Uncovering the Therapeutic Potential of Phosphocreatine in Diabetic Retinopathy: Mitigating Mitochondrial Dysfunction and Apoptosis via JAK2/STAT3 Signaling Pathway.

Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia.

Mechanism study of oleanolic acid derivative, K73-03, inducing cell apoptosis in hepatocellular carcinoma.

Oleanolic acid (3ß-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. Here, we show that K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway. Collectively, this study may provide a preliminary basis for further cancer treatment of hepatocellular carcinoma.

Research Progress and New Perspectives of Anticancer Effects of Emodin.

Emodin is a natural compound found in several traditional Chinese medicines, including Rheum palmatum and Polygonum cuspidatum. Recent studies have shown that emodin exhibits potent anticancer effects against a variety of cancer types, including liver, breast, lung, and colon cancer. Emodin's anticancer effects are mediated through several mechanisms, including inhibition of cell proliferation, induction of apoptosis, and suppression of tumor angiogenesis and metastasis. In this review, we provide an overview of recent research progress and new perspectives on emodin's anticancer effect. We summarize the current understanding of the molecular mechanisms underlying emodin's anticancer activity, including its effects on signaling pathways such as the PI3K/Akt, MAPK, and NF-[Formula: see text]B pathways. We also discuss the potential of emodin as a therapeutic agent for cancer treatment, including its use in combination with conventional chemotherapeutic drugs and as a sensitizer for radiotherapy. Furthermore, we highlight recent advances in the development of emodin derivatives and their potential as novel anticancer agents. Finally, we discuss the challenges and opportunities for the translation of emodin's anticancer properties into clinical applications, including the need for further preclinical and clinical studies to evaluate its safety and efficacy. In conclusion, emodin represents a promising natural compound with potent anticancer properties, and its potential as a therapeutic agent for cancer treatment warrants further investigation. This review provides a comprehensive overview of the current research progress and new perspectives on emodin's anticancer effects, which may facilitate the development of novel therapeutic strategies for cancer treatment.

Protective effects of phosphocreatine on human vascular endothelial cells against hydrogen peroxide-induced apoptosis and in the hyperlipidemic rat model.

Phosphocreatine (PCr) has been shown to have a cardio-protective effect during cardiopulmonary resuscitation (CPR). However, little is known about its impact on atherosclerosis. In this study, we first evaluated the pharmacological effects of PCr on antioxidative defenses and mitochondrial protection against hydrogen peroxide (H2O2) induced human umbilical vascular endothelial cells (HUVECs) damage. Then we investigated the hypolipidemic and antioxidative effects of PCr on hyperlipidemic rat model. Via in vitro studies, H2O2 significantly reduced cell viability and increased apoptosis rate of HUVECs, while pretreatment with PCr abolished its apoptotic effect. PCr could reduce the generation of ROS induced by H2O2. Moreover, PCr could increase the activity of SOD and the content of NO, as well as decrease the activity of LDH and the content of MDA. PCr could also antagonize H2O2-induced up-regulation of Bax, cleaved-caspase3, cleaved-caspase9, and H2O2-induced down-regulation of Bcl-2 and p-Akt/Akt ratio. In addition, PCr reduced U937 cells' adhesion to H2O2-stimulated HUVECs. Via in vivo study, PCr could decrease MDA, TC, TG and LDL-C levels in hyperlipidemic rats. Finally, different-concentration PCr could increase the leaching of TC, HDL, and TG from fresh human atherosclerotic plaques. In conclusion, PCr could suppress H2O2-induced apoptosis in HUVECs and reduce hyperlipidemia through inhibiting ROS generation and modulating dysfunctional mitochondrial system, which might be an effective new therapeutic strategy to further prevent atherosclerosis.

Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies.

Background Cancer remains a critical global health challenge and a leading cause of mortality. Flavonoids found in fruits and vegetables have gained attention for their potential anti-cancer properties. Fisetin, abundantly present in strawberries, apples, onions, and other plant sources, has emerged as a promising candidate for cancer prevention. Epidemiological studies linking a diet rich in these foods to lower cancer risk have sparked extensive research on fisetin's efficacy. Objective This review aims to comprehensively explore the molecular mechanisms of fisetin's anticancer properties and investigate its potential synergistic effects with other anticancer drugs. Furthermore, the review examines the therapeutic and preventive effects of fisetin against various cancers. Methods A systematic analysis of the available scientific literature was conducted, including research articles, clinical trials, and review papers related to fisetin's anticancer properties. Reputable databases were searched, and selected studies were critically evaluated to extract essential information on fisetin's mechanisms of action and its interactions with other anticancer drugs. Results Preclinical trials have demonstrated that fisetin inhibits cancer cell growth through mechanisms such as cell cycle alteration, induction of apoptosis, and activation of the autophagy signaling pathway. Additionally, fisetin reduces reactive oxygen species levels, contributing to its overall anticancer potential. Investigation of its synergistic effects with other anticancer drugs suggests potential for combination therapies. Conclusion Fisetin, a bioactive flavonoid abundant in fruits and vegetables, exhibits promising anticancer properties through multiple mechanisms of action. Preclinical trials provide a foundation for further exploration in human clinical trials. Understanding fisetin's molecular mechanisms is vital for developing novel, safe, and effective cancer prevention and treatment strategies. The potential synergy with other anticancer drugs opens new avenues for combination therapies, enhancing cancer management approaches and global health outcomes.

Procyanidins: A promising anti-diabetic agent with potential benefits on glucose metabolism and diabetes complications.

Diabetes mellitus (DM) is a complex disease with alarming worldwide health implications and high mortality rates, largely due to its complications such as cardiovascular disease, nephropathy, neuropathy, and retinopathy. Recent research has shown that procyanidins (PC), a type of flavonoid, have strong antioxidant and free radical elimination effects, and may be useful in improving glucose metabolism, enhancing pancreatic islet cell activity, and decreasing the prevalence of DM complications. This review article presents a systematic search for peer-reviewed articles on the use of PC in the treatment of DM, without any language restrictions. The article also discusses the potential for PC to sensitise DM medications and improve their efficacy. Recent in vivo and in vitro studies have demonstrated promising results in improving the biological activity and bioavailability of PC for the treatment of DM. The article concludes by highlighting the potential for novel materials and targeted drug delivery methods to enhance the pharmacokinetics and bioactivity of PC, leading to the creation of safer and more effective anti-DM medications in the future.

Protection of pancreatic ß-cell by phosphocreatine through mitochondrial improvement via the regulation of dual AKT/IRS-1/GSK-3ß and STAT3/Cyp-D signaling pathways.

Diabetes mellitus (DM) is a metabolic syndrome, caused by insufficient insulin secretion or insulin resistance (IR). DM enhances oxidative stress and induces mitochondrial function in different kinds of cell types, including pancreatic ß-cells. Our previous study has showed phosphocreatine (PCr) can advance the mitochondrial function through enhancing the oxidative phosphorylation and electron transport ability in mitochondria damaged by methylglyoxal (MG). Our aim was to explore the potential role of PCr as a molecule to protect mitochondria from diabetes-induced pancreatic ß-cell injury with insulin secretion deficiency or IR through dual AKT/IRS-1/GSK-3ß and STAT3/Cyclophilin D (Cyp-D) signaling pathways. MG-induced INS-1 cell viability, apoptosis, mitochondrial division and fusion, the morphology, and function of mitochondria were suppressed. Flow cytometry was used to detect the production of intracellular reactive oxygen species (ROS) and the changes of intracellular calcium, and the respiratory function was measured by oxygraph-2k. The expressions of AKT, IRS-1, GSK-3ß, STAT3, and Cyp-D were detected using Western blot. The result showed that the oxidative stress-related kinases were significantly restored to the normal level after the pretreatment with PCr. Moreover, PCr pretreatment significantly inhibited cell apoptosis, decreased intracellular calcium, and ROS production, and inhibited mitochondrial division and fusion, and increased ATP synthesis damaged by MG in INS-1 cells. In addition, pretreatment with PCr suppressed Cytochrome C, p-STAT3, and Cyp-D expressions, while increased p-AKT, p-IRS-1, p-GSK-3ß, caspase-3, and caspase-9 expressions. In conclusion, PCr has protective effect on INS-1 cells in vitro and in vivo, relying on AKT mediated STAT3/ Cyp-D pathway to inhibit oxidative stress and restore mitochondrial function, signifying that PCr might become an emerging candidate for the cure of diabetic pancreatic cancer ß-cell damage.

Non-energy mechanism of phosphocreatine on the protection of cell survival.

If mitochondrial energy availability or oxidative metabolism is altered, patients will suffer from insufficient energy supply Phosphocreatine (PCr) not only acts as an energy carrier, but also acts as an antioxidant and defensive agent to maintain the integrity and stability of the membrane, to maintain ATP homeostasis through regulating mitochondrial respiration. Meanwhile, PCr can enhance calcium balance and reduce morphological pathological changes, ultimately, PCr helps to reduce apoptosis. On the other aspect, the activities of ATP synthase and MitCK play a crucial role in the maintenance of cellular energy metabolic function. It is interesting to note, PCr not only rises the activities of ATP synthase as well as MitCK, but also promotes these two enzymatic reactions. Additionally, PCr can also inhibit mitochondrial permeability transition in a concentration-dependent manner, prevent ROS and CytC from spilling into the cytoplasm, thereby inhibit the release of proapoptotic factors caspase-3 and caspase-9, and eventually, effectively prevent LPS-induced apoptosis of cells. Understandably, PCr prevents the apoptosis caused by abnormal mitochondrial energy metabolism and has a protective role in a non-energy manner. Moreover, recent studies have shown that PCr protects cell survival through PI3K/Akt/eNOS, MAPK pathway, and inhibition of Ang II-induced NF-κB activation. Furthermore, PCr antagonizes oxidative stress through the activation of PI3K/Akt/GSK3b intracellular pathway, PI3K/AKT-PGC1α signaling pathway, while through the promotion of SIRT3 expression to maintain normal cell metabolism. Interestingly, PCr results in delaying the time to enter pathological metabolism through the delayed activation of AMPK pathway, which is different from previous studies, now we propose the hypothesis that the "miRNA-JAK2/STAT3 -CypD pathway" may take part in protecting cells from apoptosis, PCr may be further be involved in the dynamic relationship between CypD and STAT3. Furthermore, we believe that PCr and CypD would be the central link to maintain cell survival and maintain cell stability and mitochondrial repair under the mitochondrial dysfunction caused by oxidative stress. This review provides the modern progress knowledge and views on the molecular mechanism and molecular targets of PCr in a non-energy way.

Protective Effects of Cinnamaldehyde against Mesenteric Ischemia-Reperfusion-Induced Lung and Liver Injuries in Rats.

The aim of this study was to characterize and reveal the protective effects of cinnamaldehyde (CA) against mesenteric ischemia-reperfusion- (I/R-) induced lung and liver injuries and the related mechanisms. Sprague-Dawley (SPD) rats were pretreated for three days with 10 or 40 mg/kg/d, ig of CA, and then induced with mesenteric ischemia for 1 h and reperfusion for 2 h. The results indicated that pretreatment with 10 or 40 mg/kg of CA attenuated morphological damage in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly restored the levels of aspartate transaminase (AST) and alanine transaminase (ALT) in mesenteric I/R-injured liver tissues, indicating the improvement of hepatic function. CA also significantly attenuated the inflammation via reducing myeloperoxidase (MOP) activity and downregulating the expression of inflammation-related proteins, including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), cyclooxygenase-2 (Cox-2), and tumor necrosis factor receptor type-2 (TNFR-2) in both lung and liver tissues of mesenteric I/R-injured rats. Pretreatment with CA significantly downregulated nuclear factor kappa B- (NF-κB-) related protein expressions (NF-κB p65, NF-κB p50, I kappa B alpha (IK-α), and inhibitor of nuclear factor kappa-B kinase subunit beta (IKKß)) in both lung and liver tissues of mesenteric I/R-injured rats. CA also significantly downregulated the protein expression of p53 family members, including caspase-3, caspase-9, Bax, and p53, and restored Bcl-2 in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly reduced TUNEL-apoptotic cells and significantly inhibited p53 and NF-κB p65 nuclear translocation in both lung and liver tissues of mesenteric I/R-injured rats. CA neither induced pulmonary and hepatic histological alterations nor affected the parameters of inflammation and apoptosis in sham rats. We conclude that CA alleviated mesenteric I/R-induced pulmonary and hepatic injuries via attenuating apoptosis and inflammation through inhibition of NF-κB and p53 pathways in rats, suggesting the potential role of CA in remote organ ischemic injury protection.

miR-421 up-regulation by the oleanolic acid derivative K73-03 regulates epigenetically SPINK1 transcription in pancreatic cancer cells leading to metabolic changes and enhanced apoptosis.

SPINK1 overexpression promotes cancer cell aggressiveness and confers chemo-resistance to multiple drugs in pancreatic cancer. Oleanolic acid (OA) derivatives possess active effects against different cancers. Here we report the effect of K73-03, a new novel OA derivative, against pancreatic cancer through mitochondrial dysfunction via miR-421/SPINK1 regulation. We examined the binding ability of miR-421 with SPINK1-3'UTR Luciferase reporter assays. Moreover, miR-421/SPINK1 expressions in pancreatic cancer, with or without K73-03 treatment, were evaluated. Cells viability, migration, autophagy, mitochondrial function and apoptosis were examined with or without K73-03 treatment. We established that the K73-03 effect on the miR-421 that plays a crucial role in the regulation of SPINK1 in pancreatic cancer. Our findings indicated that K73-03 inhibited the mitochondrial function that led to inducing autophagy and apoptosis through epigenetic SPINK1 down-regulation via miR-421 up-regulation in pancreatic cancer. Furthermore, the inhibition of miR-421 expression in pancreatic cancer cells abolished the efficacy of K73-03 against SPINK1 oncogenic properties. We found an interesting finding that the interaction between miR-421 and SPINK1 is related to mitochondrial function through the effect of K73-03. Further, SPINK1 appear to be the molecular targets of K73-03 especially more than gemcitabine.

Cinnamaldehyde protects against rat intestinal ischemia/reperfusion injuries by synergistic inhibition of NF-κB and p53.

Our preliminary study shows that cinnamaldehyde (CA) could protect against intestinal ischemia/reperfusion (I/R) injuries, in which p53 and NF-κB p65 play a synergistic role. In this study, we conducted in vivo and in vitro experiments to verify this proposal. SD rats were pretreated with CA (10 or 40 mg · kg-1 · d-1, ig) for 3 days, then subjected to 1 h mesenteric ischemia followed by 2 h reperfusion. CA pretreatment dose-dependently ameliorated morphological damage and reduced inflammation evidenced by decreased TNF-α, IL-1ß, and IL-6 levels and MPO activity in I/R-treated intestinal tissues. CA pretreatment also attenuated oxidative stress through restoring SOD, GSH, LDH, and MDA levels in I/R-treated intestinal tissues. Furthermore, CA pretreatment significantly reduced the expression of inflammation/apoptosis-related NF-κB p65, IKKß, IK-α, and NF-κB p50, and downregulated apoptotic protein expression including p53, Bax, caspase-9 and caspase-3, and restoring Bcl-2, in I/R-treated intestinal tissues. We pretreated IEC-6 cells in vitro with CA for 24 h, followed by 4 h hypoxia and 3 h reoxygenation (H/R) incubation. Pretreatment with CA (3.125, 6.25, and 12.5 µmol · L-1) significantly reversed H/R-induced reduction of IEC-6 cell viability. CA pretreatment significantly suppressed oxidative stress, NF-κB activation and apoptosis in H/R-treated IEC-6 cells. Moreover, CA pretreatment significantly reversed mitochondrial dysfunction in H/R-treated IEC-6 cells. CA pretreatment inhibited the nuclear translocation of p53 and NF-κB p65 in H/R-treated IEC-6 cells. Double knockdown or overexpression of p53 and NF-κB p65 caused a synergistic reduction or elevation of p53 compared with knockdown or overexpression of p53 or NF-κB p65 alone. In H/R-treated IEC-6 cells with double knockdown or overexpression of NF-κB p65 and p53, CA pretreatment caused neither further decrease nor increase of NF-κB p65 or p53 expression, suggesting that CA-induced synergistic inhibition on both NF-κB and p53 played a key role in ameliorating intestinal I/R injuries. Finally, we used immunoprecipitation assay to demonstrate an interaction between p53 and NF-κB p65, showing the basis for CA-induced synergistic inhibition. Our results provide valuable information for further studies.

TL1A/TNFR2-mediated mitochondrial dysfunction of fibroblast-like synoviocytes increases inflammatory response in patients with rheumatoid arthritis via reactive oxygen species generation.

Rheumatoid arthritis (RA) is the major autoimmune destructive disease of joints with a complicated pathogenesis. The contribution of tumor necrosis factor-like ligand 1A (TL1A) in RA pathogenesis, especially on fibroblast-like synoviocytes (FLS), has been suggested clinically. The present study investigated the role of TL1A in mitochondrial dysfunction, induced oxidative stress in mitochondria, apoptosis resistance and the inflammatory response in FLS obtained from RA patients (RA-FLS). RA-FLS were incubated with TL1A and tumor necrosis factor receptor 2 (TNFR2) antagonist. Respiratory function, mitochondrial membrane potential and respiration associated genes of mitochondria were measured in both TL1A stimulated and non-stimulated RA-FLS. Additionally, the effects of TL1A on reactive oxygen species (ROS) production in mitochondria, apoptosis and the inflammatory response in RA-FLS were also assessed. The role of TL1A in association between ROS generation, especially mitochondrial type and the inflammatory response, was evaluated by measuring inflammation-related cytokines and signaling pathways using ROS inhibitors, diphenyleneiodonium chloride and Mito-TEMPO (Sigma-Aldrich, Miamisburg, OH, USA). We found that TL1A induced mitochondrial dysfunction by weakening mitochondrial respiration and membrane potential, which was blocked by a TNFR2 antagonist. Increased ROS synthesis in impaired mitochondria was observed with MitoSOX (Invitrogen, CA, USA) immunofluorescence staining in TL1A-stimulated RA-FLS but inhibited by a TNFR2 antagonist. TL1A influenced apoptosis resistance and inflammatory mediators via TNFR2. Inhibition of mitochondria-derived ROS compromised the production of inflammatory factors in TL1A-stimulated RA-FLS, suggesting that mitochondrial dysfunction mediated by the TL1A/TNFR2 axis might amplify the inflammatory response via regulation of mitochondria-derived ROS generation. Collectively, our results reveal that TL1A might be involved in making FLS more aggressive in RA pathogenesis via cell respiration interruption.

Phosphocreatine Improves Cardiac Dysfunction by Normalizing Mitochondrial Respiratory Function through JAK2/STAT3 Signaling Pathway In Vivo and In Vitro.

Diabetic cardiomyopathy (DCM) is one of the common cardiovascular complications in patients with diabetes. Accumulating evidence has demonstrated that DCM is thoroughly related to mitochondrial energy impairment and increases the generation of reactive oxygen species (ROS). Therefore, an ongoing study is developing strategies to protect cardiac mitochondria from diabetic complications, especially from hyperglycemia. Phosphocreatine (PCr) plays a major metabolic role in cardiac muscular cells including intracellular concentration of ATP which affects the activity of the myocardium. We hypothesized that PCr might improve oxidative phosphorylation and electron transport capacity in mitochondria impaired by hyperglycemia in vivo and in vitro. Also, we aimed to evaluate the protective effect of PCr against DCM through the JAK2/STAT3 signaling pathway. The mitochondrial respiratory capacity from rats and H9C2 cells was measured by high-resolution respirometry (HRR). Expressions of proteins Bax, Bcl-2, caspase 3, caspase 9, cleaved caspase 3, and cleaved caspase 9, as well as JAK2/STAT3 signaling pathways, were determined by western blotting. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Type 1 diabetes mellitus was induced in Wistar male rats by a single intraperitoneal injection of streptozotocin (STZ) (80 mg/kg body weight). Our results revealed that PCr possessed protective effects against DCM injury by improving the mitochondrial bioenergetics and by positively exerting protective effects against DCM in vivo and in vitro, not only improving diabetes symptom, resulting in changes of cardiac tissue using hematoxylin and eosin (H&E) stain, but also ameliorating biochemical changes. Moreover, PCr increased Bcl-2, caspase 3, and caspase 9 protein expressions and decreased Bax, cleaved caspase 3, and cleaved caspase 9 expressions as well as the JAK2/STAT3 signaling pathway. In conclusion, PCr improves mitochondrial functions and exerts an antiapoptotic effect in vivo and in vitro exposed to oxidative stress by hyperglycemia through the JAK2/STAT3 signaling pathway. Our findings suggest that PCr medication is a possible therapeutic strategy for cardioprotection.

Anticancer effect of SZC015 on pancreatic cancer via mitochondria-dependent apoptosis and the constitutive suppression of activated nuclear factor κB and STAT3 in vitro and in vivo.

Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Advances in therapeutic strategies such as chemotherapy have improved the clinical outcomes for pancreatic cancer patients. However, developing new therapeutic compounds against pancreatic cancer is still urgent due to the poor prognosis. Here, we show that SZC015, an oleanolic acid derivative, exhibits potent inhibitory effect on both pancreatic cancer cells in vitro and the corresponding xenograft tumors in vivo. Mechanistically, the activation of intrinsic apoptosis and G1 phase arrest resulting from mitochondria damage caused by SZC015 contribute significantly to the anticancer effects of SZC015. SZC015 also has remarkably inhibitory effects on the transcription factors that are extensively activated in pancreatic cancer tissues. As a constitutively activated transcription factor in pancreatic cancer, the nuclear factor κB is highly suppressed after SZC015 treatment in vitro or administration in vivo. Based on the bioinformatics analysis of microarray data, we validate that JAK2/STAT3 signaling is indeed activated in the human pancreatic cancer tissues and SZC015 also shows inhibitory effect on this signaling both in vitro and in vivo. These data suggest the potent effects of SZC015 on pancreatic cancer and also provided novel insights into the mechanisms of SZC015 as a new potent candidate for treating pancreatic cancer.

Neuroprotective effect of phosphocreatine on oxidative stress and mitochondrial dysfunction induced apoptosis in vitro and in vivo: Involvement of dual PI3K/Akt and Nrf2/HO-1 pathways.

Methylglyoxal (MGO), an active metabolite of glucose, is observed in high levels in the tissues and blood of diabetic patients. Phosphocreatine (PCr), a high-energy phosphate compound, exhibits a range of pharmacological actions but little is well known of its neuroprotective action. The aim of the present study was to investigate the neuroprotective effects and the possible mechanisms of PCr. Diabetes is closely associated with neurodegenerative diseases, leading not only to the peripheral nervous system (PNS) and but also to central nervous system (CNS) damage. Therefore, we established two rat models of diabetes in vivo induced by MGO and streptozocin (STZ) respectively, while utilized differentiated PC-12 cells in vitro. Treatment of PC-12 cells with PCr markedly attenuated MGO-induced change of viability, apoptosis, accompanied by decreased levels of caspase-3, casapse-9 and Bcl-2/Bax protein ratio. Determination of cellular respiratory function was performed with intact PC-12 cells and homogenized hippocampal neuron tissue of rat. Reactive oxygen species (ROS) generation was assessed by membrane permeable fluorescent probe DCFH-DA. The expressions of Akt, Nrf2 and HO-1 were examined by Western blot. PCr pretreatment significantly reduced oxidative stress-induced high LDH, MDA level, and ROS production of PC-12 cells. PCr pretreatment also significantly decreased mitochondrial dysfunction in vitro and in vivo. In addition, PCr pretreatment increased the expression of p-Akt, Nrf2 and HO-1, and reduced the apoptosis. Moreover, the expression of Cleaved caspase3 was partially increased and the p-Akt, Nrf2 and HO-1 was partially reduced by a PI3K inhibitor (LY294002). While, compared with LY294002 groups, pre-treatment with PCr at the concentrations of 20 mM significantly reduced the expression of Cleaved caspase3 and increased the expression of p-Akt, Nrf2 and HO-1. Molecular docking assay showed that PCr possessed powerful affinity towards to Akt with lower binding energy. In conclusion, the neuroprotective effects of PCr in vitro and in vivo rely on normalizing mitochondrial function and reducing oxidative stress via Akt mediated Nrf2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the treatment of diabetes-associated neurodegenerative diseases.

Salinomycin, as an autophagy modulator-- a new avenue to anticancer: a review.

Since Salinomycin (Sal) emerged its ability to target breast cancer stem cells in 2009, numerous experiments have been carried out to test Sal's anticancer effects. What deserve to be mentioned is that Sal can efficiently induce proliferation inhibition, cell death and metastasis suppression against human cancers from different origins both in vivo and in vitro without causing serious side effects as the conventional chemotherapeutical drugs on the body. There may be novel cell death pathways involving the anticancer effects of Sal except the conventional pathways, such as autophagic pathway. This review is focused on how autophagy involves the effects of Sal, trying to describe clearly and systematically why autophagy plays a vital role in predominant anticancer effects of Sal, including its distinctive characteristic. Based on recent advances, we present evidence that a dual role of Sal involving in autophagy may account for its unique anticancer effects - the preference for cancer cells. Further researches are required to confirm the authenticity of this suppose in order to develop an ideal anticancer drug.

Induction of autophagy by an oleanolic acid derivative, SZC017, promotes ROS-dependent apoptosis through Akt and JAK2/STAT3 signaling pathway in human lung cancer cells.

The signal transducers and activators of transcription 3 (STAT3) signaling pathway is a common feature in many solid tumors including non-small cell lung cancer, whereas current therapies usually fail to treat this disease in majority of cases. In the present study, we aimed to investigate the cytotoxic effect and the underlying mechanisms of SZC017, an oleanolic acid derivative, on human lung cancer cells. Cell viability was significantly decreased in SZC017-treated lung cancer cells. Mechanistically, SZC017 reduced A549 cell viability by activating both apoptosis and autophagy pathways. SZC017 was able to inhibit the phosphorylation of Akt, JAK2, and STAT3 in A549 cells, resulting in the inactivation of Akt and JAK2/STAT3 signaling pathways. In addition, SZC017 could induce ROS generation and Ca2+ release. Pretreatment with N-Acetyl L-Cysteine, a ROS scavenger, could fully reverse SZC017-induced ROS and increase the expression of Akt, p-STAT3, and procaspase-3, while decrease the ratio of LC3-II/I and the expression of Beclin-1. In summary, our study provides pharmacological evidence that SZC017 exhibits potential use in the treatment of lung cancer.