Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches.

Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Video Abstract.

Graphene oxide nanoarchitectures in cancer biology: Nano-modulators of autophagy and apoptosis.

Nanotechnology is a growing field, with many potential biomedical applications of nanomedicine for the treatment of different diseases, particularly cancer, on the horizon. Graphene oxide (GO) nanoparticles can act as carbon-based nanocarriers with advantages such as a large surface area, good mechanical strength, and the capacity for surface modification. These nanostructures have been extensively used in cancer therapy for drug and gene delivery, photothermal therapy, overcoming chemotherapy resistance, and for imaging procedures. In the current review, we focus on the biological functions of GO nanoparticles as regulators of apoptosis and autophagy, the two major forms of programmed cell death. GO nanoparticles can either induce or inhibit autophagy in cancer cells, depending on the conditions. By stimulating autophagy, GO nanocarriers can promote the sensitivity of cancer cells to chemotherapy. However, by impairing autophagy flux, GO nanoparticles can reduce cell survival and enhance inflammation. Similarly, GO nanomaterials can increase ROS production and induce DNA damage, thereby sensitizing cancer cells to apoptosis. In vitro and in vivo experiments have investigated whether GO nanomaterials show any toxicity in major body organs, such as the brain, liver, spleen, and heart. Molecular pathways, such as ATG, MAPK, JNK, and Akt, can be regulated by GO nanomaterials, leading to effects on autophagy and apoptosis. These topics are discussed in this review to shed some lights towards the biomedical potential of GO nanoparticles and their biocompatibility, paving the way for their future application in clinical trials.

Parental exposure of Tadalafil has beneficial effect on reflexive motor behaviors in mice offspring.

Tadalafil has positive effects on neurodevelopment and antioxidant defense system, but there is no information for its possible role during gestation on reflexive motor behavior in offspring. So current study determined the effect of prenatal exposure to the Tadalafil on reflexive motor behaviors and antioxidant activity in mice offspring and antidepressive behaviors in postpartum dams. Forty pregnant female NMRI mice were allocated into four groups. In control group, mice received water while in Groups 2-4, female mice orally gavage with Tadalafil (0.4, 0.8, and 1.6 mg/kg) at gestation day (GD) 5, 8, 11, 14, and 17, respectively. Following delivery, pups were selected and reflexive motor behaviors determined using ambulation, hind-limb foot angle, surface righting, hind-limb strength, grip strength, front-limb suspension, and negative geotaxis tests. Also, serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and total antioxidant status (TAS) were determined in offspring. On Day 2 postpartum, antidepressant activity of Tadalafil was determined by open field test (OFT), rotarod, forced swimming test (FST), and tail suspension test (TST) in dams. Based on the findings, maternal exposure to Tadalafil improved ambulation score, hind-limb suspension score, grip strength, and front-limb suspension in offspring (P < 0.05). Prenatal exposure to Tadalafil decreased surface righting, hind-limb foot angle, and negative geotaxis in offspring (P < 0.05). Tadalafil decreased blood MDA and increased SOD and GPx levels in offspring (P < 0.05). Tadalafil significantly decreased immobility time in FST and TST and increased number of squares crossed in OFT and spending time on rotarod on postpartum mice (P < 0.05). These results suggested that parental exposure of Tadalafil has positive effect on reflexive motor and postpartum behaviors.