Protective Effect Of Artesunate Research Articles

Artesunate Exerts Organ- and Tissue-Protective Effects by Regulating Oxidative Stress, Inflammation, Autophagy, Apoptosis, and Fibrosis: A Review of Evidence and Mechanisms.

The human body comprises numerous organs and tissues operating in synchrony, it facilitates metabolism, circulation, and overall organismal function. Consequently, the well-being of our organs and tissues significantly influences our overall health. In recent years, research on the protective effects of artesunate (AS) on various organ functions, including the heart, liver, brain, lungs, kidneys, gastrointestinal tract, bones, and others has witnessed significant advancements. Findings from in vivo and in vitro studies suggest that AS may emerge as a newfound guardian against organ damage. Its protective mechanisms primarily entail the inhibition of inflammatory factors and affect anti-fibrotic, anti-aging, immune-enhancing, modulation of stem cells, apoptosis, metabolic homeostasis, and autophagy properties. Moreover, AS is attracting a high level of interest because of its obvious antioxidant activities, including the activation of Nrf2 and HO-1 signaling pathways, inhibiting the release of reactive oxygen species, and interfering with the expression of genes and proteins associated with oxidative stress. This review comprehensively outlines the recent strides made by AS in alleviating organismal injuries stemming from various causes and protecting organs, aiming to serve as a reference for further in-depth research and utilization of AS.

Artesunate Inhibits Apoptosis and Promotes Survival in Schwann Cells via the PI3K/AKT/mTOR Axis in Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is an early developing complication of diabetes mellitus associated with nerve dysfunction. Artesunate (ART), a natural compound extracted from the herb Artemisia annua L., was reported to benefit neural injury. However, whether ART has a role in preventing DPN is still unknown. In this study, a rat model of DPN with a high fat diet feeding and streptozotocin (STZ) injection was established. The findings indicated that ART treatment significantly ameliorated hyperglycemia-induced hot plate reaction latency (HPRL) decline, cold sensitivity and mechanical allodynia, and nerve injury by inhibiting sciatic nerve apoptosis. Further, ART restored high glucose (HG)-induced elevated apoptosis and deficient survival in rat neuronal Schwann cells, RSC96 cells. We demonstrated that ART promoted protein kinase B (AKT) phosphorylation as well as its downstream factor mammalian target of rapamycin (mTOR) in vivo and in vitro. Of note, the protective effects of ART in RSC96 cells under HG condition could be counteracted by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Taken together, ART mitigated hyperglycemia-induced nerve injury by suppressing apoptosis and promoting the viability of Schwann cells via the PI3K/AKT/mTOR signaling pathway.

Artesunate delays the dysfunction of age-related intestinal epithelial barrier by mitigating endoplasmic reticulum stress/unfolded protein response

The impairment of the intestinal epithelial barrier and subsequent bacterial translocation are common in aging individuals, contributory to several local and systematic disorders. However, the underlying mechanism of the age-related degeneration has not been fully understood. In this study, we demonstrated that the intestinal KIT signaling declined and de-activated with aging, parallel with epithelial barrier dysfunction. Endoplasmic reticulum stress (ERS)/unfolded protein response (UPR) was obviously increased during aging. The ERS and its downstream IRE1α were highly activated in the aging colonic epithelium. Furthermore, by the use of Tunicamycin (Tm)-induced ERS mouse and cell models, we uncovered that the activity of the ERS/IRE1α accelerated the protein degradation of KIT via ubiquitin-proteasome pathway. The deficiency of KIT signaling further reduced the transcription of the tight junction protein Claudin-3. Of significance, Artesunate (ART) could be capable of ameliorating the detrimental effect of ERS/IRE1α, indicated by the re-gained KIT and Claudin-3 expressions and the restoration of the intestinal epithelial barrier. In conclusion, our present study provided novel evidence elucidating the ERS/IRE1α-induced loss of KIT and Claudin-3 in the aging colonic epithelium and also shed light on the protective effect of Artesunate on the intestinal epithelial barrier by blocking ERS/IRE1α activity during aging.

The Protective Effect of Artesunate on LPS-Induced Acute Respiratory Distress Syndrome through Inhibiting NLRP3 Inflammasome Signaling.

Background Artesunate (AS) is a derivative of artemisinin that can exert anti-inflammatory effects. This study aims to explore the effect of AS on lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Methods The newborn mice were used for experimental ARDS model establishment by intraperitoneal injection of LPS (10 mg/kg) into mice with or without AS (20 mg/kg) pretreatment. After that, the pathological morphology of mouse lung tissue was observed by H&E staining. The content of inflammatory factors in serum was measured by ELISA and mRNA expression and lung tissue was determined by qRT-PCR. The expression of NLRP3 inflammasome and related proteins in lung tissue was confirmed by immunohistochemistry and Western blot. Results AS treatment effectively alleviated the LPS-induced lung injury and pulmonary edema, and reduced the expression of IL-1β, IL-18, IL-6, IL-8, MCP-1, and TNF-α in serum and lung tissues of experimental ARDS mice. In addition, AS treatment reduced the expression of NLRP3, ASC, and caspase-1 in lung tissues of experimental ARDS mice. Conclusion AS alleviated LPS-induced lung injury in ARDS mice by inhibiting the activation of NLRP3 inflammasome.

Artesunate restores mitochondrial fusion-fission dynamics and alleviates neuronal injury in Alzheimer's disease models.

Alzheimer's disease (AD) remains a leading cause of dementia and no therapy that reverses underlying neurodegeneration is available. Recent studies suggest the protective role of artemisinin, an antimalarial drug, in neurological disorders. In this study, we investigated the therapeutic potential of artesunate, a water-soluble derivative of artemisinin, on amyloid-beta (Aβ)-treated challenged microglial BV-2, neuronal N2a cells, and the amyloid precursor protein/presenilin (APP/PS1) mice model. We found that Aβ significantly induced multiple AD-related phenotypes, including increased expression/production of pro-inflammatory cytokines from microglial cells, enhanced cellular and mitochondrial production of reactive oxygen species, promoted mitochondrial fission, inhibited mitochondrial fusion, suppressed mitophagy or biogenesis in both cell types, stimulated apoptosis of neuronal cells, and microglia-induced killing of neurons. All these in vitro phenotypes were attenuated by artesunate. In addition, the over-expression of the mitochondrial fission protein Drp-1, or down-regulation of the mitochondrial fusion protein OPA-1 both reduced the therapeutic benefits of artesunate. Artesunate also alleviated AD phenotypes in APP/PS1 mice, reducing Aβ deposition, and reversing deficits in memory and learning. Artesunate protects neuronal and microglial cells from AD pathology, both in vitro and in vivo. Maintaining mitochondrial dynamics and simultaneously targeting multiple AD pathogenic mechanisms are associated with the protective effects of artesunate. Consequently, artesunate may become a promising therapeutic for AD.

Artesunate ameliorates DSS-induced ulcerative colitis by protecting intestinal barrier and inhibiting inflammatory response.

There are very few reports on the protective effect of artesunate (ARS) in ulcerative colitis (UC). This study focused on the efficacy of ARS on intestinal barrier, inflammatory response, and potential mechanism in dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. The results suggested that ARS treatment markedly alleviated DSS-induced clinical symptoms by relieving body weight loss, the disease activity index (DAI) score, and preventing colonic shortening. HE staining and scanning electron microscope analysis revealed that ARS treatment significantly protected the integrity of intestinal barrier through alleviating DSS-induced erosion of surface epithelial cells, reduction of goblet cells, and destruction of the crypt accompanied with inflammatory cells infiltration. Immunofluorescence histochemical staining and western blot assay confirmed that ARS notably inhibited the loss of Muc2 and claudin-1 in mucosal layer with a relative higher level of Bcl-2/Bax ratio and, moreover, inhibited cleaved-caspase-3 expression in colon tissue. In addition, this study reconfirmed the anti-inflammatory function of ARS evidenced by remarkably suppressing the phosphorylation of nuclear factor-κBα (IκBα) and NF-κB p65 and the expression of IL-1β, IL-6, and TNF-α while enhancing IL-10 expression. Taken together, these data highlight that ARS has the protective effect on UC through maintaining the expression of intestinal mucosal barrier-related proteins, suppressing the apoptosis and inflammatory response. This study may facilitate to understand the action mechanism of ARS against UC.

Protective Effect of Artesunate on LPS-induced Acute Lung Injury by Anti-oxidant Through AKT/PI3K Pathway

Oxidative stress are involved in the pathogenesis of acute lung injury (ALI). Accordingly, anti-inflammatory treatment is proposed to be a possible efficient therapeutic strategy for ALI. The aim of the study was to evaluate the antioxidant efficacy of Artesunate (Ar) on ALI induced by lipopolysaccharide (LPS) in mice and explore the underlying mechanism. BALB/c mice received Ar (2, 4 mg/kg) intraperitoneally 1h prior to the in intratracheal instillation of lipopolysaccharide (LPS) challenge. Malondialdehyde (MDA) was detected to evaluate the anti-oxidant efficacy of Artesunate.Content of Superoxide Dismutase (SOD) and Catalase (CAT) were assayed by enzyme linked immunosorbent assay (ELISA).Western blot was employed to determine the protein expression of P-PI3K,PI3K, P-AKT and AKT. The results showed the severity of lung injury was attenuated by Ar (40 mg/kg) and Dex (2 mg/kg) and the levels of MDA in Ar (20, 40 mg/kg) and Dex (2mg/kg) groups were obviously lower than those in LPS group. The treatment with Ar (20, 40 mg/kg) and Dex (2 mg/kg) remarkably increased the levels of SOD and CAT. The protein expressions of signaling showed the protein expressions of PI3Kand ATK significantly enhanced compared with those in LPS group after Areating with Ar (20 and 40 mg/kg) and Dex (2 mg/kg). In conclusion, this study revealed that Artesunate could exert protective effect of on LPS-induced acute lung injury by anti-oxidant through AKT/PI3K pathway.

Neuroprotective Effect of Artesunate in Experimental Model of Traumatic Brain Injury.

Traumatic brain injuries (TBI) are an important public health challenge. In addition, subsequent events at TBI can compromise the quality of life of these patients. In fact, TBI is associated with several complications for both long and short term, some evidence shows how TBI is associated with a decline in cognitive functions such as the risk of developing dementia, cerebral atrophy, and Parkinson disease. After the direct damage from TBI, a key role in TBI injury is played by the inflammatory response and oxidative stress, that contributes to tissue damage and to neurodegenerative processes, typical of secondary injury, after TBI. Given the complex series of events that are involved after TBI injury, a multitarget pharmacological approach is needed. Artesunate is a more stable derivative of its precursor artemisin, a sesquiterpene lactone obtained from a Chinese plant Artemisia annua, a plant used for centuries in traditional Chinese medicine. artesunate has been shown to be a pluripotent agent with different pharmacological actions. therefore, in this experimental model of TBI we evaluated whether the treatment with artesunate at the dose of 30 mg\\Kg, had an efficacy in reducing the neuroinflammatory process after TBI injury, and in inhibiting the NLRP3 inflammasome pathway, which plays a key role in the inflammatory process. We also assessed whether treatment with artesunate was able to exert a neuroprotective action by modulating the release of neurotrophic factors. our results show that artesunate was able to reduce the TBI-induced lesion, it also showed an anti-inflammatory action through the inhibition of Nf-kb, release of proinflammatory cytokines IL-1β and TNF-α and through the inhibition NLRP3 inflammasome complex, furthermore was able to reduce the activation of astrocytes and microglia (GFAP, Iba-1). Finally, our results show that the protective effects of artesunate also occur through the modulation of neurotrophic factors (BDNF, GDNF, NT-3) that play a key role in neuronal survival.

Artesunate ameliorates high glucose-induced rat glomerular mesangial cell injury by suppressing the TLR4/NF-κB/NLRP3 inflammasome pathway

Inflammatory response is important for the development and progression of diabetic nephropathy (DN). Artesunate (ART), an antimalarial drug, possesses anti-inflammatory effect and exhibits protective effect on chronic kidney diseases. However, the effect of ART on DN is unknown. The aim of the present study was to evaluate the effect and the molecular mechanism of ART on DN in an in vitro model. The rat mesangial cell line, HBZY-1, was induced by high glucose (HG; 30 mM d-glucose) in the presence or absence of ART (15 and 30 μg/ml) and incubated for 24 h. We found that HG induced the proliferation of HBZY-1 cells, while treatment with ART inhibited the cell proliferation. Treatment with ART inhibited HG-induced inflammatory cytokines production and expression of extracellular matrix (ECM). Besides, HG induced reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and inhibited the superoxide dismutase (SOD) activity of HBZY-1 cells, and the effects were attenuated by ART treatment. ART decreased HG-induced the expression levels of toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88), nuclear factor κB (NF-κB) p-p65, and nod-like receptor protein 3 (NLRP3). Inhibition of the TLR4/NF-κB pathway suppressed NLRP3 inflammasome in HBZY-1 cells. In conclusion, ART exhibited protective effect on HG-induced HBZY-1 cells by inhibiting the inflammatory response, oxidative stress and ECM accumulation. The TLR4/NF-κB/NLRP3 inflammasome pathway was involved in the protective effect of ART. The results suggested that ART might be a potential therapy agent for the DN treatment.

Protective effect of artesunate and aspirin in experimental model of colorectal cancer

Protective effect of artesunate and aspirin in experimental model of colorectal cancer

Attenuation of gastric mucosal damage by artesunate in rat: Modulation of oxidative stress and NFκB mediated signaling

A number of factors like alcohol consumption, stress, use of non steroidal anti-inflammatory drugs and acidity are well known to increase the risk of development of gastric ulcers. The present study was carried out to investigate the protective effect of artesunate against gastric injury induced in rats by oral administration of ethanol and by pylorus ligation in independent sets of experiments. The groups included in each set (n = 6 per group) were normal control, experimental control and drug treated groups: artesunate 50 and 150 mg/kg (ART 50 and ART 150) and famotidine 20 mg/kg (FAM 20). Artesunate and famotidine were given orally 1 h before induction of gastric ulceration and the macroscopic changes, median ulcer score, gastric juice parameters (volume, pH and acidity), markers of oxidative stress and inflammation (GSH, SOD, TBARS and MPO) and tissue histology were evaluated in both the models. The study was extended further for determination of tissue levels of TNF-α and expression of IL-1β, IL-6 and NFκB (p65) in ethanol induced gastric ulcer model. The results of the present study show that pretreatment with artesunate significantly decreased hemorrhagic lesions and mucosal damage with marked reduction in median ulcer score in both the models. The protective effect of artesunate was concomitant with dose-dependent normalization of gastric juice parameters, markers of oxidative stress and lipid peroxidation. The ameliorative effect of artesunate was also supported by restoration of histological architecture. Furthermore, artesunate pretreatment also alleviated the gastric mucosal inflammation as revealed by significant decrease in the tissue level of pro-inflammatory cytokine TNF-α (p < 0.01) and tissue expression of IL-1β, IL-6 and NFκB (p65). The protective effect of artesunate was found to be comparable to that of famotidine. Conclusively, artesunate afforded significant gastroprotection in rat due to its anti-oxidant and anti-inflammatory properties with transcription factor NFκB(p65) and its downstream inflammatory cascade as a plausible target for its action.

Artesunate Protects Against Sepsis-Induced Lung Injury Via Heme Oxygenase-1 Modulation.

Artesunate, a derivative of artemisinin, has anti-inflammatory properties and exerts protective roles in sepsis. Heme oxygense-1 (HO-1) inhibits the inflammatory response through reduction of proinflammatory cytokines and leukocyte influx into tissues. The present study investigated the effects of artesunate on HO-1 and septic lung injury. Cecal ligation and puncture (CLP) was employed to induce septic lung injury. Mice pretreated with artesunate (AS) (15mg/kg) exhibited decreased sepsis-induced mortality and lung injury and alleviated lung pathological changes and neutrophil infiltration. In addition, AS lowered the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the serum and bronchoalveolar lavage fluid (BALF) and inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase isoform (iNOS) expression and NF-κB activation in lung tissue. In addition, AS enhanced NF-E2-related factor-2 (Nrf2) activation and HO-1 expression and enzymatic activity in lung tissue. However, the protective effects of AS on sepsis-induced lung injury were eliminated by ZnPP IX, an HO-1 competitive inhibitor. Therefore, AS plays protective roles in septic lung injury related to the upregulation of HO-1. These findings suggest an effective and applicable treatment to sepsis-induced lung injury and provide new insights into the molecular mechanisms and actions of AS.

Protective effects of artesunate on septic lung injury in mice via modulation of heme oxygenase-1

Objective To investigate the effects of artesunate (AS) on septic lung injury in mice and to study the modulation of heme oxygenase-1 (HO-1) in lung in order to clarify the mechanism of AS action. Methods Sixty male Kunming mice were randomly (random number) divided into four groups: Sham group ( n =15 ) , CLP group ( n =15) , AS+CLP group ( n =15) and AS+ZnPP+CLP group ( n =15). Cecal ligation and puncture (CLP) method was employed to induce septic lung injury. AS (15 mg/kg) was injected into the abdomen of mice 2 hours before the CLP procedures, and ZnPP IX, an inhibitor of HO-1, was intraperitoneally injected in dose of 40 μmol/kg 1 hour after the AS injection. The equivalent volume of normal saline was intraperitoneally injected instead in mice of Sham group and CLP group. The mice were sacrificed 24 hours after the CLP procedures. The TNF-α, IL-6 in serum were assayed by ELISA method. The lung injury score and wet/dry ratio were measured. The western blotting and immunohistochemistry methods were used to determine HO-1 protein expression in lung tissue. The protein level of nuclear factor-E2-related factor-2 (Nrf-2) , an important transcriptional factor of HO-1 in lung tissue was also analyzed by western blotting. One-way analysis of variance (ANOVA) was used for comparisons among the groups, and SNK-q (Student-Newman-Keuls) test was performed for further comparison, and difference was statistically significant at P <0.05. Results The TNF-α (pg/mL) (54.37 ± 15.59 vs. 627.45±117.03, P 0.05; wet/dry weight ratio: 6.78 ± 0.73 vs. 6.29±0.82, P >0.05). Conclusions AS plays protective roles in septic lung injury, and it is attributed to limiting lung inflammation via up-regulation of HO-1. Key words: Artesunate; Sepsis; Heme oxgenase-1; Acute lung injury

Artesunate protects pancreatic beta cells against cytokine-induced damage via SIRT1 inhibiting NF-κB activation

Artesunate (ART) has been known as the most effective and safe reagents to treat malaria for many years. In this study, we explored whether ART could protect pancreatic beta-cell against cytokine-induced damage. The production of nitrite (NO) was detected with the Griess Assay Kit. SIRT1 and inducible nitric oxide synthase (iNOS) expression were determined with Western blot. The transcriptional activity of NF-κB was evaluated by luciferase reporter assay. The expression of Sirt1 was silenced by RNA interference. Glucose-stimulated insulin secretion (GSIS) and potassium-stimulated insulin secretion (KSIS) assays were performed to measure the effect of ART on pancreatic beta-cells' function. The effect of ART on beta-cells apoptosis was evaluated by using Hochest/PI staining and TUNEL assay. ART enhanced GSIS (KSIS) and reduced apoptosis of pancreatic beta-cells induced by IL-1β. Further study showed that ART inhibited IL-1β-induced increase of NF-κB activity, iNOS expression, and NO production. Moreover, ART up-regulated SIRT1 expression in INS-1 cells and islets exposed to IL-1β. Inhibition of SIRT1 expression could partially abolished the inhibitory effect of ART on NF-κB activity in IL-1β-treated beta-cells. More importantly, the protective effect of ART on cytokine-induced damage was reversed by silencing SIRT1 expression. ART can elicit a protective effect on beta-cells exposed to IL-1β by stimulating SIRT1 expression, which resulted in the decrease of NF-κB activity, iNOS expression, and NO production. Hence, ART might be an effective drug for diabetes.