Current Molecular Medicine - Volume 23, Issue 9, 2023

Epigenetics is a powerful regulator of gene expression. With advanced discoveries in underlying molecular mechanisms that can alter chromatin response to internal and external signals, epigenetic alterations have been implicated in various developmental pathways and human disorders. The extent to which this epigenetic effect contributes to eye development and progression of ocular disorders is currently less defined. However, emerging evidence suggests that epigenetic changes are relevant in the development of eye and ocular disorders like pterygium, age-related macular degeneration, glaucoma and more. This brief review will discuss the relevance of epigenetic mechanisms like DNA methylation, histone modifications, polycomb proteins and noncoding RNAs in the context of eye development and selected ocular disorders.

Due to higher adaptability and mutability, there is always a possibility for RNA viral disease outbreaks. There are no approved antivirals for the majority of RNA viruses, including SARS-CoV-2, CHIKV, DENV, JEV, ZIKV, and EBOV. To treat these infections and prepare for future epidemics, it is necessary to identify effective therapeutic strategies with broad-spectrum actions against RNA viruses. Unregulated inflammation is the major cause of the severity associated with these viral diseases. Quercetin is a privileged molecule that is known to interfere at different levels of inflammatory response. Besides, it modulates pathways responsible for viral translation as well as the immune response of the host. It has also been found to inhibit replication by targeting critical targets of some of these viruses. Due to its abilities to inhibit viral targets, modulate host factors or a combination of both, quercetin has been demonstrated to help recover from some of these viral diseases in preclinical /clinical studies. Thus, it can be a drug candidate for application against a broad range of viral diseases. However, its translational value is limited by the lack of large-scale clinical studies. A major hurdle for oral application is poor solubility. Thus, developing a suitable form of quercetin can enable adequate bioavailability, leading to its translational application.

Treatment of neurological disorders has always been one of the challenges facing scientists due to poor prognosis and symptom overlap, as well as the progress of the disease process. Neurological disorders such as Huntington’s, Parkinson's, Alzheimer's diseases, and Amyotrophic Lateral Sclerosis are very debilitating. Therefore, finding a biomarker is essential for early diagnosis and treatment goals. Recent studies have focused more on molecular factors and gene manipulation to find effective diagnostic and therapeutic biomarkers. Among these factors, microRNAs (miRNAs/ miRs) have attracted much attention. On the other hand, a growing correlation between miRNAs and neurological disorders has caused scientists to consider it as a diagnostic and therapeutic target. In this line, the miR-153 is one of the most important and highly conserved miRNAs in mice and humans, whose expression level is not only altered in neurological disorders but also improves neurogenesis. MiR-153 can regulate multiple biological processes by targeting various factors. Furthermore, the miR-153 expression also can be regulated by important regulators, such as long non-coding RNAs (e.g., KCNQ1OT1) and some compounds (e.g., Tanshinone IIA) altering the expression of miR-153. Given the growing interest in miR-153 as a biomarker and therapeutic target for neurological diseases as well as the lack of comprehensive investigation of miR-153 function in these disorders, it is necessary to identify the downstream and upstream targets and also it's potential as a therapeutic biomarker target. In this review, we will discuss the critical role of miR-153 in neurological disorders for novel diagnostic and prognostic purposes and its role in multi-drug resistance.

Breast cancer is the most commonly diagnosed type of cancer and ranks second among cancer that leads to death. From becoming the foremost reason for global concern, this multifactorial disease is being treated by conventional chemotherapies that are associated with severe side effects, with chemoresistance being the ruling reason. Exemestane, an aromatase inhibitor that has been approved by the US FDA for the treatment of breast cancer in post-menopausal women, acts by inhibiting the aromatase enzyme, in turn, inhibiting the production of estrogen. However, the clinical application of exemestane remains limited due to its poor aqueous solubility and low oral bioavailability. Furthermore, the treatment regimen of exemestane often leads to thinning of bone mineral density. Thymoquinone, a natural compound derived from the oil of the seeds of Nigella sativa Linn, possesses the dual property of being a chemosensitizer and chemotherapeutic agent. In addition, it has been found to exhibit potent bone protection properties, as evidenced by several studies. To mitigate the limitations associated with exemestane and to deliver to the cancerous cells overcoming chemoresistance, the present hypothesis has been put forth, wherein a natural chemosensitizer and chemotherapeutic agent thymoquinone will be incorporated into a lipid nanocarrier along with exemestane for combinatorial delivery to cancer cells. Additionally, thymoquinone being bone protecting will help in ousting the untoward effect of exemestane at the same time delivering it to the required malignant cells, safeguarding the healthy cells, reducing the offsite toxicity, and providing potent synergistic action.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, and its consequences severely influence the quality of a patient's life and mobility. PD is characterized by bradykinesias with tremors and/or rigidity. Pathophysiologically, PD is associated with the gradual degeneration of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, neuroinflammation, increased accumulation of the alpha (α)-synuclein, overburden of oxidative stress, and mitochondrial dysfunction. To date, there are no effective therapies with underlying shreds of evidence that alters the progression of PD. Exendin-4, a glucagon-like peptide 1 (GLP-1) receptor agonist, has gained attention for its tremendous neuroprotective potential against numerous neurodegenerative disorders, including PD. Further, several pieces of research evidence have suggested the beneficial role of Exendin-4 in PD-like experimental models. The present review article highlights the preclinical and clinical evidence of the therapeutic benefits of Exendin-4 against PD. Exendin-4 reverses the PD-like symptoms in experimental animals by dramatically minimizing the loss of dopaminergic neuronal and accumulation of α-synuclein in the PD-like brain. Further, it also reduces the mitochondrial toxicity and expression of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. These observations designate that Exendin-4 is a multifactorial compound that could be considered a safe, effective, and new ingredient for developing clinically useful pharmacotherapy for managing PD-like manifestations.

Increased hyperglycemia due to uncontrolled diabetes is the major cause of secondary diabetic complications such as retinopathy, neuropathy, nephropathy, and cardiovascular diseases. Although it is well known that increased oxidative stress, activation of the polyol pathway, protein kinase C and increased generation of advanced glycation end products could contribute to the development of diabetic complications, recent studies implicated the role of innate immunity and its related inflammatory responses in the pathophysiology of secondary diabetic complications. Increased activation of oxidative stress signaling could regulate NLRP3 inflammasome-mediated innate immune responses as well as NF-ΚB signalosome-mediated pro-inflammatory responses. This review article focused on the pathogenic role of innate immune and inflammatory responses in the progression of hyperglycemia-induced secondary diabetic complications. Specifically, we discussed in depth how deregulated innate immune and inflammatory responses could lead to an aggravated release of cytokines, chemokines, and growth factors resulting in the development of various secondary complications of diabetes.

MicroRNAs are non-coding ribonucleic acids that are evolutionarily protected. MiRNAs control the expression of genes after transcription by mRNA decomposition or the inhibition of their translation. These molecular structures control physiological and pathological processes; therefore, many of them can play vital roles as oncogenes or tumor inhibitors. Besides, the occurrence of various mutations in miRNAs can lead to cancer. In this review article, we want to peruse the role of miR-491-5p in various cancers. In recent years, many experiments and studies have been performed on the involvement of miR-491-5p in cancer, invasion, and cell metastasis. Metastasis is an event that makes cancer more advanced and harder to treat. When cancer is invasive, the cancer cells invade nearby tissues or other organs and develop cancer. Tumor studies have shown that miR-491-5p can inhibit cell growth, invasion, and metastasis. Thus, expression enhancement of miR-491-5p disrupts cell migration and improves cancer.

Among the different approaches present in regenerative medicine and tissue engineering, the one that has attracted the most interest in recent years is the possibility of printing functional biological tissues. Bioprinting is a technique that has been applied to create cellularized three-dimensional structures that mimic biological tissues and thus allow their replacement. Hydrogels are interesting materials for this type of technique. Hydrogels based on natural polymers are known due to their biocompatible properties, in addition to being attractive biomaterials for cell encapsulation. They provide a threedimensional aqueous environment with biologically relevant chemical and physical signals, mimicking the natural environment of the extracellular matrix (ECM). Bioinks are ink formulations that allow the printing of living cells. The controlled deposition of biomaterials by bioinks needs to maintain cell viability and offer specific biochemical and physical stimuli capable of guiding cell migration, proliferation, and differentiation. In this work, we analyze the theoretical and practical issues of bioprinting, citing currently used methods, their advantages, and limitations. We present some important molecules that have been used to compose bioinks, as well as the cellular responses that have been observed in different tissues. Finally, we indicate future perspectives of the method.

A great number of research has been focused on plants as a source of medicine against many diseases to overcome the many side effects of chemical drugs. Safranal, one of the main constituents of saffron [Crocus sativus], has a broad spectrum of pharmacological effects, including anti-inflammatory, antioxidant, and antiapoptotic effects. The present review elaborates on the current understanding of the neuroprotective effects of safranal. According to data published so far, safranal has the potential to exert neuroprotective effects in neurological disorders such as epilepsy, stroke, multiple sclerosis, Parkinson, and Alzheimer’s disease. Safranal could be considered a promising therapeutic agent in the future, although there is a great need for clinical trial studies.

Background: In high-risk human papillomavirus (HR-HPV)-positive cervical cancer, E6-associated protein (E6AP), an E3 ubiquitin ligase, mediates the ubiquitination and proteasomal degradation of the tumor suppressor p53. Here, we addressed the question of whether caffeic acid phenethyl ester (CAPE), a natural product mainly derived from propolis, can disrupt the interaction between E6AP and p53, inhibit ubiquitination degradation of p53 and exhibit anti-cervical cancer activity. Methods: The ability of CAPE to inhibit growth and to induce apoptosis was shown in HR-HPV-positive cervical cancer cell lines by performing CCK-8, colony formation and TUNEL assays. Apoptosis-related proteins were tested by western blotting. Coimmunoprecipitation, ubiquitination assay and protein stability assay were carried out to determine whether CAPE can disrupt the E6AP-p53 interaction and inhibit ubiquitination degradation of p53. Results: Our results showed that CAPE inhibits the growth of HR-HPV-positive cervical cancer cells and induces the activation of apoptosis-related pathways. Importantly, CAPE inhibits E6AP expression and disrupts the interaction between E6AP and p53. It inhibits the ubiquitination of p53 and promotes its stabilization. Conclusion: In summary, CAPE has a therapeutic effect on HPV-positive malignant cells, so further studies are needed to assess its clinical application.

Objective: Acute acalculous cholecystitis (AAC) is characterized by acute onset, rapid progression, high mortality, and various complications. Cyclophilin D (CypD) regulates the mitochondrial permeability transition pore (MPTP) and is involved in the occurrence of ischemia-reperfusion injury and inflammation; however, the role of CypD in AAC remains unclear. Methods: Guinea pigs of 300–350 g were randomly divided into three groups, namely the sham group, the common bile duct ligation-24h group (CBDL-24h group), and the CBDL-48h group. Western blot and qRT-PCR were applied to analyze the differential expression of CypD in each group, and transmission electron microscopy was employed to detect changes in mitochondrial structure. Inhibiting the activity of CypD by Cyclosporine A (CsA), we evaluated the difference of mitochondrial utilizing mitochondrial swelling, reactive oxygen species (ROS) detection and mitochondrial membrane potential. Results: Compared with the sham group, the prolongation of obstruction aggravated gallbladder inflammation and upregulated CypD expression in the CBDL-24h and CBDL-48h groups. The degree of mitochondrial swelling was increased, and the opening of MPTP was prolonged in the CBDL-24h and 48h groups. Decreasing the expression of CypD could repress the opening of MPTP, prevent manipulation of the mitochondrial membrane potential, and ultimately diminish the levels of intracellular ROS and apoptosis. Conclusion: CypD plays a proinflammatory role in the development of AAC by regulating the opening of MPTP. Inhibiting the activity of CypD could reduce the levels of ROS and apoptosis, rescue the function of mitochondria and finally alleviate AAC. Therefore, CypD might serve as a potential therapeutic target for ACC.

Background: Osteoarthritis (OA) is a degenerative joint disease involving both cartilage and synovium. Activating transcription factor 3 (ATF3) and regulator of G protein signaling 1 (RGS1) have been reported to be up-regulated in OA. However, little is known regarding the relationship between these two genes and the mechanism of this relationship in OA development. Therefore, the present study explores the mechanism of ATF3-mediated RGS1 in the proliferation, migration, and apoptosis of synovial fibroblasts. Methods: After the OA cell model was constructed with TGF-β1 induction, human fibroblast-like synoviocytes (HFLSs) were transfected with ATF3 shRNA or RGS1 shRNA alone or co-transfected with ATF3 shRNA and pcDNA3.1-RGS1. Then, proliferation, migration, apoptosis, and the expression of ATF3, RGS1, α-SMA, BCL-2, caspase3, and cleaved-caspase3 were measured. Meanwhile, the potential relationship between ATF3 and RGS1 was predicted and validated. Results and Discussion: Analysis of the GSE185059 dataset suggested that RGS1 was up-regulated in OA synovial fluid exosomes. Moreover, ATF3 and RGS1 were both highly expressed in TGF-β1-induced HFLSs. Transfection of ATF3 shRNA or RGS1 shRNA significantly reduced proliferation and migration and promoted apoptosis of TGF- β1-induced HFLSs. Mechanistically, ATF3 bound to the RGS1 promoter and elevated RGS1 expression. Silencing ATF3 repressed proliferation and migration and enhanced apoptosis of TGF-β1-induced HFLSs by down-regulating RGS1. Conclusion: ATF3 binds to the RGS1 promoter and enhances RGS1 expression to accelerate cell proliferation and block cell apoptosis in TGF-β1-induced synovial fibroblasts.