A Novel Small-Molecule Inhibitor Displays Its Therapeutic Potency Through Mitochondria-Mediated Apoptosis And Autophagy In Melanoma

Melanoma is the most aggressive skin cancer with high mortality. It is vital to develop novel low toxicity drugs with anti-proliferation activity and metastasis suppressive activity in melanoma. Here, we reported a novel anti-tumor drug SCZ0148, and then investigated its inhibition effect on melanoma. The anticancer efficacy of SCZ0148 was confirmed by using cytotoxicity test, colony formation assay, wound-healing assay, cell apoptosis detection, mitochondrial potential assay, reactive oxygen species (ROS) production and western-blot analysis. The cytotoxicity test showed that SCZ0148 inhibited melanoma cell lines proliferation in a dose- and time-dependent manner without obvious toxicity and side effects on normal cells. The results of the colony formation assay were in agreement with the cytotoxicity test. In addition, SCZ0148 induced melanoma cell apoptosis and promoted cell destructive autophagy through the ROS-mediated mitochondrial apoptosis pathway. Notably, SCZ0148 significantly inhibited the migration of melanoma cells through the matrix metalloprotein 9 (MMP-9) mediated pathway. In conclusion, these findings suggest that SCZ0148 may be a potential therapeutic drug to inhibit the proliferation and metastasis of melanoma.

A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity

Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug. Graphical Abstract

Modulatory effect of Persea Americana oil against diethylnitrosamine-induced hepatotoxicity in rats: a proposed mechanism

Background The purpose of this study was to investigate the effectiveness of Persea Americana (avocado) oil against diethylnitrosamine (DEN)-induced hepatotoxicity in rats. Methods For the induction of hepatotoxicity, DEN was administrated orally in a dose of 20 mg/kg B.wt for 6 successive weeks, and then the animals were gavaged with Persea Americana oil in a dose of 4 mL/kg b.wt. daily for another 6 weeks. Serum caspase-3 activity and poly (ADP-ribose) polymerase-1 (PARP-1) levels were estimated; in addition to gene expressions for NADPH oxidase, inducible nitric oxide synthase (iNOS), Bcl-2, and Bax were detected. Results The DEN-intoxicated group exhibited a remarkable increase in NADPH oxidase and iNOS expression combined with over-activation of PARP-1 and increased antiapoptotic Bcl-2 gene expression, whereas the expression of apoptotic biomarkers significantly decreased. On the other hand, treatment with Persea Americana oil significantly suppressed the elevated levels of hepatic enzymes and improved histopathological alterations in the liver. Furthermore, these groups displayed marked downregulation in NADPH oxidase and iNOS expressions. Persea Americana oil suppressed the expression of the antiapoptotic Bcl-2, activated the intrinsic mitochondrial apoptosis pathway through upregulation of pro-apoptotic Bax, and induced an obvious increase in caspase-3 activity. Moreover, Persea Americana oil administration markedly inhibited the activity of PARP-1. Conclusions This study indicated the promising potential of Persea Americana oil against DEN-induced hepatic injury through its anti-oxidative activity and pro-apoptotic effect via caspase activation and PARP-1 inhibition.

Influence of Ca2+ on mitochondrial apoptosis activation and yak meat tenderization during postmortem aging

The objective of this study was to investigate the underlying molecular mechanisms of mitochondrial Ca2+ homeostasis disequilibrium in mitochondrial apoptosis and its impact on yak meat tenderness. Results indicated that CaCl2 treatment significantly promoted glycolysis by increasing lactic acid level and decreasing glycogen content, pH, and ATP production (P < 0.01 and P < 0.05). The activities of Na+-K+-ATPase pump and Ca2+-ATPase pump in the early aging stage were significantly influenced by CaCl2 treatment. The activities of synchronous digital hierarchy and citrate synthase were also significantly improved by CaCl2 treatment (P < 0.01 and P < 0.05). Mitochondrial reactive oxygen species (ROS) levels were significantly higher in the CaCl2 group than in the control group (P < 0.01); at 24 h, the value in the Ca2+ group was 64.27% higher than that in the control group. Furthermore, CaCl2 treatment significantly enhanced the mitochondrial apoptosis cascade reaction and meat tenderization by improving the myofibril fragmentation index and shear force (P < 0.01). These results demonstrated that the imbalance of mitochondrial Ca2+ homeostasis played a significant role in the mitochondrial apoptosis pathway by regulating energy metabolism factors, meat intracellular environment, mitochondrial functions, and ROS-mediated oxidative stress. These conditions further improved meat tenderization during postmortem aging.

A Redox-Responsive Dihydroartemisinin Dimeric Nanoprodrug For Enhanced Antitumor Activity

Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (>90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of these nanoparticles was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug.

Scutellarin alleviates type 2 diabetes (HFD/low dose STZ)-induced cardiac injury through modulation of oxidative stress, inflammation, apoptosis and fibrosis in mice

Background Diabetes is a serious global health concern which severely affected public health as well as socio-economic growth worldwide. Scutellarin (SCU), a bioactive flavonoid, is known for its efficacious action against a range of ailments including cardiovascular problems. The present study was conducted to find out possible protective effect and its associated mechanisms of SCU on experimental type 2 diabetes-induced cardiac injury. Methods Type 2 diabetes was induced by treating animals with high fat diet for 4 weeks and a single intraperitoneal dose (35 mg/kg body weight) of streptozotocin and diabetic animals received SCU (10 or 20 mg/kg/day) for 6 weeks. Results Scutellarin attenuated type 2 diabetes-induced hyperglycemia, bodyweight loss, hyperlipidaemia, cardiac functional damage with histopathological alterations and fibrosis. Scutellarin treatment to type 2 diabetic mice ameliorated oxidative stress, inflammatory status and apoptosis in heart. Furthermore, the underlying mechanisms for such mitigation of oxidative stress, inflammation and apoptosis in heart involved modulation of Nrf2/Keap1 pathway, TLR4/MyD88/NF-κB mediated inflammatory pathway and intrinsic (mitochondrial) apoptosis pathway, respectively. Conclusions The current findings suggest that SCU is effective in protecting type 2 diabetes-induced cardiac injury by attenuating oxidative stress and inflammatory responses and apoptosis, and it is also worth considering the efficacious potential of SCU to treat diabetic cardiomyopathy patients.

Enhancement of O-GlcNAcylation on Mitochondrial Proteins with 2-(4-Methoxyphenyl)Ethyl-2-Acetamido-2-Deoxy-β-d-Pyranoside, Contributes to the Mitochondrial Network, Cellular Bioenergetics and Stress Response in Neuronal Cells under Ischemic-like Conditions

O-GlcNAcylation is a nutrient-driven post-translational modification known as a metabolic sensor that links metabolism to cellular function. Recent evidences indicate that the activation of O-GlcNAc pathway is a potential pro-survival pathway and that acute enhancement of this response is conducive to the survival of cells and tissues. 2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (SalA-4g), is a salidroside analogue synthesized in our laboratory by chemical structure-modification, with a phenyl ring containing a para-methoxy group and a sugar ring consisting of N-acetylglucosamine. We have previously shown that SalA-4g elevates levels of protein O-GlcNAc and improves neuronal tolerance to ischemia. However, the specific target of SalA-4g regulating O-GlcNAcylation remains unknown. To address these questions, in this study, we have focused on mitochondrial network homeostasis mediated by O-GlcNAcylation in SalA-4g’s neuroprotection in primary cortical neurons under ischemic-like conditions. O-GlcNAc-modified mitochondria induced by SalA-4g demonstrated stronger neuroprotection under oxygen glucose deprivation and reoxygenation stress, including the improvement of mitochondrial homeostasis and bioenergy, and inhibition of mitochondrial apoptosis pathway. Blocking mitochondrial protein O-GlcNAcylation with OSMI-1 disrupted mitochondrial network homeostasis and antagonized the protective effects of SalA-4g. Collectively, these data demonstrate that mitochondrial homeostasis mediated by mitochondrial protein O-GlcNAcylation is critically involved in SalA-4g neuroprotection.

In situ delivery of biobutyrate by probiotic Escherichia coli for cancer therapy

Butyrate has a bioactive function to reduce carcinogenesis. To achieve targeted cancer therapy, this study developed bacterial cancer therapy (BCT) with butyrate as a payload. By metabolic engineering, Escherichia coli Nissle 1917 (EcN) was reprogrammed to synthesize butyrate (referred to as biobutyrate) and designated EcN-BUT. The adopted strategy includes construction of a synthetic pathway for biobutyrate and the rational design of central metabolism to increase the production of biobutyrate at the expense of acetate. With glucose, EcN-BUT produced primarily biobutyrate under the hypoxic condition. Furthermore, human colorectal cancer cell was administrated with the produced biobutyrate. It caused the cell cycle arrest at the G1 phase and induced the mitochondrial apoptosis pathway independent of p53. In the tumor-bearing mice, the injected EcN-BUT exhibited tumor-specific colonization and significantly reduced the tumor volume by 70%. Overall, this study opens a new avenue for BCT based on biobutyrate.