Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal components. Afterward, autophagosomes assemble with lysosomes to recycle or remove degradative cargo. The regulation of autophagy has bipolar roles in cancer suppression and promotion in diverse cancers. Furthermore, autophagy modulates the features of tumorigenesis, cancer metastasis, cancer stem cells, and drug resistance against anticancer agents. Some autophagy regulators are used to modulate autophagy for anticancer therapy but the dual roles of autophagy limit their application in anticancer therapy, and present as the main reason for therapy failure. In this review, we summarize the mechanisms of autophagy, tumorigenesis, metastasis, cancer stem cells, and resistance against anticancer agents. Finally, we discuss whether targeting autophagy is a promising and effective therapeutic strategy in anticancer therapy.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death due to its aggressive metastasis in later stages. Although there is a growing interest in the tumorigenic role of cellular prion protein (PrP^C) in the process of metastasis, the precise mechanism behind the cellular communication involving prion proteins remains poorly understood. This study found that hypoxic tumor microenvironment increased the PrP^C-expressing exosomes from CRC, and these exosomes regulate the CRC cell behavior and tumor progression depending on the expression of PrP^C. Hypoxic exosomes from CRC cells promoted sphere formation, the expression of tumor-inducing genes, migration, invasion, and tumor growth. Furthermore, these exosomes increased endothelial permeability, migration, invasion, and angiogenic cytokine secretion. These effects were associated with PrP^C expression. Application of anti-PrP^C antibody with 5-fluorouracil significantly suppressed the CRC progression in a murine xenograft model. Taken together, these findings indicate that PrP-expressing exosomes secreted by hypoxic CRC cells are a key factor in the tumorigenic CRC-to-CRC and CRC-to-endothelial cell communication. Significance: These findings suggest that inhibiting PrP^C in hypoxic exosomes during chemotherapy may be an effective therapeutic strategy in colorectal cancer.

Dysfunction in the olfactory system of a person can have adverse effects on their health and quality of life. It can even increase mortality among individuals. Olfactory dysfunction is related to many factors, including post-viral upper respiratory infection, head trauma, and neurodegenerative disorders. Although some clinical therapies such as steroids and olfactory training are already available, their effectiveness is limited and controversial. Recent research in the field of therapeutic nanoparticles and stem cells has shown the regeneration of dysfunctional olfactory systems. Thus, we are motivated to highlight these regenerative approaches. For this, we first introduce the anatomical characteristics of the olfactory pathway, then detail various pathological factors related to olfactory dysfunctions and current treatments, and then finally discuss the recent regenerative endeavors, with particular focus on nanoparticle-based drug delivery systems and stem cells. This review offers insights into the development of future therapeutic approaches to restore and regenerate dysfunctional olfactory systems.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity, commonly leading to long-term impairments in cognition, sensorimotor function, and personality. While neuroprotective drugs have demonstrated some efficacy in vitro cultures and in vivo animal models, their clinical applications remain debated. Intranasal delivery to the brain parenchyma, bypassing the blood-brain barrier for more direct access to target sites, offers a favorable and safe approach. This review illuminates current advancements in intranasal delivery systems for TBI treatment. We begin with an overview of TBI and its current clinical treatment options. We then outline recent developments in intranasal delivery systems of molecules and cells, emphasizing their efficacy in animal models. Finally, we discuss future clinical perspectives on emerging trends, offering insights into leveraging intranasal delivery for effective TBI therapeutics.

Diabetes mellitus contributes to 15–25% of all chronic foot ulcers. Peripheral vascular disease is a cause of ischemic ulcers and exacerbates diabetic foot disease. Cell-based therapies are viable options to restore damaged vessels and induce the formation of new vessels. Adipose-derived stem cells (ADSCs) have the potential for angiogenesis and regeneration because of their greater paracrine effect. Preclinical studies are currently using other forced enhancement techniques (e.g., genetic modification or biomaterials) to increase the efficacy of human ADSC (hADSC) autotransplantation. Unlike genetic modifications and biomaterials, many growth factors have been approved by the equivalent regulatory authorities. This study confirmed the effect of enhanced human ADSC (ehADSC)s with a cocktail of FGF and other pharmacological agents to promote wound healing in diabetic foot disease. In vitro, ehADSCs exhibited a long and slender spindle-shaped morphology and showed significantly increased proliferation. In addition, it was shown that ehADSCs have more functionalities in oxidative stress toleration, stem cell stemness, and mobility. In vivo, the local transplantation of 1.2 × 10⁶ hADSCs or ehADSCs was performed in animals with diabetes induced by STZ. The ehADSC group showed a statistically decreased wound size and increased blood flow compared with the hADSC group and the sham group. Human Nucleus Antigen (HNA) positive cells were observed in some ADSC-transplanted animals. The ehADSC group showed a relatively higher portion of HNA-positive animals than the hADSC group. The blood glucose levels showed no significant difference among the groups. In conclusion, the ehADSCs showed a better performance in vitro, compared with conventional hADSCs. Additionally, a topical injection of ehADSCs into diabetic wounds enhanced wound healing and blood flow, while improving histological markers suggesting revascularization.

PARP‐1 over‐activation results in cell death via excessive PAR generation in different cell types, including neurons following brain ischemia. Glycolysis, mitochondrial function, and redox balance are key cellular processes altered in brain ischemia. Studies show that PAR generated after PARP‐1 over‐activation can bind hexokinase‐1 (HK‐1) and result in glycolytic defects and subsequent mitochondrial dysfunction. HK‐1 is the neuronal hexokinase and catalyzes the first reaction of glycolysis, converting glucose to glucose‐6‐phosphate (G6P), a common substrate for glycolysis, and the pentose phosphate pathway (PPP). PPP is critical in maintaining NADPH and GSH levels via G6P dehydrogenase activity. Therefore, defects in HK‐1 will not only decrease cellular bioenergetics but will also cause redox imbalance due to the depletion of GSH. In brain ischemia, whether PAR‐mediated inhibition of HK‐1 results in bioenergetics defects and redox imbalance is not known. We used oxygen–glucose deprivation (OGD) in mouse cortical neurons to mimic brain ischemia in neuronal cultures and observed that PARP‐1 activation via PAR formation alters glycolysis, mitochondrial function, and redox homeostasis in neurons. We used pharmacological inhibition of PARP‐1 and adenoviral‐mediated overexpression of wild‐type HK‐1 (wtHK‐1) and PAR‐binding mutant HK‐1 (pbmHK‐1). Our data show that PAR inhibition or overexpression of HK‐1 significantly improves glycolysis, mitochondrial function, redox homeostasis, and cell survival in mouse cortical neurons exposed to OGD. These results suggest that PAR binding and inhibition of HK‐1 during OGD drive bioenergetic defects in neurons due to inhibition of glycolysis and impairment of mitochondrial function.