Unraveling Dysregulated Cell Signaling Pathways, Genetic and Epigenetic Mysteries of Parkinson's Disease.

Parkinson's disease (PD) is a prevalent and burdensome neurodegenerative disorder that has been extensively researched to understand its complex etiology, diagnosis, and treatment. The interplay between genetic and environmental factors in PD makes its pathophysiology difficult to comprehend, emphasizing the need for further investigation into genetic and epigenetic markers involved in the disease. Early diagnosis is crucial for optimal management of the disease, and the development of novel diagnostic biomarkers is ongoing. Although many efforts have been made in the field of recognition and interpretation of the mechanisms involved in the pathophysiology of the disease, the current knowledge about PD is just the tip of the iceberg. By scrutinizing genetic and epigenetic patterns underlying PD, new avenues can be opened for dissecting the pathology of the disorder, leading to more precise and efficient diagnostic and therapeutic approaches. This review emphasizes the importance of studying dysregulated cell signaling pathways and molecular processes associated with genes and epigenetic alterations in understanding PD, paving the way for the development of novel therapeutic strategies to combat this devastating disease.

Cancer cells same as zombies reprogram normal cells via the secreted microenvironment.

The cancer microenvironment plays a crucial role in promoting metastasis and malignancy even in normal cells. In the present study, the effect of acidic and conditioned media of cancer cells (MDA-MB-231), separately and in combination, was studied for the first time on the cell death mechanisms and DNA methylation of normal fibroblasts (NIH/3T3). Cell survival of conditioned media was rescued by the addition of acidic media to conditioned media, as shown by the results. Cell metabolic activity is deviated in a direction other than the Krebs cycle by acidic media The mitochondrial metabolic activity of all groups was enhanced over time, except for acidic media. Unlike the highest amount of ROS in conditioned media, its level decreased to the level of acidic media in the combination group. Furthermore, cells were deviated towards autophagy, rather than apoptosis, by the addition of acidic media to the conditioned media, unlike the conditioned media. Global DNA methylation analysis revealed significantly higher DNA hypomethylation in acidic media than in normal and combination media. Not only were cells treated with conditioned media rescued by acidic media, but also DNA hypomethylation and apoptosis in the combination group were decreased through epigenetic modifications. The acidic and conditioned media produced by cancer cells can remotely activate malignant signaling pathways, much like zombies, which can cause metabolic and epigenetic changes in normal cells.

Dutasteride nanoemulsion preparation to inhibit 5-alpha-hair follicle reductase enzymes in the hair follicle; an ex vivo study.

Alopecia is a treatable disorder that usually occurs due to high levels of 5-alpha dihydrotestosterone in hair follicles. To enhance the storage capacity of hair follicles and alleviate the inherent characteristics of dutasteride, 5-alpha reductase inhibitor, a prolonged-release nanocarrier was synthesised, and its influence on rat abdomen's skin was investigated. Results showed the lower ratio of S/Co (higher ethanol concentration) increased the hydrodynamic nanocarriers' particle size due to thermodynamic disturbance and Ostwald ripening. In contrast, an increase in surfactant through a decrease in interfacial tension resulted in smaller nanocarriers of 32.4 nm. Moreover, an increase in viscosity had an inverse correlation with the nanoemulsions' particle size. Nanocarriers containing ethanol showed less entrapment efficacy, perhaps due to the rapid dissolution of dutasteride into ethanol during nanoemulsification, while, based on Stokes' equation, the addition of ethanol resulted in smaller particle size and stability of the system. Skin permeation analysis using Franz diffusion cells showed nanocarriers could pass through the skin and release dutasteride for 6 days. In conclusion, the optimum concentration of ingredients is decisive in guaranteeing the ideal particle size, stability, and skin permeation of nanocarriers. The Present dutasteride nanocarrier would promise a prolonged and sustained-release drug delivery system for Alopecia therapy.

The Twofold Role of Osteogenic Small Molecules in Parkinson's Disease Therapeutics: Crosstalk of Osteogenesis and Neurogenesis.

Deemed one of the most problematic neurodegenerative diseases in the elderly population, Parkinson's disease remains incurable to date. Ongoing diagnostic studies, however, have revealed that a large number of small molecule drugs that trigger the BMP2-Smad signaling pathway with an osteogenic nature may be effective in Parkinson's disease treatment. Although BMP2 and Smad1, 3, and 5 biomolecules promote neurite outgrowth and neuroprotection in dopaminergic cells as well, small molecules are quicker at crossing the BBB and reaching the damaged dopaminergic neurons located in the substantia nigra due to a molecular weight less than 500 Da. It is worth noting that osteogenic small molecules that inhibit Smurf1 phosphorylation do not offer therapeutic opportunities for Parkinson's disease; whereas, osteogenic small molecules that trigger Smad1, 3, and 5 phosphorylation may have strong therapeutic implications in Parkinson's disease by increasing the survival rate of dopaminergic cells and neuritogenesis. Notably, from a different perspective, it might be said that osteogenic small molecules can possibly put forth therapeutic options for Parkinson's disease by improving neuritogenesis and cell survival.

Strong Binding of Phytochemicals to the Catalytic Domain of Tyrosine Hydroxylase as a Trojan Horse Decreases Dopamine in Dopaminergic Cells: Pharmaceutical Considerations in Schizophrenia and Parkinson's Disease.

BACKGROUND: Imbalances in dopamine levels result in neurological and psychological disorders such as elevated dopamine in Parkinson's disease. OBJECTIVE: Despite a considerable number of advertisements claiming Aloe-vera's effectiveness in PD treatment, it has hidden long-term disadvantages for healthy people and PD patients. METHODS: In the present investigation, the impacts of Aloe-vera on dopaminergic cells were evaluated. RESULTS: The results indicated that the focal adhesion kinase (FAK) enhancement was in line with the Bax/Bcl2 ratio decrement, reactive oxygen specious (ROS) production, and nonsignificant alteration in the sub-G1phase of the cell cycle. It led to glial cell-derived neurotrophic factor (GDNF) upregulation but did not significantly change the BDNF level involved in depression and motor impairment recovery. These events apparently resulted in the enhancement in dopaminergic cell viability and neurite length and attenuated PI+ cells. However, it also induced neuronal nitric oxide synthase (nNOS) overexpression and nitric oxide (NO) and lactate dehydrogenase (LDH) production. Notably, docking results of the catalytic domain in tyrosine hydroxylase (TH) with the Aloe-vera constituents showed strong binding of most Aloe-vera constituents with the catalytic domain of TH, even stronger than L-tyrosine as an original substrate. Following the docking results, Aloe-vera downregulated TH protein and attenuated dopamine. CONCLUSION: It can be hypothesized that Aloe-vera improves PD symptoms through enhancement in antiapoptotic markers and neurotrophic factors, while it suppresses TH and dopamine in the form of a Trojan horse, later resulting in the future deterioration of the disease symptoms. The results provide cues to pharmaceutical companies to use the active components of Aloe-vera as putative agents in neurological and psychiatric disorders and diseases to decrease dopamine in patients with enhanced dopamine levels.

Modulation of autophagy by melatonin via sirtuins in stroke: From mechanisms to therapies.

Sirtuins perform an important effect on the neural cell fate following stroke. Several mechanisms that have been correlated with stroke are oxidative stress, apoptosis, necrosis and autophagy. Autophagy is usually regarded as unitary of the neural cell survival mechanisms. Recently, the importance of the sirtuins effect on autophagy by antioxidant agents for stroke treatment mentioned in various studies. One of these agents is melatonin. Melatonin can modulate autophagy by changing on sirtuin pathways. Melatonin and its metabolites adjust various sirtuins pathways related to apoptosis, proliferation, metastases, autophagy and inflammation in case of stroke. In this review, we will discuss about the modulation of autophagy by melatonin via sirtuins in stroke.

Fingolimod Nanoemulsions at Different Particle Sizes Define the Fate of Spinal Cord Injury Recovery.

Spinal cord injury (SCI) is a debilitating condition for which no definitive treatment has yet been identified. Notably, it influences other tissues through inflammatory reactions and metabolic disturbances. Therefore, fingolimod (FTY-720), as an FDA-approved inflammatory modulator, would be promising. In the present study, nanocarriers with two distinct monodisperse particle sizes of 60 (nF60) and 190 (nF190) nm were prepared via low-(stirring) and high-energy (probe ultrasound) emulsion oil in water (O/W) methods. Larger nanocarriers showed higher EE% and sustained-release profile than smaller nanocarriers. Neural stem cell (NSC) viability and lactate dehydrogenase (LDH) release were studied in the presence of nanocarriers and free FTY-720. The results indicated that nanocarriers and free FTY-720 enhanced NSC viability compared with the control group. However, nF190 induced significantly less cell membrane damage than nF60. Nanocarriers and free FTY-720 enhanced motor neuron recovery in SCI rats, while body weight and return to bladder reflux by nF190 were significantly higher than those in the nF60 group. Return to bladder reflux might be due to the role of FTY-720 in the regulation of detrusor muscle tone and preservation of the integrity of vessels by acting on endothelial cells. Moreover, nF190 gained higher soleus muscle weight than the free drugs; probably decreasing proinflammatory cytokines in the soleus diminishes muscular atrophy in SCI rats. In summary, it might be said that larger nanocarriers with sustained-release profile and less cell membrane damage seem to be more efficient than smaller ones to manage SCI and enhance bladder reflux. These data will help pharmaceutical companies select the correct particle size for nanodrugs and develop more efficient drug formulations to treat SCI.

Can we Succeed in the Fight Against SARS-CoV-2 with its Emerging New Variants?

In 2019, the whole world came together to confront a life-threatening virus named SARS-CoV-2, causing COVID-19 illness. The virus infected the human host by attaching to the ACE2 and CD147 receptors in some human cells, resulting in cytokine storm and death. The new variants of the virus that caused concern are Alpha, Beta, Gamma, Delta, and Epsilon, according to the WHO label. However, Pango lineages designated them as B.1.1.7, B.1.351, P.1, B.1.617.2, and B.1.429. Variants may be progressively formed in one chronic COVID-19 patient and transmitted to others. They show some differences in cellular and molecular mechanisms. Mutations in the receptor-binding domain (RBD) and N-terminal domain (NTD) lead to alterations in the host's physiological responses. They show significantly higher transmissibility rates and viral load while evading neutralizing antibodies at different rates. These effects are through mutations, deletion, and conformational alterations in the virus, resulting in the enhanced affinity of RBD to PD of ACE2 protein, virus entry, and spike conformational change. In the clinical laboratory, new variants may diagnose from other variants using specific primers for RBD or NTD. There are some controversial findings regarding the efficacy of the developed vaccines against the new variants. This research aimed to discuss the cellular and molecular mechanisms beyond COVID-19 pathogenesis, focusing on the new variants. We glanced at why the mutations and the ability to transmit the virus increase and how likely the available vaccines will be effective against these variants.

Dexamethasone: Insights into Pharmacological Aspects, Therapeutic Mechanisms, and Delivery Systems.

Dexamethasone (DEX) has been widely used to treat a variety of diseases, including autoimmune diseases, allergies, ocular disorders, cancer, and, more recently, COVID-19. However, DEX usage is often restricted in the clinic due to its poor water solubility. When administered through a systemic route, it can elicit severe side effects, such as hypertension, peptic ulcers, hyperglycemia, and hydro-electrolytic disorders. There is currently much interest in developing efficient DEX-loaded nanoformulations that ameliorate adverse disease effects inhibiting advancements in scientific research. Various nanoparticles have been developed to selectively deliver drugs without destroying healthy cells or organs in recent years. In the present review, we have summarized some of the most attractive applications of DEX-loaded delivery systems, including liposomes, polymers, hydrogels, nanofibers, silica, calcium phosphate, and hydroxyapatite. This review provides our readers with a broad spectrum of nanomedicine approaches to deliver DEX safely.

Dual role of quercetin in enhancing the efficacy of cisplatin in chemotherapy and protection against its side effects: a review.

Chemotherapy has opened a new window in cancer therapy. However, the resistance of cancer cells has dramatically reduced the efficacy of chemotherapy. Cisplatin is a chemotherapeutic agent and its potential in cancer therapy has been restricted by resistance of cancer cells. As a consequence, the scientists have attempted to find new strategies in elevating chemotherapy efficacy. Due to great anti-tumour activity, naturally occurring compounds are of interest in polychemotherapy. Quercetin is a flavonoid with high anti-tumour activity against different cancers that can be used with cisplatin to enhance its efficacy and also are seen to sensitise cancer cells into chemotherapy. Furthermore, cisplatin has side effects such as nephrotoxicity and ototoxicity. Administration of quercetin is advantageous in reducing the adverse effects of cisplatin without compromising its anti-tumour activity. In this review, we investigate the dual role of quercetin in enhancing anti-tumour activity of cisplatin and simultaneous reduction in its adverse effects.

The World Against Versatile SARS-Cov-2 Nanomachines: Mythological or Reality?

Nanomachines hold promise for the next generation of emerging technology; however, nanomachines are not a new concept. Viruses, nature's nanomachines, have already existed for thousands of years. In 2019, the whole world had to come together to confront a life-threatening nanomachine named "SARS-CoV-2", which causes COVID-19 illness. SARS-CoV-2, a smart nanomachine, attaches itself to the ACE2 and CD147 receptors present on the cell surfaces of the lungs, kidneys, heart, brain, intestines, testes, etc. and triggers pathogenesis. Cell entry triggers a cascade of inflammatory responses resulting in tissue damage, with the worst affected cases leading to death. SARS-CoV-2 influences several receptors and signalling pathways; therefore, finding a biomaterial that caps these signalling pathways and ligand sites is of interest. This research aimed to compare the similarities and differences between COVID-19 and its elderly sisters, MERS and SARS. Furthermore, we glanced at emerging therapeutics that carry potential in eliminating SARS-CoV-2, and the tissue damage it causes. Simple prophylactic and therapeutic strategies for the treatment of COVID- 19 infection have been put forward.

Chitosan: A versatile bio-platform for breast cancer theranostics.

Breast cancer is considered one of the utmost neoplastic diseases globally, with a high death rate of patients. Over the last decades, many approaches have been studied to early diagnose and treat it, such as chemotherapy, hormone therapy, immunotherapy, and MRI and biomarker tests; do not show the optimal efficacy. These existing approaches are accompanied by severe side effects, thus recognizing these challenges, a great effort has been done to find out the new remedies for breast cancer. Main finding: Nanotechnology opened a new horizon to the treatment of breast cancer. Many nanoparticulate platforms for the diagnosis of involved biomarkers and delivering antineoplastic drugs are under either clinical trials or just approved by the Food and Drug Administration (FDA). It is well known that natural phytochemicals are successfully useful to treat breast cancer because these natural compounds are safer, available, cheaper, and have less toxic effects. Chitosan is a biocompatible and biodegradable polymer. Further, it has outstanding features, like chemical functional groups that can easily modify our interest with an exceptional choice of promising applications. Abundant studies were directed to assess the chitosan derivative-based nanoformulation's abilities in delivering varieties of drugs. However, the role of chitosan in diagnostics and theranostics not be obligated. The present servey will discuss the application of chitosan as an anticancer drug carrier such as tamoxifen, doxorubicin, paclitaxel, docetaxel, etc. and also, its role as a theranostics (i.e. photo-responsive and thermo-responsive) moieties. The therapeutic and theranostic potential of chitosan in cancer is promising and it seems that to have a good potential to get to the clinic.

Anti-inflammatory ethosomal nanoformulation in combination with iontophoresis in chronic wound healing: An ex vivo study.

Prescription of anti-inflammatory drugs may be considered as a promising strategy in chronic wound healing where the inflammatory disturbance has delayed the healing process. It seems that hydrocortisone 17-butyrate (HB17) would be promising in the form of a nano-formulation to enhance drug delivery efficacy. In the present study, transdermal delivery of nano-HB17 in combination with iontophoresis was investigated ex vivo. Ethosomal-HB17 was synthesised using lecithin, ethanol and cholesterol with a different ratio by hot method. The negative ethosomal-HB17 particle size was around 244 ± 4.3 nm with high stability of up to 30 days. Additionally, evaluated entrapment efficiency of HB17 in ethosomes by high performance liquid chromatography was 40.6 ± 2.21%. Moreover, the permeation speed and amount of H17B in complete-thickness rat skin in the presence and absence of iontophoresis showed that the penetration of free H17B and ethosomal-H17B formulations were zero and 7.98 µg/cm2 in 120 min, respectively. Whereas in the case of applying iontophoresis, permeation amount obtained was zero and 19.69 µg/cm2 in 30 min in free H17B and ethosomal-H17B formulations, respectively. It has been concluded that transdermal delivery of ethosomal-H17B is an effective strategy to enhance drug delivery and it will be improved when it is combined with iontophoresis.

Small nucleolar RNA host genes promoting epithelial-mesenchymal transition lead cancer progression and metastasis.

The small nucleolar RNA host genes (SNHGs) belong to the long non-coding RNAs and are reported to be able to influence all three levels of cellular information-bearing molecules, that is, DNA, RNA, and proteins, resulting in the generation of complex phenomena. As the host genes of the small nucleolar RNAs (snoRNAs), they are commonly localized in the nucleolus, where they exert multiple regulatory functions orchestrating cellular homeostasis and differentiation as well as metastasis and chemoresistance. Indeed, worldwide literature has reported their involvement in the epithelial-mesenchymal transition (EMT) of different histotypes of cancer, being able to exploit peculiar features, for example, the possibility to act both in the nucleus and the cytoplasm. Moreover, SNHGs regulation is a fundamental topic to better understand their role in tumor progression albeit such mechanism is still debated. Here, we reviewed the biological functions of SNHGs in particular in the EMT process and discussed the perspectives for new cancer therapies.

The role of nanotechnology in current COVID-19 outbreak.

COVID-19 has recently become one of the most challenging pandemics of the last century with deadly outcomes and a high rate of reproduction number. It emphasizes the critical need for the designing of efficient vaccines to prevent virus infection, early and fast diagnosis by the high sensitivity and selectivity diagnostic kits, and effective antiviral and protective therapeutics to decline and eliminate the viral load and side effects derived from tissue damages. Therefore, non-toxic antiviral nanoparticles (NPs) have been under development for clinical application to prevent and treat COVID-19. NPs showed great promise to provide nano vaccines against viral infections. Here, we discuss the potentials of NPs that may be applied as a drug itself or as a platform for the aim of drug and vaccine repurposing and development. Meanwhile, the advanced strategies based on NPs to detect viruses will be described with the goal of encouraging scientists to design effective and cost-benefit nanoplatforms for prevention, diagnosis, and treatment.

Paving the Road Toward Exploiting the Therapeutic Effects of Ginsenosides: An Emphasis on Autophagy and Endoplasmic Reticulum Stress.

Programmed cell death processes such as apoptosis and autophagy strongly contribute to the onset and progression of cancer. Along with these lines, modulation of cell death mechanisms to combat cancer cells and elimination of resistance to apoptosis is of great interest. It appears that modulation of autophagy and endoplasmic reticulum (ER) stress with specific agents would be beneficial in the treatment of several disorders. Interestingly, it has been suggested that herbal natural products may be suitable candidates for the modulation of these processes due to few side effects and significant therapeutic potential. Ginsenosides are derivatives of ginseng and exert modulatory effects on the molecular mechanisms associated with autophagy and ER stress. Ginsenosides act as smart phytochemicals that confer their effects by up-regulating ATG proteins and converting LC3-I to -II, which results in maturation of autophagosomes. Not only do ginsenosides promote autophagy but they also possess protective and therapeutic properties due to their capacity to modulate ER stress and up- and down-regulate and/or dephosphorylate UPR transducers such as IRE1, PERK, and ATF6. Thus, it would appear that ginsenosides are promising agents to potentially restore tissue malfunction and possibly eliminate cancer.

Will stem cells from fat and growth factors from blood bring new hope to female patients with reproductive disorders?

Female reproductive system disorders (FRSD) with or without infertility are prevalent women's health problems with a variety of treatment approaches including surgery and hormone therapy. It currently considering to sub-branch of regenerative medicine including stem cells or growth factors injection-based delivery treatment might be improved female reproductive health life. The most common products used for these patients treatment are autologous cell or platelet-based products from patients, including platelet-rich plasma, plasma rich in growth factor, platelet-rich fibrin, and stromal vascular fraction. In this review, we discuss each of the above products used in treatment of FRSD and critically evaluate the clinical outcome.

C-Myc Signaling Pathway in Treatment and Prevention of Brain Tumors.

Brain tumors are responsible for high morbidity and mortality worldwide. Several factors such as the presence of blood-brain barrier (BBB), sensitive location in the brain, and unique biological features challenge the treatment of brain tumors. The conventional drugs are no longer effective in the treatment of brain tumors, and scientists are trying to find novel therapeutics for brain tumors. In this way, identification of molecular pathways can facilitate finding an effective treatment. c-Myc is an oncogene signaling pathway capable of regulation of biological processes such as apoptotic cell death, proliferation, survival, differentiation, and so on. These pleiotropic effects of c-Myc have resulted in much fascination with its role in different cancers, particularly brain tumors. In the present review, we aim to demonstrate the upstream and down-stream mediators of c-Myc in brain tumors such as glioma, glioblastoma, astrocytoma, and medulloblastoma. The capacity of c-Myc as a prognostic factor in brain tumors will be investigated. Our goal is to define an axis in which the c-Myc signaling pathway plays a crucial role and to provide direction for therapeutic targeting in these signaling networks in brain tumors.