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Histological analyses of the kidney, heart, liver, spleen, lung and brain in crude protein-treated mice. The mice intraperitoneally administrated with crude protein underwent degeneration of renal tubular epithelial cells in the kidney. No marked difference was observed in other tissues or organs.
Source publication
The aim of the present study was to determine the toxic targets of proteins from Croton tiglium L. and to investigate the potential mechanism of their toxicity. The toxic targets were determined by oral medication and intraperitoneal injection. The median lethal dose of oral medication in mice was calculated using Bliss software (2,752.8-3,407.5 mg...
Context in source publication
Context 1
... mice intraperitoneally administrated with crude protein underwent degeneration of renal tubular epithelial cells in the kidney. No marked difference was observed in other tissues or organs (Fig. 2). Evaluation of intestinal permeability with FITC-dextran. Compared with the control group (Fig. 3), croton proteins significantly increased the intestinal permeability of the oral administration group. When the dose reached 3 g/kg, the intestinal permeability reached maximum. Following 4 h of treatment, the digestive tract was most ...
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Citations
... Modern pharmacological studies have shown that CF possessed good effects on lung cancer (Niu et al. 2020), colon cancer (Aboulthana et al. 2022), skin fungal infection (Lin et al. 2016), tuberculosis , and leukemia (Kupchan et al. 1976). However, CF could cause gastrointestinal injury (Liu et al. 2017) and inflammation (Dzietko et al. 2015), and the underlying mechanism is still unknown. ...
Crotonis Fructus (CF), a poisonous traditional laxative, has been used to treat constipation, edema, ascites, and inflammation for more than 2000 years. However, CF possesses toxicity and its toxic mechanism is still unclear. Thus, this research explored the deleterious impacts and underlying mechanisms of CF by evaluating alterations in gut microbiota composition and metabolites. High-throughput sequencing was employed on the 16S rDNA gene to explore the intestinal flora. The untargeted metabolomics method was utilized for evaluating serum metabolomics analysis. The results showed that CF could induce obvious hepatic and gastrointestinal damage by histopathologic morphology of the liver, stomach, duodenum, and colon. According to 16S rDNA sequencing, CF can cause gut microbiota disturbance in rats, and the abundance of opportunistic pathogens such as Clostridia_UCG_014_unclassified increased significantly, while the levels of beneficial bacterial Lactobacillus remarkably declined after CF treatment. Additionally, metabolomics analysis demonstrated that CF may induce toxicity by disrupting the glycerophospholipid metabolism pathway and metabolites such as phosphatidylcholine and phosphatidylethanolamine. Moreover, a correlation study revealed the link between intestinal flora, serum metabolites, and toxicity-related biochemical markers. The results provide a new idea for the research and clinical application of toxic traditional medicine.
Key points
• Crotonis Fructus could affect the gut flora and serum metabolic disruption in SD rats.
• Crotonis Fructus could promote the proliferation of harmful bacteria and inhibit beneficial bacteria.
• Glycerophospholipid metabolism was disturbed by Crotonis Fructus.
... Croton tiglium Linn. is reported to have severe purgative action. It primarily impairs Intestinal tract and Kidneys [3,4]. Croton tiglium Linn. ...
Background:
Croton tiglium Linn. (CT) which is commonly called Jaypal is used in Ayurvedic preparations like Ichhabhedi Ras, Asvakancuki Rasa. Due to its toxic contents, seeds of Croton tiglium are purified before use, by the process mentioned in classical Ayurvedic texts called Shodhana meaning purification.
Objectives:
The objective of the present study is to study the impact of Ayurvedic Purification process on cytotoxicity and genotoxicity of Croton tiglium Linn.
Materials and methods:
Croton tiglium Linn. Seeds were processed for Shodhana by soaking in water, heating with milk (Snehan) and later grinding in Lemon Juice (Bhavana). Aqueous and Hydroalcoholic extracts were prepared before and after purification i.e. Shodhana. Cytotoxicity of the Croton tiglium was studied against Chinese Hamster Ovary cell line by MTT assay. Ames test was performed to study the mutagenicity of the extracts in Salmonella typhi TA 98, 100 and 102 strains. Phytoconstituents were studied by using LCMS analysis.
Results:
The results indicated decrease in cytotoxic concentration (IC50) of Croton tiglium seeds after purificationa from 3.03 mg/mL to 0.99 mg/mL in aqueous extract and 18.56 mg/mL to 5.45 mg/mL. Genotoxicity study by Ames test indicated Croton tiglium Linn. Croton tiglium Linn. Seeds are non-genotoxic in strains like S. typhi, TA 98, 100 and 102. There was change in Phytochemical profile before and after shodhana.
Conclusion:
Although both the concentrations are practically non-toxic, the decrease in cytotoxic concentration indicates Purification process as described in classical ayurvedic texts i.e. Shodhana has definitely increased the potency of the seeds of Croton tiglium Linn.
... Furthermore, the proinflammatory signalling pathway in macrophages further determines the production of these factors. The MAPK signalling pathway is an important pathway responsible for inflammatory responses [49,50] . ...
Aloe vera Linne or aloe barbadensis Miller is a succulent from the Aloe family (400 different species), a tropical plant which is easily grown in hot and dry climates and widely distributed in Asia, Africa and other tropical areas. The use of aloe vera is being promoted for a large variety of conditions. The aim of this systematic review was to summarize all dermatology-oriented in vitro and in vivo experiments and clinical trials on aloe vera preparations. Extensive literature search were carried out to identify all in vitro and in vivo studies as well as clinical trials on the subject. Data were extracted from these in a predefined standardized manner. Forty studies were located. The results suggest that oral administration of aloe vera in mice is effective on wound healing, can decrease the number and size of papillomas and reduce the incidence of tumors and leishmania parasitemia by >90% in the liver, spleen, and bone marrow. Topical application of aloe vera is not an effective prevention for radiation-induced injuries and has no sunburn or suntan protection. It can be effective for genital herpes, psoriasis, human papilloma virus, seborrheic dermatitis, aphthous stomatitis, xerosis, lichen planus, frostbite, burn, wound healing and inflammation. It can also be used as a biological vehicle and an anti-microbial and antifungal agent and also as a candidate for photodynamic therapy of some kinds of cancer. Even though there are some promising results with the use of aloe vera for diverse dermatologic conditions, clinical effectiveness of oral and topical aloe vera is not sufficiently and meticulously explored as yet.
Keywords aloe vera, varieties, economic value, by product and Pharmacological & Phytochemistry properties
... Mitogen-activated protein kinase (MAPK), an extracellular signal-regulated kinase, is another important pathway protein for macrophage function (78,79). It is suggested that the MAPK signaling pathway plays a key role in kidney injury molecular 1(KIM-1) mediated renal injury by promoting macrophage phenotypic transformation and migration (80). ...
A growing number of studies have confirmed that immune cells play various key roles in the pathophysiology of acute kidney injury (AKI) development. After the resident immune cells and intrinsic renal cells are damaged by ischemia and hypoxia, drugs and toxins, more immune cells will be recruited to infiltrate through the release of chemokines, while the intrinsic cells promote macrophage polarity conversion, and the immune cells will promote various programmed deaths, phenotypic conversion and cycle arrest of the intrinsic cells, ultimately leading to renal impairment and fibrosis. In the complex and dynamic immune microenvironment of AKI, the bidirectional interaction between immune cells and intrinsic renal cells affects the prognosis of the kidney and the progression of fibrosis, and determines the ultimate fate of the kidney.
... mg/kg. [127] Diarrhoea C. tiglium is traditionally used in China as a laxative. ECT can enhance the short-circuit current of rat ileum epithelium activated by forskolin, but has little effect on the short-circuit current of rat ileum epithelium not activated by forskolin. ...
... Second, pharmacological studies of C. tiglium have focused on the evaluation of different components and extracts isolated from the plant, such as antitumour, analgesic, anti-inflammatory, antibacterial and antivirus effects. However, most of the studies are in vitro, and extensive in vivo experiments are required to verify [79] Inducing death ECT 1000 mg/kg Albino mice \ \ in vivo [123] Inducing death ECT 125-2000 mg/kg SD rat \ MC in vivo [125] Inducing cell death ECT 125-250 mg/ml Zebrafish embryos \ Egg water in vivo [126] Inducing cell death Croton oil 20 μl HaCaT cells ATP \ in vitro [124] Causing diarrhea Influencing ion transport across the rat ileal epithelia ECT 200 mg/ml SD rat Ouabain, Bumetanide \ in vivo [88] Causing diarrhea ECT 500 mg/kg F344 rat \ \ in vivo [125] Exhibiting gastrointestinal and intestinal damage Croton protein 0.75-3 g/kg ICR mice \ Saline in vivo [127] Carcinogenesis Inducing embryo lethality and developmental toxicity ECT 125-250 mg/ml Zebrafish embryos \ Egg water in vivo [126] Inducing genotoxicity 12-20 mg/ml CTX Inducing skin papilloma genesis Croton oil 1/100 ...
... μg/ml WB-F344 cells TPA in vitro [89] Clastogenic potential after in vivo exposure in vitro [129] Inducing inflammation Inducing inflammation Croton protein 25-400 mg/kg ICR mice \ Saline in vivo [127] Inducing the release of the proinflammatory cytokines Croton protein 50-400 µg/ml RAW264.7 cells \ DMEM in vivo [127] Inducing edema Croton oil 20 μl Male Swiss mice \ \ in vivo [124] Up-regulating COX mRNA Croton oil 20 μg/ml RAW 264.7 cells \ \ in vitro [130] Inducing ear inflammation Croton oil 50 μL ICR mice \ \ in vivo [130,131] Inducting pharyngitis Croton oil 10%-80% ...
Objectives
Croton tiglium Linn. (Euphorbiaceae) is an ancient medicinal plant that has been used for a long time, which is widely distributed in tropical and subtropical regions. And it is widely used for defecation, induced labour, treatment of gastrointestinal diseases, headache, as well as rheumatoid arthritis.
Key findings
Approximately 150 compounds have been isolated and identified from the seeds, stems, leaves and branches of C. tiglium, including fatty acids, terpenoids, alkaloids, the plants proteins and other types of components. Based on a wide range of biological properties, C. tiglium has a wide range of pharmacological effects, such as antitumor, anti-HIV, analgesic, anti-inflammatory and antibacterial effects.
Summary
The review aims to provide a critical and comprehensive evaluation of the botany, phytochemistry, pharmacology and toxicity of C. tiglium, with a vision for promoting further pharmaceutical research to explore its complete potential for better clinical application. The tigliane diterpenoids have been the most studied compounds isolated from C. tiglium, which showing a variety of biological activities, but there is insufficient evidence to explain the mechanism of action. In addition, C. tiglium may have potential toxic effects, and it is necessary to reduce the toxic effects to ensure the safety of clinical medication, which may promote the discovery and development of new drugs.
... e extract of C. tiglium inhibited α-amylase with 55.1% at 80 μg/mL [16]. Oral medication can cause severe gastrointestinal syndrome and even mortality because of irritating oils and croton proteins [58]. Tigliane-type diterpenoids are the predominant secondary metabolite constituents in C. tiglium L. [59]. ...
Objectives:
To explore the effective and safe medicines for treating diabetes.
Methods:
Hydroalcoholic extracts of 130 medicinal plants belonging to 66 families were evaluated using porcine pancreatic lipase (PPL) inhibition and glucose uptake methods together with a literature review.
Results:
The extracts of 22 species showed the PPL inhibition activity; 18 extracts of 15 species stimulated glucose uptake in 3T3-L1 adipocytes. Among them, Mansonia gagei J.R. Drumm., Mesua ferrea L., and Centella asiatica (L.) Urb. exhibited both activities. The extracts of Caladium lindenii (André) Madison rhizomes and Azadirachta indica A. Juss. leaves presented the utmost lipase inhibitory activity with IC50 of 6.86 ± 0.25 and 11.46 ± 0.06 μg/mL, respectively. The extracts of Coptis teeta Wall. rhizomes and Croton tiglium L. seeds stimulated the maximum glucose uptake. Ten species are reported to have antidiabetic activity for the first time. Flavonoids and triterpenoids are the dominant antidiabetic compounds in selected medicinal plants from Myanmar.
Conclusions:
P. zeylanica, L. cubeba, H. crenulate, M. gagei, C. teeta, and M. ferrea are worthy to advance further study according to their strong antidiabetic activities and limited research on effects in in vivo animal studies, unclear chemical constitutes, and safety.
... They are native to South Eastern and Southern Asian countries such as Malaysia, Vietnam, and Thailand. C. tiglium is a well-known medicinal and toxic species [37] found in local/traditional medicine preparations. It is also a source of co-carcinogenic phorbolesters, being one of the core species in early investigations of the phorbolesters' pharmacological profile [38]. ...
Selecting candidates for drug developments using computational design and empirical rules has resulted in a broad discussion about their success. In a previous study, we had shown that a species’ abundance [as expressed by the GBIF (Global Biodiversity Information Facility)] dataset is a core determinant for the development of a natural product into a medicine. Our overarching aim is to understand the unique requirements for natural product-based drug development. Web of Science was queried for research on alkaloids in combination with plant systematics/taxonomy. All alkaloids containing species demonstrated an average increase of 8.66 in GBIF occurrences between 2014 and 2020. Medicinal Species with alkaloids show higher abundance compared to non-medicinal alkaloids, often linked also to cultivation. Alkaloids with high biodiversity are often simple alkaloids found in multiple species with the presence of ’driver species‘ and are more likely to be included in early-stage drug development compared to ‘rare’ alkaloids. Similarly, the success of an alkaloid containing species as a food supplement (‘botanical’) is linked to its abundance. GBIF is a useful tool for assessing the druggability of a compound from a certain source species. The success of any development programme from natural sources must take sustainable sourcing into account right from the start.
... Acute toxicity of MoFTI was evaluated through the intraperitoneal route, which has been used to study the toxicity of some compounds, including plant proteins [37,38]. In addition, the dose used was determined to be at least 10-fold greater than the highest therapeutic dose tested for this protein in other studies (unpublished data) and is close to the dose used in other studies employing the same route. ...
... In addition, the dose used was determined to be at least 10-fold greater than the highest therapeutic dose tested for this protein in other studies (unpublished data) and is close to the dose used in other studies employing the same route. For example, Liu et al [37] used an intraperitoneal injection at 195.8-272.6 mg/kg to study the acute toxicity of a crude protein from Croton tiglium seeds. ...
Background
Protease inhibitors have been isolated from plants and present several biological activities, including immunomod-ulatory action.
Objective
This work aimed to evaluate a Moringa oleifera flower trypsin inhibitor (MoFTI) for acute toxicity in mice, hemolytic activity on mice erythrocytes and immunomodulatory effects on mice splenocytes.
Methods
The acute toxicity was evaluated using Swiss female mice that received a single dose of the vehicle control or MoFTI (300 mg/kg, i.p.). Behavioral alterations were observed 15–240 min after administration, and survival, weight gain, and water and food consumption were analyzed daily. Organ weights and hematological parameters were analyzed after 14 days. Hemolytic activity of MoFTI was tested using Swiss female mice erythrocytes. Splenocytes obtained from BALB/c mice were cultured in the absence or presence of MoFTI for the evaluation of cell viability and proliferation. Mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) levels were also determined. Furthermore, the culture supernatants were analyzed for the presence of cytokines and nitric oxide (NO).
Results
MoFTI did not cause death or any adverse effects on the mice except for abdominal contortions at 15–30 min after administration. MoFTI did not exhibit a significant hemolytic effect. In addition, MoFTI did not induce apoptosis or necrosis in splenocytes and had no effect on cell proliferation. Increases in cytosolic and mitochondrial ROS release, as well as ΔΨm reduction, were observed in MoFTI-treated cells. MoFTI was observed to induce TNF-α, IFN-γ, IL-6, IL-10, and NO release.
Conclusion
These results contribute to the ongoing evaluation of the antitumor potential of MoFTI and its effects on other immunological targets.
... These studies, therefore, suggest a neuroprotective effect of CTE. In one study, pro-inflammatory effect of C. tiglium L. have been reported [28]. Pro-inflammatory cytokines, including TNF-α and IL-1β, were significantly increased in the macrophage cell line RAW264.7 treated with crude proteins of Croton tiglium L., and the inflammatory effects was associated with p38-MAPK. ...
Neuroinflammation is involved in various neurological diseases. Activated microglia secrete many pro-inflammatory factors and induce neuronal cell death. Thus, the inhibition of excessive proinflammatory activity of microglia leads to a therapeutic effect that alleviates the progression of neuronal degeneration. In this study, we investigated the effect of Croton tiglium (C. tiglium) Linn. extract (CTE) on the production of pro- and anti-inflammatory mediators in microglia and astrocytes via RT-PCR, Western blot, and nitric oxide assay. Neurotoxicity was measured by cell viability assay and GFP image analysis. Phagocytosis of microglia was measured using fluorescent zymosan particles. CTE significantly inhibited the production of neurotoxic inflammatory factors, including nitric oxide and tumor necrosis factor-α. In addition, CTE increased the production of the neurotrophic factor, brain-derived neurotrophic factor, and the M2 phenotype of microglia. The culture medium retained after CTE treatment increased the survival of neurons, thereby indicating the neuroprotective effect of CTE. Our findings indicated that CTE inhibited pro-inflammatory response and increased the neuroprotective ability of microglia. In conclusion, although CTE is known to be a poisonous plant and listed on the FDA poisonous plant database, it can be used as a medicine if the amount is properly controlled. Our results suggested the potential benefits of CTE as a therapeutic agent for different neurodegenerative disorders involving neuroinflammation.
... Additionally, by using p38 MAPK inhibitor, researchers found that MC4R induced hyperalgesia and allodynia after CCI by the activation of p38 MAPK in dorsal root ganglion (DRG) ( Chu et al., 2012b,c). c-Jun N-terminal kinase (JNK) is another branched signaling pathway of MAPK that can be triggered by various stress stimuli and leads to the upregulation of proinflammatory mediators ( Liu et al., 2017;Yu et al., 2018). Recently, augmenting reports have suggested that JNK is involved in the regulation of neuropathic pain (Cao et al., 2015;Chen et al., 2016). ...
Background
Neuropathic pain can develop after nerve injury, when deleterious changes occur in injured neurons and glia cells. Melanocortin 4 receptor (MC4R) is involved in the regulation of pain due to its high expressions in brain. Moreover, MC4R could mediate the c-Jun N-terminal kinase (JNK) signaling pathway, but whether the MC4R-regulated JNK signaling pathway participated in neuropathic pain after chronic constriction injury (CCI) is still unclear.
Methods
A total of 128 Sprague-Dawley rats were allocated into four experiment groups: the SHAM group, CCI + NaCl group, CCI + HS group, and CCI + SP + HS group. For the CCI + NaCl group, the sciatic nerves were ligated. For the SHAM group, an identical manner to the CCI without ligation was performed. For CCI + HS and CCI + SP + HS groups, rats were injected with MC4R inhibitor (HS014) and HS014 plus JNK inhibitor (SP600125), respectively, from days 3 to 14 after CCI. Paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) were used to assess the nociceptive behavior. ELISA was used to detect the levels of inflammatory cytokines. qRT-PCR and Western blots (WB) were utilized to examine the mRNA and protein expressions of JNK signaling pathway-related genes. Meanwhile, the expression levels of MC4R and p-JNK were further evaluated by immunohistochemistry (IHC) and immunofluorescence (IF) experiments. Finally, in order to confirm the in vivo results, astrocytes were isolated and transfected with MC4R-overexpression plasmid. Furthermore, the protein expressions of JNK signaling pathway-related genes were tested by WB.
Results
It was showed that the values of PWL and PWT were significantly increased in CCI + HS group and CCI + SP + HS group compared with CCI + NaCl group. The increased interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) secretion in CCI + NaCl group was lowered by HS and SP + HS. MC4R, p-JNK, ATF3, and c-Jun levels were up-regulated with CCI surgery, but down-regulated with HS and SP + HS treatments. Moreover, the IHC and IF results further revealed that MC4R and p-JNK expressions in CCI + NaCl group were remarkably higher than those in HS group and HS + SP group. In vitro data also indicated that HS, SP, and SP + HS could down-regulate the expressions of MC4R, p-JNK, ATF3, and c-Jun in M1830 astrocytes.
Conclusion
Our findings indicated that MC4R is involved in neuropathic pain by regulating JNK signaling pathway after CCI.
