Current Molecular Medicine - Volume 23, Issue 10, 2023

Aging is an inevitable risk factor for many diseases, including cardiovascular diseases, neurodegenerative diseases, cancer, and diabetes. Investigation into the molecular mechanisms involved in aging and longevity will benefit the treatment of age-dependent diseases and the development of preventative medicine for agingrelated diseases. Current evidence has revealed that FoxO3, encoding the transcription factor (FoxO)3, a key transcription factor that integrates different stimuli in the intrinsic and extrinsic pathways and is involved in cell differentiation, protein homeostasis, stress resistance and stem cell status, plays a regulatory role in longevity and in age-related diseases. However, the precise mechanisms by which the FoxO3 transcription factor modulates aging and promotes longevity have been unclear until now. Here, we provide a brief overview of the mechanisms by which FoxO3 mediates signaling in pathways involved in aging and aging-related diseases, as well as the current knowledge on the role of the FoxO3 transcription factor in the human lifespan and its clinical prospects. Ultimately, we conclude that FoxO3 signaling pathways, including upstream and downstream molecules, may be underlying therapeutic targets in aging and age-related diseases.

MicroRNAs (miRNAs) are a class of non-coding small RNAs with about 22 nucleotides in eukaryotes. They regulate gene expression at the post-transcriptional level and play a key role in physiological and pathological processes. As one of the most abundant miRNAs in the human brain, miRNA-9 (miR-9) has attracted extensive attention due to its important role in the maintenance of normal function of the nervous system and the occurrence and development of nervous system diseases. Hence, we reviewed the neuroprotective effect of miR-9 in neurological diseases. MiR-9 may be a potential target of nervous system diseases.

Epigenetic modifications play a vital role in gene regulation associated with different pathologies. Various nutrients in our diet, such as vitamins can modulate these epigenetic mechanism. They also can regulatenderlying pathophysiological factors and processes that directly or indirectly. Most importantly, A, B, C, and D vitamins have recently been shown to be involved in this type of regulation together with vitamins E and K. Despite their effect on the DNA methylation process, an in-depth understanding of vitamin-mediated epigenetic alterations have yet to be investigated. Moreover, the role of vitamins in DNA methylation as nutraceuticals might be important to use for targeted therapy of various human diseases. Overall, this review provides a brief survey of the role of vitamins as epigenetic modulators or nutraceuticals, emphasizing their potential in epigenetic therapy.

The CD99 antigen is a transmembrane protein expressed in a broad variety of tissues, particularly in hematopoietic cells, thymus, endothelial cells, etc. It participates in several crucial biological processes, including cell adhesion, migration, death, differentiation, and inflammation. CD99 has shown oncogenic or tumor suppressor roles in different types of cancer. Therefore, it has been used as a biomarker and therapeutic target for several types of cancer. Moreover, it has also been reported to be involved in several critical immune processes, such as T cell activation and differentiation, dendritic cell differentiation, and so on. Hence, CD99 may have potential values in cancer immunotherapy. Anti-CD99 antibodies have shown therapeutic effects on certain types of cancer, especially on Ewing sarcoma and T cell acute lymphoblastic leukemia (ALL). This review summarizes the recent progress of CD99 in cancer research and targeting therapies, especially in cancer immunotherapy, which may help researchers understand the crucial roles of CD99 in cancer development and design new therapeutic strategies.

ADAM10 is part of the ADAM superfamily containing cell surface proteins with special structures and potential adhesion and protease domains. This paper provides a review of the specific effects of ADAM10 in kidney development as well as its relations with renal diseases. ADAM10 plays an important role in developing tissues and organs and the pathogenesis of multiple diseases. The catalytic mechanism of ADAM10 on kidney-related molecules, including Notch, epidermal growth factor receptors, tumor necrosis factor-α, CXCL16, E-cadherin, cell adhesion molecule 1, meprin and klotho. ADAM10 is also closely associated with the progress of glomerular diseases, acute kidney injury and renal fibrosis. It probably is a good therapeutic target for renal diseases.

Objective: Osteoporosis is a systemic bone disease that seriously threatens the health and quality of life in middle-aged and older adults. In this review, we describe the relationship between bone marrow adipose tissue and aging osteoporosis and mainly focus on bone marrow mesenchymal stem cell osteogenic-adipose differentiation fate with aging along with the relevant mechanisms responsible for these changes. Methods: We summarized recent advances in regulating the bone marrow mesenchymal stem cell differentiation due to aging in this review. Results: Aging-related bone mass loss is accompanied by expanding bone marrow adipose because of an imbalance of bone marrow mesenchymal stem cell differentiation, resulting in adipogenesis. Ectopic adipocytes in the bone marrow increase with age and are a key factor responsible for the aging-related bone mass decrease. Transcription factors and classical regulating pathways are involved in this process during aging. Conclusion: As the global aging population increases, not only older women but also older men face a great fracture risk. Therefore, finding molecular mechanisms controlling the stimulating adipogenesis in BMSC during aging is important for providing the new cue for prevention and therapeutics for aging-related bone loss. Furthermore, upon physical examination of older people, except for the bone mineral density and bone turnover biochemical marker, the bone marrow adipose measurement should be taken into account when assessing the fracture risk and treatment plan that will be beneficial in clinical practice.

Ankylosing spondylitis (AS) is a chronic and progressive immunoinflammatory disease, which mainly affects the spine and sacroiliac joints and shows a high rate of late disability. Inflammation, bone destruction, and new bone formation are typical pathological changes of AS. AS is dominated by inflammation at the early stage. While bone destruction and heterotopic ossification, the two contradictory manifestations of AS, occur at a later stage and reflect the imbalance between osteogenesis and osteoclastogenesis in AS patients. Till now, the pathogenesis of AS remains unclear. MicroRNAs (miRNAs) are a class of highly conserved single-stranded noncoding RNAs (ncRNAs) with a length of about 22 bases characterized by temporal sequence and tissue specificity. MiRNAs are key modulators in bone formation, resorption, remodeling and regeneration by regulating the immune responses and the differentiation and functions of osteoblasts, osteoclasts and chondrocytes. The present review summarizes the roles and potential mechanisms of miRNAs’ involvement in AS by regulating immuno-inflammatory responses, bone destruction, heterotopic ossification, cell death and autophagy, and the involved signaling including the Wnt/β-catenin and BMP/Smads pathways. In addition, the feasibility of miRNAs as diagnostic biomarkers and therapeutic targets for AS are also discussed.

Leptin, as one of the most important cytokines within the circulation, has been confirmed to play a vital role in the hypothalamus of the central nervous system (CNS), which could modulate energy homeostasis by suppressing food intake. Furthermore, leptin could also influence cell metabolism by acting directly on the leptin receptor, which is a relatively small peptide and is mainly produced and released by fat tissue in mammals. On the other hand, the excessive extracellular matrix (ECM) could induce damage in normal tissues or organ structures, which might further induce fibrotic development in multiple tissues or organs, including the liver, heart, and kidneys. Notably, the sustainable development of fibrosis promotes the structural lesion and functional decline of different organs, which subsequently threatens human health and poses serious risks to human life. Emerging evidence has shown that leptin plays an important role in the fibrotic progression within multiple tissues and organs in mammals and has an alleviating effect on fibrosis. Concerning this notion, it has been proposed that leptin could be identified as a vital therapeutic strategy for fibrotic progression in clinical practice. Consequently, this review summarized the potential mechanisms of leptin in modulating fibrotic development in diverse tissues and organs to provide a theoretical basis for treating fibrotic-related diseases. In addition, the potential mechanisms whereby leptin affects the development of fibrosis were also summarized in the current review.

Postoperative cognitive dysfunction (POCD) is a common complication of the central nervous system (CNS) in elderly patients after surgery, showing cognitive changes such as decreased learning and memory ability, impaired concentration, and even personality changes and decreased social behavior ability in severe cases. POCD may appear days or weeks after surgery and persist or even evolve into Alzheimer's disease (AD), exerting a significant impact on patients’ health. There are many risk factors for the occurrence of POCD, including age, surgical trauma, anesthesia, neurological diseases, etc. The level of circulating inflammatory markers increases with age, and elderly patients often have more risk factors for cardiovascular diseases, resulting in an increase in POCD incidence in elderly patients after stress responses such as surgical trauma and anesthesia. The current diagnostic rate of POCD is relatively low, which affects the prognosis and increases postoperative complications and mortality. The pathophysiological mechanism of POCD is still unclear, however, central nervous inflammation is thought to play a critical role in it. The current review summarizes the related studies on neuroinflammation-mediated POCD, such as the involvement of key central nervous cells such as microglia and astrocytes, proinflammatory cytokines such as TNF-α and IL-1β, inflammatory signaling pathways such as PI3K/Akt/mTOR and NF-ΚB. In addition, multiple predictive and diagnostic biomarkers for POCD, the risk factors, and the positive effects of anti-inflammatory therapy in the prevention and treatment of POCD have also been reviewed. The exploration of POCD pathogenesis is helpful for its early diagnosis and long-term treatment, and the intervention strategies targeting central nervous inflammation of POCD are of great significance for the prevention and treatment of POCD.

Background: The severity and mortality of sepsis are related to excessive inflammation and cytokine storm. Nevertheless, little is known about why sepsis has a significant increase in proinflammatory cytokine production, which leads to more severe inflammatory damage. Methods: Mesenchymal stem cells have achieved certain results in the treatment of sepsis, but the specific mechanism remains to be further clarified. Results: Therefore, this paper will elaborate on the currently recognized mechanism of mesenchymal stem cells in the treatment of sepsis, the protein phosphorylation mechanism of sepsis inflammatory response, and the possibility that mesenchymal stem cells may block the occurrence and development of sepsis by regulating relevant pathways or protein phosphorylation. Conclusion: It provides a novel target for mesenchymal stem cells to prevent intervention or therapeutically block the development of sepsis.

Background: Microvascular dysfunction is a hallmark of diabetic retinopathy (DR), which may lead to visual impairment and blindness. Procyanidin B2 (PB2) is a subclass of flavonoids and is widely known due to its anti-oxidant and antiinflammatory effects. However, little is known about the effect of PB2 on hyperglycemia stress-induced retinal microvascular dysfunction. Objective: The purpose of this study was to investigate the effect of PB2 against hyperglycemia stress in rat retinal capillary endothelial cells (TR-iBRB2) as well as the underpinning mechanism. Methods: Cell viability was determined using MTT assay. ROS, NOX activity analysis, Western blot analysis, and immunofluorescence analysis were applied in the study. Results: The results showed that PB2 pre-treatment significantly reduced high glucose- induced cytotoxicity in TR-iBRB2 cells by suppressing oxidative stress and inflammasome activation. Mechanistical study revealed that redoxosomes were formed and activated in TR-iBRB2 cells upon hyperglycemia stress, resulting in activation of NF- ΚB and thus induction of oxidative stress and inflammasomes activation. However, PB2 pre-treatment dose-dependently attenuated the above events, indicating the protective effect of PB2 against hyperglycemia stress was achieved by regulating redoxosomes/ NF-kB signaling. Conclusion: Our findings may contribute to the potential clinical use of PB2 in treating DR and suggest redoxosomes/NF-kB signaling may be a potential therapeutic target of this disease.

Objectives: As a distinct type of cardiomyopathy, diabetic cardiomyopathy (DCM) is featured as diastolic or systolic cardiac dysfunction in diabetic patients. In order to broaden the understanding of molecular mechanisms in DCM, we intended to explore the mechanism of the interaction between PDK4 protein and Hmgcs2 in high glucose (HG)-induced myocardial damage. Methods: PDK4 and Hmgcs2 expression in the myocardium of diabetes mellitus (DM) model rats and HG-incubated cardiomyocyte line H9C2 was analyzed by western blot analysis. Echocardiography and TUNEL assay were utilized for respective assessment of cardiac structure and function and cardiomyocyte apoptosis in DM rats after silencing PDK4 or/and Hmgcs2. In vitro, the impact of PDK4 and Hmgcs2 on HG-induced cardiomyocyte injuries was identified with cell counting kit-8 and flow cytometry assays, along with detection of LDH release, caspase-3/7 activities, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Moreover, a coimmunoprecipitation assay was utilized to test the interaction between PDK4 and Hmgcs2. Results: Both PDK4 and Hmgcs2 were highly expressed in the myocardial tissues of DM rats. Mechanistically, PDK4 interacted with Hmgcs2 to upregulate Hmgcs2 expression in HG-induced H9C2 cells. Silencing PDK4 improved cardiac function and reduced cardiomyocyte apoptosis in DM rats. In HG-induced H9C2 cells, PDK4 or Hmgcs2 silencing enhanced cell viability and reduced LDH release, caspase-3/7 activities, cell apoptosis, and ROS and MDA levels, and these trends were further promoted by the simultaneous silencing of PDK4 and Hmgcs2. Conclusion: In summary, the silencing of PDK4 and Hmgcs2 alleviated HG-induced myocardial injuries through their interaction.

Background: Asiaticoside (AC) is a triterpenoid saponin found in Centella asiatica (L.) urban extract that has a wide range of pharmacological properties. Our previous study demonstrated that AC could promote angiogenesis in diabetic wounds, but the specific mechanisms remain unknown. Objective: This study aimed to examine the effectiveness and mechanism of AC on human umbilical vein endothelial cells (HUVECs) exposed to tert-butyl hydroperoxide (t-BHP) toxicity. Methods: Senescence was confirmed using senescence-associated betagalactosidase (SA-β-gal) activity and expression of the cell cycle phase markers p16 and p21. The levels of SOD, NO, MDA, GSH-Px, and ROS were tested. Furthermore, several cell death-related genes and proteins (p53, Bax, Bcl-2 and Caspase-3) were assessed with RT-qPCR and Western blotting. Results: AC significantly reduced SA-β-gal activity, with both the suppression of cellcycle inhibitors p16 and p21. We also found that the induced oxidative stress and apoptosis caused by t-BHP treatment resulted in the decrease of antioxidant enzymes activities, the surge of ROS and MDA, the up-regulation of p53, Bax and caspase-3, and the decrease of SOD, NO, GSH-Px and Bcl-2. These biochemical changes were all reversed by treatment with varying doses of AC. Conclusion: AC alleviates t-BHP-induced oxidative injury and apoptosis in HUVECs through the ROS-dependent p53/Bcl-2/Caspase-3 signaling pathway. It may be a potential antioxidant applied in metabolic disorders and pharmaceutical products.

Background: Mitochondria mediate airway inflammatory responses to cigarette smoke (CS). Removal of damaged or defective mitochondrial (mitophagy) may prevent the detrimental impact of CS extract (CSE) on airway and lung epithelial cells. Methods: We studied the effect of a mitophagy activator (Urolithin A, UA) and a mitophagy inhibitor (Liensinine diperchlorate, Ld) on CSE-exposed alveolar (A549) and airway (BEAS-2B) epithelial cell proliferation, intracellular and mitochondrial ROS, inflammatory response, mitochondrial membrane potential (Δψm), mitochondrial morphology, mitochondrial complex activities, and protein levels of mitochondrial fission (DRP1, MFF) and mitophagy (SQSTM1/p62, LC3B). In both cell types, CSE exposure led to increased intracellular and mitochondrial oxidative stress, decreased Δψm and resulted in structural disruption of the mitochondrial network. CSE increased the expression of DRP1, MFF and SQSTM1/p62 while decreasing LC3B-II/I protein expression ratio. CSE also increased inflammatory (IL-1β, IL-6, IL-18, CXCL1, CXCL8) and necroptosis factors (RIPK1, RIPK3, MLKL) mRNA expression. Results: Pre-treatment with UA attenuated CSE-induced oxidative stress, inflammatory and necroptosis gene expression and restored mitochondrial structure and function. UA also prevented CSE-evoked increases in DRP1, MFF and SQSTM1/p62 protein expression and increased LC3B-II/I ratio. Conversely, pre-treatment with Ld aggravated CSE-induced cellular and mitochondrial responses. Conclusion: In conclusion, mitophagy mediates CSE-induced damage and inflammation of lung epithelial cells and may represent a therapeutic target in CS-driven diseases.