Curcumin and its derivatives in cancer therapy: Potentiating antitumor activity of cisplatin and reducing side effects.
Abadi Asal Jalal,Mirzaei Sepideh,Mahabady Mahmood Khaksary,Hashemi Farid,Zabolian Amirhossein,Hashemi Fardin,Raee Pourya,Aghamiri Shahin,Ashrafizadeh Milad,Aref Amir Reza,Hamblin Michael R,Hushmandi Kiavash,Zarrabi Ali,Sethi Gautam
Phytotherapy research : PTR
Curcumin is a phytochemical isolated from Curcuma longa with potent tumor-suppressor activity, which has shown significant efficacy in pre-clinical and clinical studies. Curcumin stimulates cell death, triggers cycle arrest, and suppresses oncogenic pathways, thereby suppressing cancer progression. Cisplatin (CP) stimulates DNA damage and apoptosis in cancer chemotherapy. However, CP has adverse effects on several organs of the body, and drug resistance is frequently observed. The purpose of the present review is to show the function of curcumin in decreasing CP's adverse impacts and improving its antitumor activity. Curcumin administration reduces ROS levels to prevent apoptosis in normal cells. Furthermore, curcumin can inhibit inflammation via down-regulation of NF-κB to maintain the normal function of organs. Curcumin and its nanoformulations can reduce the hepatoxicity, neurotoxicity, renal toxicity, ototoxicity, and cardiotoxicity caused by CP. Notably, curcumin potentiates CP cytotoxicity via mediating cell death and cycle arrest. Besides, curcumin suppresses the STAT3 and NF-ĸB as tumor-promoting pathways, to enhance CP sensitivity and prevent drug resistance. The targeted delivery of curcumin and CP to tumor cells can be mediated nanostructures. In addition, curcumin derivatives are also able to reduce CP-mediated side effects, and increase CP cytotoxicity against various cancer types.
10.1002/ptr.7305
The Intestinal Redox System and Its Significance in Chemotherapy-Induced Intestinal Mucositis.
Oxidative medicine and cellular longevity
Chemotherapy-induced intestinal mucositis (CIM) is a significant dose-limiting adverse reaction brought on by the cancer treatment. Multiple studies reported that reactive oxygen species (ROS) is rapidly produced during the initial stages of chemotherapy, when the drugs elicit direct damage to intestinal mucosal cells, which, in turn, results in necrosis, mitochondrial dysfunction, and ROS production. However, the mechanism behind the intestinal redox system-based induction of intestinal mucosal injury and necrosis of CIM is still undetermined. In this article, we summarized relevant information regarding the intestinal redox system, including the composition and regulation of redox enzymes, ROS generation, and its regulation in the intestine. We innovatively proposed the intestinal redox "Tai Chi" theory and revealed its significance in the pathogenesis of CIM. We also conducted an extensive review of the English language-based literatures involving oxidative stress (OS) and its involvement in the pathological mechanisms of CIM. From the date of inception till July 31, 2021, 51 related articles were selected. Based on our analysis of these articles, only five chemotherapeutic drugs, namely, MTX, 5-FU, cisplatin, CPT-11, and oxaliplatin were shown to trigger the ROS-based pathological mechanisms of CIM. We also discussed the redox system-mediated modulation of CIM pathogenesis via elaboration of the relationship between chemotherapeutic drugs and the redox system. It is our belief that this overview of the intestinal redox system and its role in CIM pathogenesis will greatly enhance research direction and improve CIM management in the future.
10.1155/2022/7255497
Chemotherapy induced gastrointestinal toxicities.
Advances in cancer research
Chemotherapy-induced gastrointestinal dysfunction is a common occurrence associated with many different classes of chemotherapeutic agents. Gastrointestinal toxicity includes mucositis, diarrhea, and constipation, and can often be a dose-limiting complication, induce cessation of treatment and could be life threatening. The gastrointestinal epithelium is rich in rapidly dividing cells and hence is a prime target for chemotherapeutic drugs. The incidence of gastrointestinal toxicity, including diarrhea and mucositis, is extremely high for a wide array of chemotherapeutic and radiation regimens. In fact, 60%-100% of patients on high-dose chemotherapy suffer from gastrointestinal side effects. Unfortunately, treatment options are limited, and therapy is often restricted to palliative care. Therefore, there is a great unmet therapeutic need for preventing and treating chemotherapy-induced gastrointestinal toxicities in the clinic. In this review, we discuss our current understanding of the mechanisms underlying chemotherapy-induced diarrhea and mucositis, and emerging mechanisms involving the enteric nervous system, smooth muscle cells and enteric immune cells. Recent evidence has also implicated gut dysbiosis in the pathogenesis of not only chemotherapy-induced mucositis and diarrhea, but also chemotherapy-induced peripheral neuropathy. Oxidative stress induced by chemotherapeutic agents results in post-translational modification of ion channels altering neuronal excitability. Thus, investigating how chemotherapy-induced changes in the gut- microbiome axis may lead to gut-related toxicities will be critical in the discovery of new drug targets for mitigating adverse gastrointestinal effects associated with chemotherapy treatment.
10.1016/bs.acr.2022.02.007
Cell proliferation within small intestinal crypts is the principal driving force for cell migration on villi.
Parker Aimee,Maclaren Oliver J,Fletcher Alexander G,Muraro Daniele,Kreuzaler Peter A,Byrne Helen M,Maini Philip K,Watson Alastair J M,Pin Carmen
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
The functional integrity of the intestinal epithelial barrier relies on tight coordination of cell proliferation and migration, with failure to regulate these processes resulting in disease. It is not known whether cell proliferation is sufficient to drive epithelial cell migration during homoeostatic turnover of the epithelium. Nor is it known precisely how villus cell migration is affected when proliferation is perturbed. Some reports suggest that proliferation and migration may not be related while other studies support a direct relationship. We used established cell-tracking methods based on thymine analog cell labeling and developed tailored mathematical models to quantify cell proliferation and migration under normal conditions and when proliferation is reduced and when it is temporarily halted. We found that epithelial cell migration velocities along the villi are coupled to cell proliferation rates within the crypts in all conditions. Furthermore, halting and resuming proliferation results in the synchronized response of cell migration on the villi. We conclude that cell proliferation within the crypt is the primary force that drives cell migration along the villus. This methodology can be applied to interrogate intestinal epithelial dynamics and characterize situations in which processes involved in cell turnover become uncoupled, including pharmacological treatments and disease models.-Parker, A., Maclaren, O. J., Fletcher, A. G., Muraro, D., Kreuzaler, P. A., Byrne, H. M., Maini, P. K., Watson, A. J. M., Pin, C. Cell proliferation within small intestinal crypts is the principal driving force for cell migration on villi.
10.1096/fj.201601002
Intestinal Homeostasis and Longevity: Drosophila Gut Feeling.
Fan Xiaolan,Gaur Uma,Yang Mingyao
Advances in experimental medicine and biology
The association between intestinal homeostasis and life span has caught the attention of the research community worldwide. There have been multiple evidences which support the role of gut homeostasis in aging. The Drosophila gastrointestinal tract is very similar to the mammalian gut, and therefore it can directly be used as a model to understand the association between gut microbiota, immune system, and aging in humans. In current review we have discussed the importance of gut microbiota in aging. Also we have highlighted the importance of host immune system and gut aging. Since the increased microbial load in the gut activates the host immune system, the dysregulated microbiota can have direct implications in gut aging. The proliferation and renewal of intestinal stem cells can also affect gut aging. Another important aspect that we have discussed is the communication between the gut and the other organ systems which affect the overall aging process. Altogether we propose that the Drosophila gut can be a good model to improve our understanding of human gut aging.
10.1007/978-981-13-1117-8_10
Saponins regulate intestinal inflammation in colon cancer and IBD.
Dong Jianyi,Liang Wei,Wang Tianxiao,Sui Jingru,Wang Jingyu,Deng Zhaobin,Chen Dapeng
Pharmacological research
The saponins are natural surface-active glycosides which are the principal components of many popular herbal medicinal plants such as ginseng, astragalus, and bupleurum. Recent studies have suggested that saponins can exert strong anti-inflammatory effects and induce immune homeostasis in many diseases. Intestinal-inflammation-related digestive diseases include inflammatory bowel disease (IBD), irritable bowel syndrome, intestinal ischemia-reperfusion injury, necrotizing enterocolitis and radiation proctitis, as well as intestinal inflammation caused by nonsteroidal anti-inflammatory drugs. The pathogenesis of these diseases is poorly understood, and the patients with these diseases suffer from mental stress and physical pain, while their families (and society) experience heavy economic losses. Results from animal experiments suggest that saponins can suppress intestinal inflammation, promote intestinal barrier repair, maintain the diversity of the intestinal flora, and decrease the incidence rate of colon-inflammation-related colon cancer. In this review, we discuss new findings regarding the effects of saponins on intestinal inflammation and digestive diseases with intestinal inflammation. In addition, we provide a summary of the underlying mechanism for saponins-induced treatment on intestinal-inflammation-related disease.
10.1016/j.phrs.2019.04.010
Sestrin protects Drosophila midgut from mercury chloride-induced damage by inhibiting oxidative stress and stimulating intestinal regeneration.
Chen Zhi,Zhang Wen,Wang Fen,Mu Ren,Wen Di
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP
Overproduction of the deleterious reactive oxygen species (ROS) is one of the major causes of mercury, a heavy metal with diverse applications and environmental presence, induced neuronal and gastrointestinal adversities in exposed organism including Drosophila melanogaster. Sestrin, an oxidative stress responsive gene, emerges as a novel player in the management of oxidative stress response. Due to limited information regarding the role of sestrin in mercury-induced gastrointestinal adversities, it was hypothesized that modulation of sestrin may improve the mercury-induced gastrointestinal adversities in Drosophila. Here, we fed Drosophila with 400 μM HgCl and found that sestrin transcriptional level was significantly increased in midguts. Sestrin knockdown in HgCl-exposed midguts decreased survival rates and climbing ability of flies, and inhibited superoxide dismutase and glutathione-S-transferase activities of midgut epithelieum. Meanwhile, sestrin knockdown in midgut aggravated the HgCl-induced disruption of intestinal organization by worsening ROS production and cell apoptosis. Immunohistochemical staining data revealed that sestrin knockdown inhibited intestinal stem cell division in HgCl-exposed midguts. Furthermore, JNK signaling was found to mediated sestrin expression in midgut. Taken together, the study demonstrated that sestrin protects Drosophila midgut from HgCl-induced oxidative damage by inhibiting ROS production and stimulating the tissue regeneration program under regulation of JNK signaling pathway. This work suggests therapeutic implications of sestrin against heavy metal-induced gastrointestinal adversities in mammals.
10.1016/j.cbpc.2021.109083
The reduction of oxidative stress by nanocomposite Fullerol decreases mucositis severity and reverts leukopenia induced by Irinotecan.
Arifa Raquel Duque Nascimento,Paula Talles Prosperi de,Madeira Mila Fernandes Moreira,Lima Renata Lacerda,Garcia Zélia Menezes,Ÿvila Thiago Vinícius,Pinho Vanessa,Barcelos Lucíola Silva,Pinheiro Maurício Veloso Brant,Ladeira Luiz Orlando,Krambrock Klaus,Teixeira Mauro Martins,Souza Danielle Glória
Pharmacological research
Irinotecan is a useful chemotherapeutic agent for the treatment of several solid tumors. However, this therapy is associated with side effects, including leukopenia and mucositis. Reactive oxygen species (ROS) activate inflammatory pathways and contribute to Irinotecan-induced mucositis. Fullerol is a nanocomposite with anti-oxidant properties that may reduce tissue damage after inflammatory stimuli. In this paper, the effects of Fullerol and mechanisms of protection were investigated in a model of Irinotecan-induced mucositis. Mucositis was induced by an injection of Irinotecan per 4 days in C57BL/6. Fullerol or a vehicle was injected every 12h. On day 7, the intestines were removed to evaluate histological changes, leukocyte influx, and the production of cytokines and ROS. Irinotecan therapy resulted in weight loss, an increased clinical score and intestinal injury. Treatment with Fullerol attenuated weight loss, decreased clinical score and intestinal damage. Irinotecan also induced increased ROS production in enterocytes, oxidative stress, IL-1β production, neutrophil and eosinophil influx in the ileum. Fullerol treatment decreased production of ROS in the enterocytes, oxidative stress, IL-1β production, neutrophil and eosinophil influx in the ileum. Irinotecan therapy also induced leukopenia in an ROS-dependent manner because leukopenia reverted in WT mice treated with Fullerol or Apocynin or in Gp91phox(-/-) mice. Mice treated with Irinotecan presented less melanoma tumor growth compared to the control group. Fullerol does not interfere in the anti-tumor action of Irinotecan. Fullerol has a great pharmacology potential to decreases the severity of mucositis and of leukopenia during chemotherapy treatment.
10.1016/j.phrs.2016.03.004
Musashi expression in intestinal stem cells attenuates radiation-induced decline in intestinal permeability and survival in Drosophila.
Sharma Amit,Akagi Kazutaka,Pattavina Blaine,Wilson Kenneth A,Nelson Christopher,Watson Mark,Maksoud Elie,Harata Ayano,Ortega Mauricio,Brem Rachel B,Kapahi Pankaj
Scientific reports
Exposure to genotoxic stress by environmental agents or treatments, such as radiation therapy, can diminish healthspan and accelerate aging. We have developed a Drosophila melanogaster model to study the molecular effects of radiation-induced damage and repair. Utilizing a quantitative intestinal permeability assay, we performed an unbiased GWAS screen (using 156 strains from the Drosophila Genetic Reference Panel) to search for natural genetic variants that regulate radiation-induced gut permeability in adult D. melanogaster. From this screen, we identified an RNA binding protein, Musashi (msi), as one of the possible genes associated with changes in intestinal permeability upon radiation. The overexpression of msi promoted intestinal stem cell proliferation, which increased survival after irradiation and rescued radiation-induced intestinal permeability. In summary, we have established D. melanogaster as an expedient model system to study the effects of radiation-induced damage to the intestine in adults and have identified msi as a potential therapeutic target.
10.1038/s41598-020-75867-z
Capsaicin Functions as Drosophila Ovipositional Repellent and Causes Intestinal Dysplasia.
Li Yaoxing,Bai Peng,Wei Longsheng,Kang Ruxue,Chen Lirong,Zhang Mingliang,Tan Eng King,Liu Wei
Scientific reports
Plants generate a plethora of secondary compounds (toxins) that potently influence the breadth of the breeding niches of animals, including Drosophila. Capsaicin is an alkaloid irritant from hot chili peppers, and can act as a deterrent to affect animal behaviors, such as egg laying choice. However, the mechanism underlying this ovipositional avoidance remains unknown. Here, we report that Drosophila females exhibit a robust ovipositional aversion to capsaicin. First, we found that females were robustly repelled from laying eggs on capsaicin-containing sites. Second, genetic manipulations show that the ovipositional aversion to capsaicin is mediated by activation of nociceptive neurons expressing the painless gene. Finally, we found that capsaicin compromised the health and lifespan of flies through intestinal dysplasia and oxidative innate immunity. Overall, our study suggests that egg-laying sensation converts capsaicin into an aversive behavior for female Drosophila, mirroring an adaptation to facilitate the survival and fitness of both parents and offspring.
10.1038/s41598-020-66900-2
Homeostatic Regulation of ROS-Triggered Hippo-Yki Pathway via Autophagic Clearance of Ref(2)P/p62 in the Drosophila Intestine.
Nagai Hiroki,Tatara Hiroshi,Tanaka-Furuhashi Kyoko,Kurata Shoichiro,Yano Tamaki
Developmental cell
Homeostasis of intestinal epithelia is maintained by coordination of the proper rate of regeneration by stem cell division with the rate of cell loss. Regeneration of host epithelia is normally quiescent upon colonization of commensal bacteria; however, the epithelia often develop dysplasia in a context-dependent manner, the cause and underlying mechanism of which remain unclear. Here, we show that in Drosophila intestine, autophagy lowers the sensitivity of differentiated enterocytes to reactive oxygen species (ROS) that are produced in response to commensal bacteria. We find that autophagy deficiency provokes ROS-dependent excessive regeneration and subsequent epithelial dysplasia and barrier dysfunction. Mechanistically, autophagic substrate Ref(2)P/p62, which co-localizes and physically interacts with Dachs, a Hippo signaling regulator, accumulates upon autophagy deficiency and thus inactivates Hippo signaling, resulting in stem cell over-proliferation non-cell autonomously. Our findings uncover a mechanism whereby suppression of undesirable regeneration by autophagy maintains long-term homeostasis of intestinal epithelia.
10.1016/j.devcel.2020.12.007