Pulmonary arterial hypertension (PAH) is a severe progressive disease that may cause early right ventricular failure and eventual cardiac failure. The pathogenesis of PAH involves endothelial dysfunction, aberrant proliferation of pulmonary artery smooth muscle cells (PASMCs), and vascular fibrosis. Hypoxia has been shown to induce elevated secretion of vascular endothelial growth factor (VEGF), leading to the development of hypoxic PAH. However, the molecular mechanisms underlying hypoxic PAH remain incompletely understood. Programmed cell death (PCD) is a natural cell death and regulated by certain genes. Emerging evidence suggests that apoptotic resistance contributes to the development of PAH. Moreover, several novel types of PCD, such as autophagy, pyroptosis, and ferroptosis, have been reported to be involved in the development of PAH. Additionally, multiple diverse epigenetic mechanisms including RNA methylation, DNA methylation, histone modification, and the non-coding RNA molecule-mediated processes have been strongly linked to the development of PAH. These epigenetic modifications affect the expression of genes, which produce important changes in cellular biological processes, including PCD. Consequently, a better understanding of the PCD processes and epigenetic modification involved in PAH will provide novel, specific therapeutic strategies for diagnosis and treatment. In this review, we aim to discuss recent advances in epigenetic mechanisms and elucidate the role of epigenetic modifications in regulating PCD in hypoxia-induced PAH.

The filamentous fungus Aspergillus oryzae (A. oryzae) has been extensively used for the biosynthesis of numerous secondary metabolites with significant applications in agriculture and food and medical industries, among others. However, the identification and functional prediction of metabolites through genome mining in A. oryzae are hindered by the complex regulatory mechanisms of secondary metabolite biosynthesis and the inactivity of most of the biosynthetic gene clusters involved. The global regulatory factors, pathway-specific regulatory factors, epigenetics, and environmental signals significantly impact the production of secondary metabolites, indicating that appropriate gene-level modulations are expected to promote the biosynthesis of secondary metabolites in A. oryzae. This review mainly focuses on illuminating the molecular regulatory mechanisms for the activation of potentially unexpressed pathways, possibly revealing the effects of transcriptional, epigenetic, and environmental signal regulation. By gaining a comprehensive understanding of the regulatory mechanisms of secondary metabolite biosynthesis, strategies can be developed to enhance the production and utilization of these metabolites, and potential functions can be fully exploited.

Pulmonary hypertension is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular failure, and premature death. It is a threat to public health globally. Autophagy, as a highly conserved self-digestion process, plays crucial roles with autophagy-related (ATG) proteins in various diseases. The components of autophagy in the cytoplasm have been studied for decades and multiple studies have provided evidence of the importance of autophagic dysfunction in pulmonary hypertension. The status of autophagy plays a dynamic suppressive or promotive role in different contexts and stages of pulmonary hypertension development. Although the components of autophagy have been well studied, the molecular basis for the epigenetic regulation of autophagy is less understood and has drawn increasing attention in recent years. Epigenetic mechanisms include histone modifications, chromatin modifications, DNA methylation, RNA alternative splicing, and non-coding RNAs, which control gene activity and the development of an organism. In this review, we summarize the current research progress on epigenetic modifications in the autophagic process, which have the potential to be crucial and powerful therapeutic targets against the autophagic process in pulmonary hypertension development.

Extracellular adenosine (eADO) signaling has emerged as an increasingly important regulator of immune responses, including tumor immunity. eADO is mainly produced from extracellular ATP (eATP) hydrolysis. eATP is rapidly accumulated in the extracellular space following cell death or cellular stress triggered by hypoxia, nutrient starvation, or inflammation. eATP plays a pro-inflammatory role by binding and activating the P2 purinergic receptors (P2X and P2Y), while eADO has been reported in many studies to mediate immunosuppression by activating the P1 purinergic receptors (A1, A2A, A2B, and A3) in diverse immune cells. Consequently, the hydrolysis of eATP to eADO alters the immunosurveillance in the tumor microenvironment (TME) not only by reducing eATP levels but also by enhancing adenosine receptor signaling. The effects of both P1 and P2 purinergic receptors are not restricted to immune cells. Here we review the most up-to-date understanding of the tumor adenosinergic system in all cell types, including immune cells, tumor cells, and stromal cells in TME. The potential novel directions of future adenosinergic therapies in immuno-oncology will be discussed.

Hepatic ischemia-reperfusion injury (HIRI) is a major complication in liver transplantation, hepatic surgeries, and shock-induced acute liver failure. This injury is characterized by mitochondrial dysfunction, oxidative stress, and calcium overload, with the mitochondrial permeability transition pore (mPTP) playing a pivotal role in mediating hepatocyte death. Cyclophilin D (CypD), a key regulator of mPTP opening, has long been associated with the exacerbation of HIRI. However, recent research has uncovered a protective aspect of CypD, revealing that it can regulate intermittent or “flickering” mPTP openings to control calcium overload, preserve mitochondrial integrity, and mitigate damage during ischemic stress. This review highlights the dual role of CypD in regulating mitochondrial damage through mPTP dynamics and its complex interplay with autophagy, specifically mitophagy, in liver injury. We also explore the emerging pharmacological and genetic approaches targeting PPIF, offering potential avenues for mitigating liver injury in clinical settings. This review integrates recent findings on PPIF’s role in mPTP regulation, inflammation, autophagy, and mitophagy, proposing a nuanced view of its therapeutic potential in managing hepatic ischemia-reperfusion injury.

Background: Skin whitening agents often face challenges such as poor stability and low permeability. To overcome these issues, a novel 4-butylresorcinol (4-BR)/D-a- Tocopherol Polyethylene Glycol Succinate (TPGS) deep eutectic solvent (DES) system was developed, which can self-assemble into carrier-free nanoparticles (NPs). Methods: The 4-BR/TPGS DES was synthesized and characterized by theoretical calculations, DSC, FTIR, 1H-NMR, and 2D NMR to confirm its successful formation. Results: The self-assembled 4-BR/TPGS DES NPs showed a 3.46-fold increase in skin permeability, a 1.53-fold improvement in 4-BR stability, a 1.55-fold increase in melanin inhibition in B16 cells, and a 2.16-fold higher melanin suppression in zebrafish compared with traditional 4-BR oil-based formulations. These results indicated the excellent whitening efficacy and transdermal delivery potential of this formulation. Conclusions: The combination of TPGS-based DES and self-assembly technology represents a revolutionary approach for advanced transdermal delivery and the development of skin care products.