comparable to mometasone and showed no significant difference from standard treatment. On the other hand, the topical application of C. arizonica essential oil failed to alleviate imiquimod-induced psoriasis symptoms as observed in the PSAI score, the histopathological investigation, and the spleen index. CONCLUSION: The essential oils of P. canariensis C.Sm., and C. lusitanica Mill aerial parts could be promising candidates for psoriasis treatment and for further studies on inflammation-related skin diseases.

Phyllostachys nigra Munro var alleviates inflammatory chemokine expression and DNCB-induced atopic-like dermatitis in BALB/c mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Phyllostachys nigra (PN) is an herbal medicine that originates from the inner bark of Phyllostachys nigra Munro var. henosis Stapf or Phyllostachys bambusoides Siebold et Zuccarini. It has long been used to relieve fever and to treat diarrhea and inflammation. PN has been shown to possess inhibitory effects on pneumonia, intestinal inflammation, tumors, and fatigue. However, its potential efficacy in the treatment of atopic dermatitis (AD) has not been extensively studied or reported. AIM OF THE STUDY: The objective of this research was to investigate the impact of PN on HaCaT and HMC-1 cells, as well as its potential in an experimental model of AD induced by 1-chloro-2,4-dinitrobenzene (DNCB). METHODS: We analyzed the anti-inflammatory efficacy of PN in HaCaT cells and HMC-1 cells using ELISA and PCR, and investigated invasion of inflammatory cell, change of dermis and epidermis, and the SCORAD index in AD-like mice model. We also measured the MAPK signaling pathway using the dorsal tissue of mice. RESULTS: Our results show that PN reduced the expressions of TARC, GM-CSF, TNF-α, MCP-1, and IL-6 in vitro. PN also decreased the SCORAD index, thickening of epidermis and dermis, and inhibited the invasions of mast cells and eosinophils as well as CD4+ T and CD8+ T cells. Furthermore, PN suppressed the level of IgE and IL-6, and also inhibited the MAPK phosphorylation in the dorsal skin. CONCLUSION: These results demonstrate that PN could be an effective alternative medicine for allergic inflammatory disease.