The protective effect of parthenolide in an in vitro model of Parkinson's disease through its regulation of nuclear factor-kappa B and oxidative stress.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, and is due to the degeneration of dopaminergic neurons. It is multifactorial, caused by genetic and environmental factors and currently has no definitive cure. We have investigated the protective effects of parthenolide (PTN), a compound with known anti-inflammatory and antioxidant properties, in an in vitro model of PD, that is induced by 6-OHDA, and that causes neurotoxicity in SH-SY5Y human neuroblastoma cells. METHODS AND RESULTS: SH-SY5Y cells were pretreated with PTN to assess its protective effects in 6-OHDA-induced cellular damage. Cell viability was measured using Alamar blue. Apoptosis was evaluated using an Annexin V-FITC/PI kit. Reactive oxygen species (ROS) levels were quantified, and expression levels of apoptotic markers (Bax, Bcl-2, p53) and NF-κB were analyzed via Western blotting and Quantitative real-time- (qRT-) PCR. We found that 6-OHDA reduced cell viability, that was inhibited significantly by pre-treatment with PTN (p < 0.05). Flow cytometry revealed that PTN reduced apoptosis induced by 6-OHDA. PTN also reduced the ROS levels raised by 6-OHDA (p < 0.05). Moreover, PTN decreased the expression of Bax, p53, NF-κB, and p-NF-κB that were increased by treatment with 6-OHDA. CONCLUSION: These findings indicate the potential beneficial effects of PTN in an in vitro model of PD via mitigating oxidative stress and inflammation, suggested PTN as a promising agent to be used for PD therapy, warranting further investigation in preclinical and clinical studies.

The Role of Epigenetic Mechanisms in the Treatment of GI Cancers.

Epigenetic mechanisms have been shown to play a critical role in the development and progression of gastrointestinal [GI] cancers. These mechanisms involve modifications to DNA and histones that can alter gene expression patterns and may contribute to the initiation and progression of cancers. In recent years, epigenetic therapies have emerged as a promising approach to treating GI cancers. These therapies target specific epigenetic modifications, such as DNA methylation and histone acetylation, to restore normal gene expression patterns and inhibit cancer cell growth. Several epigenetic drugs have been approved for the treatment of GI cancers. Moreover, the use of epigenetic therapies in combination with other treatments, such as chemotherapeutic agents, is being studied to improve treatment outcomes. We have provided an overview of the role of epigenetic mechanisms in GI cancer treatment aimed to focus on recent evidence of the use of epigenetic agents in clinical and preclinical GI cancer studies, including gastric, esophageal, hepatic, pancreatic, and colorectal cancers. Overall, the role of epigenetic mechanisms in GI cancer treatments is an active area of research with the potential to improve patients' treatment outcomes and advance cancer treatment strategies.

Evaluation of epidemiological and microbiological characteristics, clinical features, and outcomes of adult patients with infective endocarditis in Mashhad, Iran.

INTRODUCTION: Infective endocarditis (IE) is a serious problem with high morbidity and mortality. However, there is a paucity of data regarding its epidemiology in non-high-income settings. Here, we described the characteristics of patients with IE. METHODOLOGY: Between March 2012 to March 2020, all adults (≥ 16 years) with a diagnosis of IE who were admitted to a university hospital in Mashhad, Iran, were included in the study. RESULTS: We evaluated 46 cases of IE with a median age of 42 years (interquartile range 31 to 58.3 years), of whom 21 (46%) had a definite diagnosis. The presence of a prosthetic valve or intracardiac device was the leading predisposing factor (N = 14, 30%). The etiology of IE in 22 subjects (48%) remained unknown. Staphylococcus aureus (N = 12, 26%) was the most common causative pathogen. Echocardiography revealed the mitral valve as the most affected valve (N = 18, 39%). Intravenous drug users (IVDU) had a higher chance of right-sided IE, as compared to no IVDU patients (odds ratio: 35, 95% CI: 3.7 to 425.0). The most prevalent complications were lung infarction, acute heart failure, and neurologic involvement (N = 5, 11% for each), and 15 patients (33%) died because of IE. CONCLUSIONS: In our study, the median age of IE onset was relatively low. The most frequent predisposing factor was a prosthetic valve or intracardiac device. The proportion of negative blood cultures was unacceptably high. Thus, our findings emphasize promoting laboratory infrastructure, developing a national protocol for early initiation of appropriate treatment, and eliminating predisposing factors.

Harmaline exerts potentially anti-cancer effects on U-87 human malignant glioblastoma cells in vitro.

BACKGROUND: Harmaline is a ß-carboline alkaloid that can be extracted from the seeds of Peganum harmala. Harmaline has been shown to exhibit a potent cytotoxic effect against tumor cells. In this study, the anti-glioblastoma activity of harmaline was investigated in vitro. METHODS AND RESULTS: Cell viability, apoptosis, and cell cycle arrest were assessed in U-87 cells treated with harmaline at different doses. Reactive oxygen species (ROS) generation and the mRNA expression of apoptosis-associated genes were assessed. The anti-metastatic effect of harmaline on U-87 cells was evaluated by gelatin zymography assay where matrix metalloproteinase [MMP]-2/-9 enzymatic activity was measured, and the scratch assay was used to assess migratory responses. Flow cytometry demonstrated that harmaline could suppress the proliferation and induce sub-G1 cell cycle arrest and apoptotic cell death in glioblastoma cells. Harmaline treatment was also associated with an upregulation of the cell cycle-related genes, p21 and p53, and pro-apoptotic Bax, as well as the induction of ROS. The zymography assay indicated that the essential steps of metastasis were potently suppressed by harmaline through inhibiting the expression of MMP-2 and - 9. In addition, the migration of U-87 cells was significantly reduced after harmaline treatment. CONCLUSION: Our data suggest a basis for further research of harmaline which has potential cytotoxic activities in glioblastoma cells; inducing cell cycle arrest and apoptosis, repression of migration, possibly invasion, and metastasis.

Long non-coding RNAs and melanoma: From diagnosis to therapy.

Although extremely rare, malignant melanoma is the deadliest type of skin malignancy with the inherent capability to invade other organs and metastasize to distant tissues. In 2021, it was estimated that approximately 106,110 patients may have received the diagnosis of melanoma, with a mortality rate of 7180. Surgery remains the common choice for treatment in patients with melanoma. Despite many advances in the treatment of melanoma, some patients, such as those who have received cytotoxic chemotherapeutic and immunotherapic agents, a significant number of patients may show inadequate treatment response following initiating these treatments. Non-coding RNAs, including lncRNAs, have become recently popular and attracted the attention of many researchers to make new insights into the pathogenesis of many diseases, particularly malignancies. LncRNAs have been thoroughly investigated in multiple cancers such as melanoma and have been shown to play a major role in regulating various physiological and pathological cellular processes. Considering their core regulatory function, these non-coding RNAs may be appropriate candidates for melanoma patients' diagnosis, prognosis, and treatment. In this review, we will cover all the current literature available for lncRNAs in melanoma and will discuss their potential benefits as diagnostic and/or prognostic markers or potent therapeutic targets in the treatment of melanoma patients.

Role of interleukin-6-mediated inflammation in the pathogenesis of inflammatory bowel disease: focus on the available therapeutic approaches and gut microbiome.

Inflammatory bowel disease (IBD) is considered a chronic inflammatory and multifactorial disease of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are two types of chronic IBD. Although there is no accurate information about IBD pathophysiology, evidence suggests that various factors, including the gut microbiome, environment, genetics, lifestyle, and a dysregulated immune system, may increase susceptibility to IBD. Moreover, inflammatory mediators such as interleukin-6 (IL-6) are involved in the immunopathogenesis of IBDs. IL-6 contributes to T helper 17 (Th17) differentiation, mediating further destructive inflammatory responses in CD and UC. Moreover, Th1-mediated responses participate in IBD, and the antiapoptotic IL-6/IL-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3) signals are responsible for preserving Th1 cells in the site of inflammation. It has been revealed that fecal bacteria isolated from UC-active and UC-remission patients stimulate the hyperproduction of several cytokines, such as IL-6, tumor necrosis factor-α (TNF-α), IL-10, and IL-12. Given the importance of the IL-6/IL-6R axis, various therapeutic options exist for controlling or treating IBD. Therefore, alternative therapeutic approaches such as modulating the gut microbiome could be beneficial due to the failure of the target therapies so far. This review article summarizes IBD immunopathogenesis focusing on the IL-6/IL-6R axis and discusses available therapeutic approaches based on the gut microbiome alteration and IL-6/IL-6R axis targeting and treatment failure.

Application of Quercetin in the Treatment of Gastrointestinal Cancers.

Many cellular signaling pathways contribute to the regulation of cell proliferation, division, motility, and apoptosis. Deregulation of these pathways contributes to tumor cell initiation and tumor progression. Lately, significant attention has been focused on the use of natural products as a promising strategy in cancer treatment. Quercetin is a natural flavonol compound widely present in commonly consumed foods. Quercetin has shown significant inhibitory effects on tumor progression via various mechanisms of action. These include stimulating cell cycle arrest or/and apoptosis as well as its antioxidant properties. Herein, we summarize the therapeutic effects of quercetin in gastrointestinal cancers (pancreatic, gastric, colorectal, esophageal, hepatocellular, and oral).

MicroRNA let-7 and viral infections: focus on mechanisms of action.

MicroRNAs (miRNAs) are fundamental post-transcriptional modulators of several critical cellular processes, a number of which are involved in host defense mechanisms. In particular, miRNA let-7 functions as an essential regulator of the function and differentiation of both innate and adaptive immune cells. Let-7 is involved in several human diseases, including cancer and viral infections. Several viral infections have found ways to dysregulate the expression of miRNAs. Extracellular vesicles (EV) are membrane-bound lipid structures released from many types of human cells that can transport proteins, lipids, mRNAs, and miRNAs, including let-7. After their release, EVs are taken up by the recipient cells and their contents released into the cytoplasm. Let-7-loaded EVs have been suggested to affect cellular pathways and biological targets in the recipient cells, and can modulate viral replication, the host antiviral response, and the action of cancer-related viruses. In the present review, we summarize the available knowledge concerning the expression of let-7 family members, functions, target genes, and mechanistic involvement in viral pathogenesis and host defense. This may provide insight into the development of new therapeutic strategies to manage viral infections.

MicroRNA and Exosome in Retinal-related Diseases: Their Roles in the Pathogenesis and Diagnosis.

The precise and exquisite architecture of the retina is directly related to vision. Therefore, any mechanisms associated with disruption of retinal structure could affect the quality of vision. A large number of studies indicated that several cellular and molecular processes are involved in retina pathogenesis. Among different risk factors reported as important players in retina diseases, deregulation of epigenetic contributors has critical roles in the pathogenesis of these diseases. MicroRNAs (miRNAs) are a type of small non-coding RNAs that are involved in various signaling pathways involved in retina diseases. These molecules exert their function by targeting a sequence of cellular and molecular signals. Long-non coding RNAs (lncRNAs) and circular RNAs are other non-coding RNAs, which can exert their regulatory roles via miRNA sponging. In this regard, it has been showed that miRNA sponging could modulate a variety of pathways in retinal diseases. Besides miRNAs, exosomes are other players in the pathogenesis of retinal diseases. Exosomes are biological vectors that could carry their cargos to recipient cells. The cargos of exosomes (i.e., proteins, lncRNAs, miRNAs, and fragments of DNA) change behaviors of host cells. Here, we summarized the roles of miRNAs, miRNAs sponging and exosomes in the pathogenesis of retinal diseases.

Toward individually tunable compound eyes with transparent graphene electrode.

We present tunable compound eyes made of ionic liquid lenses, of which both curvatures (R 1 and R 2 in the lensmaker's equation) can be individually changed using electrowetting on dielectric (EWOD) and applied pressure. Flexible graphene is used as a transparent electrode and is integrated on a flexible polydimethylsiloxane (PDMS)/parylene hybrid substrate. Graphene electrodes allow a large lens aperture diameter of between 2.4 mm and 2.74 mm. Spherical aberration analysis is performed using COMSOL to investigate the optical property of the lens under applied voltage and pressure. The final lens system shows a resolution of 645.1 line pair per millimeter. A prototype of a tunable lens array is proposed for the application of a compound eye.

Versatile Miniature Tunable Liquid Lenses Using Transparent Graphene Electrodes.

This paper presents, for the first time, versatile and low-cost miniature liquid lenses with graphene as electrodes. Tunable focal length is achieved by changing the droplet curvature using electrowetting on dielectric (EWOD). Ionic liquid and KCl solution are utilized as lens liquid on the top of a flexible Teflon-coated PDMS/parylene membrane. Transparent and flexible, graphene allows transmission of visible light as well as large deformation of the polymer membrane to achieve requirements for different lens designs and to increase the field of view without damaging of electrodes. The tunable range for the focal length is between 3 and 7 mm for a droplet with a volume of 3 µL. The visualization of bone marrow dendritic cells is demonstrated by the liquid lens system with a high resolution (456 lp/mm).