Polyphenols target miRNAs as a therapeutic strategy for diabetic complications.

MiRNAs are a large group of non-coding RNAs which participate in different cellular pathways like inflammation and oxidation through transcriptional, post-transcriptional, and epigenetic regulation. In the post-transcriptional regulation, miRNA interacts with the 3'-UTR of mRNAs and prevents their translation. This prevention or dysregulation can be a cause of pathological conditions like diabetic complications. A huge number of studies have revealed the association between miRNAs and diabetic complications, including diabetic nephropathy, cardiomyopathy, neuropathy, retinopathy, and delayed wound healing. To address this issue, recent studies have focused on the use of polyphenols as selective and safe drugs in the treatment of diabetes complications. In this article, we will review the involvement of miRNAs in diabetic complications' occurrence or development. Finally, we will review the latest findings on targeting miRNAs by polyphenols like curcumin, resveratrol, and quercetin for diabetic complications therapy.

Critical Role of Surface Energy in Guiding Crystallization of Solution-Coated Conjugated Polymer Thin Films.

It is well-known that substrate surface properties have a profound impact on the morphology of thin films solution coated atop and the resulting solid-state properties. However, design rules for guiding the substrate selection have not yet been established. Such design rules are particularly important for solution-coated semiconducting polymers, as the substrate-directed thin film morphology can impact charge transport properties by orders of magnitude. We hypothesize that substrate surface energies dictate the thin film morphology by modulating the free energy barrier to heterogeneous nucleation. To test this hypothesis, we systematically vary the substrate surface energy via surface functionalization techniques. We perform in-depth morphology and device characterizations to establish the relationship between substrate surface energy, thin film morphology and charge transport properties, employing donor-acceptor (D-A) conjugated polymers. We find that decreasing the substrate surface energy progressively increases thin film crystallinity, degree of molecular ordering, and extent of domain alignment. Notably, the enhanced morphology on the lowest surface energy substrate leads to a 10-fold increase in the charge carrier mobility. We further develop a free energy model relating the substrate surface energy to the penalty of heterogeneous nucleation from solution in the thin film geometry. The model correctly predicts the experimental trend, thereby validating our hypothesis. This work is a significant step toward establishing design rules and understanding the critical role of substrates in determining morphology of solution-coated thin films.

Multiple function of lncRNA MALAT1 in cancer occurrence and progression.

Long non-coding RNAs (lncRNAs) have received particular attention in the last decade due to its engaging in carcinogenesis and tumorigenesis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA that plays physiological and pathological roles in many aspects of genome function as well as biological processes involved in cell development, differentiation, proliferation, invasion, and migration. In this article, we will review the effects of lncRNA MALAT1 on the progression of six prevalent human cancers by focusing on MALAT1 ability to regulate post-transcriptional modification and signaling pathways.

Quercetin and Methotrexate in Combination have Anticancer Activity in Osteosarcoma Cells and Repress Oncogenic MicroRNA-223.

INTRODUCTION: Osteosarcoma (OS) is one of the most common bone neoplasms in adolescents. Notable short- and long-term toxic effects of OS chemotherapy regimens have been reported. Hence, new chemotherapeutic agents with the ability to potentiate OS chemotherapy drugs and protect non-tumorous tissues are required. METHODS: Saos-2 cells were treated with Methotrexate (MTX) and Quercetin (Que) (a polyphenolic flavonoid with anti-tumor effects) alone and in combination. MTT assay was performed to investigate the cytotoxicity of the drugs. Moreover, apoptosis-involved genes, including miR-223, p53, BCL-2, CBX7, and CYLD expression were analyzed via qRT-PCR. Annexin V-FITC/PI kit was employed to assess the apoptosis rate. RESULTS: The MTT results showed that Que increases MTX cytotoxicity on OS cells. The measured IC50s are 142.3 µM for QUE and 13.7 ng/ml for MTX. A decline in MTX IC50 value was observed from 13.7 ng/ml to 8.45 ng/ml in the presence of Que. Moreover, the mRNA expression outcomes indicated that the combination therapy significantly up-regulates the tumor suppressor genes, such as p53, CBX7, and CYLD, and declines anti-apoptotic genes BCL-2 and miR-223, which can lead to proliferation inhibition and apoptosis inducement. Furthermore, the apoptosis rate increased significantly from 6.03% in the control group to 38.35% in Saos-2 cells that were treated with the combination of MTX and Que. CONCLUSION: Que, with the potential to boost the anticancer activity of MTX on Saos-2 cancer cells through proliferation inhibition and apoptosis induction, is a good candidate for combination therapy.

TNF-α Blockers Showed Prophylactic Effects in Preventing COVID-19 in Patients with Rheumatoid Arthritis and Seronegative Spondyloarthropathies: A Case-Control Study.

INTRODUCTION: The interaction between angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 is a crucial factor in the viral infections leading to the release of inflammatory proteins, such as TNF-α. Thus, it is hypothesized that TNF-α blockers can prevent either COVID-19 incidence or its serious symptoms. TNF-α blockers are prescribed to treat various autoimmune disorders, including rheumatoid arthritis (RA) and seronegative spondyloarthropathies (SpA). Therefore, the objective of this work was to examine this hypothesis that TNF-α blockers can prevent COVID-19 incidence in patients with RA or SpA. METHODS: A case-control study was conducted through interviews based on a structured questionnaire to investigate the frequency of COVID-19 incidence in 254 eligible patients with RA or SpA about whom 45% were under treatment with one type of TNF-α blockers including infliximab, adalimumab, and etanercept at least for 3 months during the COVID-19 pandemic. Interviews were carried out twice, at the beginning and the end of the study (June-December 2020). Patients with COVID-19 during the study or before that were considered as cases. The control group was patients without COVID-19 experience. Data were analyzed using descriptive statistics, and logistic regression was used to determine the relationships between COVID-19 incidence and independent variables. RESULTS: A small percentage of patients treated with TNF-α blockers (5.22%, 6/115) experienced COVID-19, while a large percentage of patients with COVID-19 did not receive TNF-α blockers (27.34%, 38/139). According to odds ratio, adalimumab, infliximab, and etanercept decreased significantly the risk of developing COVID-19 up to 96.8, 95, and 80.3% (p < 0.05), respectively. Therefore, TNF-α blockers could probably decrease the chances of the COVID-19 incidence in patients with RA or SpA. CONCLUSIONS: A direct and positive correlation between the use of TNF-α blockers and a reduction in the incidence of COVID-19 could suggest the prophylactic role of these drugs in preventing COVID-19 in patients with RA and SpA.

TNF-α Blockers Showed Prophylactic Effects in Preventing COVID-19 in Patients with Rheumatoid Arthritis and Seronegative Spondyloarthropathies: A Case-Control Study.

INTRODUCTION: The interaction between angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 is a crucial factor in the viral infections leading to the release of inflammatory proteins, such as TNF-α. Thus, it is hypothesized that TNF-α blockers can prevent either COVID-19 incidence or its serious symptoms. TNF-α blockers are prescribed to treat various autoimmune disorders, including rheumatoid arthritis (RA) and seronegative spondyloarthropathies (SpA). Therefore, the objective of this work was to examine this hypothesis that TNF-α blockers can prevent COVID-19 incidence in patients with RA or SpA. METHODS: A case-control study was conducted through interviews based on a structured questionnaire to investigate the frequency of COVID-19 incidence in 254 eligible patients with RA or SpA about whom 45% were under treatment with one type of TNF-α blockers including infliximab, adalimumab, and etanercept at least for 3 months during the COVID-19 pandemic. Interviews were carried out twice, at the beginning and the end of the study (June-December 2020). Patients with COVID-19 during the study or before that were considered as cases. The control group was patients without COVID-19 experience. Data were analyzed using descriptive statistics, and logistic regression was used to determine the relationships between COVID-19 incidence and independent variables. RESULTS: A small percentage of patients treated with TNF-α blockers (5.22%, 6/115) experienced COVID-19, while a large percentage of patients with COVID-19 did not receive TNF-α blockers (27.34%, 38/139). According to odds ratio, adalimumab, infliximab, and etanercept decreased significantly the risk of developing COVID-19 up to 96.8, 95, and 80.3% (p < 0.05), respectively. Therefore, TNF-α blockers could probably decrease the chances of the COVID-19 incidence in patients with RA or SpA. CONCLUSIONS: A direct and positive correlation between the use of TNF-α blockers and a reduction in the incidence of COVID-19 could suggest the prophylactic role of these drugs in preventing COVID-19 in patients with RA and SpA.

The molecular mechanism of nuclear signaling for degradation of cytoplasmic DNA: Importance in DNA damage response and cancer.

This review summarizes and addresses non-coding RNAs (rRNA, tRNA, Vault and Y RNA, snRNA, and miRNA) cytoplasmic decay pathways, the molecules, enzymes, and modifications such as uridylation, which play vital roles in the degradation processes in various eukaryotic organisms. Plus, SIRT1's role in fundamental cellular processes, including autophagy, DNA repair, DNA damage response (DDR), and the molecular mechanisms, is explored. Further, the HuR (an RNA-binding protein) impact on the expression of genes following DNA damage, and the pathways that regulate HuR function, which is through phosphorylation by Chk1/Cdk1 and Chk2, are specified. Finally, the role of DIF1/ Rnr2-Rnr4 in DDR has been discussed.

Orientation-Dependent Host-Dopant Interactions for Manipulating Charge Transport in Conjugated Polymers.

Molecular orientation plays a critical role in controlling carrier transport in organic semiconductors (OSCs). However, this aspect has not been explored for surface doping of OSC thin films. The challenge lies in lack of methods to precisely modulate relative molecular orientation between the dopant and the OSC host. Here, the impact of molecular orientation on dopant-host electronic interactions by large modulation of conjugated polymer orientation via solution coating is reported. Combining synchrotron-radiation X-ray measurements with spectroscopic and electrical characterizations, a quantitative correlation between doping-enhanced charge carrier mobility and the Herman's orientation parameter is presented. This direct correlation can be attributed to enhanced charge-transfer interactions at host/dopant interface with increasing face-on orientation of the polymer. These results demonstrate that the surface doping effect can be fundamentally manipulated by controlling the molecular orientation of the OSC layer, enabling optimization of carrier transport.

miR-192 enhances sensitivity of methotrexate drug to MG-63 osteosarcoma cancer cells.

Chemo-resistance remains a considerable obstacle encountered in osteosarcoma (OS) therapy. Evidence has implied that a reduction in the expression of microRNAs (miRs/miRNAs) leads to exacerbated chemo-resistance. Hence, to better understand the role of miR-192 in the pathogenesis of OS during methotrexate (MTX) treatment, we restore miR-192 in the MG-63 cells and investigate the mechanisms, which are associated with MTX-resistance in OS. Exogenetic overexpression of miR-192 was established by transfecting miR-192 mimics into MG-63 cells using Lipofectamine. Trypan blue dye exclusion test was performed to evaluate the proliferation of the MG-63 cells. Chemo-resistance to MTX was determined using the MTT method after 48 h. ELISA cell death assay was performed to evaluate the apoptosis rate. The quantitative RT-PCR (RT-qPCR) was applied to determine the mRNA expression levels before and after the transfection. Our results illustrated that miR-192 is down-regulated in OS tumor cells. Transfection of miR-192 noticeably alleviated the mRNA expression levels of MMP9, c-Myc, K-Ras, CXCR-4, and ADAMTS compared with the control groups (P-values< 0.05). MTX Combination treatment with miR-192 noticeably elevated the cytotoxic effect of MTX and alleviated its IC50 (P < 0.05). Moreover, miR-192 significantly increased the apoptotic effect of MTX. These results implied that miR-192 enhances the sensitivity of MG-63 cells to MTX. Collectively, our results elucidated that miR-192 contributes to chemo-sensitizing MG-63 cells to MTX, and could be considered as a promising agent to overcome MTX-resistance in OS.

Modulation of telomerase expression and function by miRNAs: Anti-cancer potential.

Telomerase is a nucleoprotein reverse transcriptase that maintains the telomere, a protective structure at the ends of the chromosome, and is active in cancer cells, stem cells, and fetal cells. Telomerase immortalizes cancer cells and induces unlimited cell division by preventing telomere shortening. Immortalized cancer cells have unlimited proliferative potential due to telomerase activity that causes tumorigenesis and malignancy. Therefore, telomerase can be a lucrative anti-cancer target. The regulation of catalytic subunit of telomerase (TERT) determines the extent of telomerase activity. miRNAs, as an endogenous regulator of gene expression, can control telomerase activity by targeting TERT mRNA. miRNAs that have a decreasing effect on TERT translation mediate modulation of telomerase activity in cancer cells by binding to TERT mRNA and regulating TERT translation. In this review, we provide an update on miRNAs that influence telomerase activity by regulation of TERT translation.

Role of Multivalent Interactions in Dynamic-Template-Directed Assembly of Conjugated Polymers.

Dynamic-template-directed assembly is a promising method to enhance molecular ordering and electronic properties of solution-coated polymer semiconductor thin films over a large area. In this work, we establish that multicomponent dynamic templates of complementary chemistries can promote polymer crystallization through cooperative multivalent interactions. We investigate this phenomenon using a combination of templating substrates including a fluoropolymer, a hydrogen-bonded liquid, and an ionic liquid (IL). Template-dependent multiscale morphology is studied by a comprehensive set of characterization techniques to understand how introducing diverse chemical moieties modulates polymer assembly. Our results clearly confirm synergistic effects between components of complementary chemistries constituting the dynamic template. The relative degree of crystallinity is improved by 50-150% for films deposited on multicomponent dynamic templates compared to their neat constituents. In addition, macroscopic alignment is increased significantly (2-5 times) compared to single-component templates. As a result, highly anisotropic charge transport is observed with apparent hole mobilities up to 3.6 cm2 V-1 s-1. In contrast, such a synergistic effect is not observed when using a multicomponent dynamic template of comparable chemistries (i.e., IL and polymerized IL). We elucidate the origin of this synergistic effect by using attenuated total reflectance Fourier transform infrared spectroscopy and isothermal titration calorimetry. When the dynamic template comprises two or more components interacting with complementary binding sites on the conjugated polymer (CP) (esp. backbone vs side chain), the template-polymer interactions is significantly enhanced compared to the sum of single component contributions. These results provide valuable insights into surface-directed CP crystallization during large-area solution coating. Template dynamics is rarely studied and represents a new opportunity for guiding assembly of soft functional matter.

Ion Gel Dynamic Templates for Large Modulation of Morphology and Charge Transport Properties of Solution-Coated Conjugated Polymer Thin Films.

Dynamic surfaces play a critical role in templating highly ordered complex structures in living systems but are rarely employed for directing assembly of synthetic functional materials. We design ion gel templates with widely tunable dynamics ( Tg) to template solution-coated conjugated polymers. We hypothesize that the ion gel expedites polymer nucleation by reconfiguring its surface to facilitate cooperative multivalent interactions with the conjugated polymer, validated using both experimental and computational approaches. Varying ion gel dynamics enables large modulation of alignment, molecular orientation, and crystallinity in templated polymer thin films. At the optimal conditions, ion-gel-templated films exhibit 55 times higher dichroic ratio (grazing incidence X-ray diffraction) and 49% increase in the relative degree of crystallinity compared to those templated by the neat polymer matrix. As a result, the maximum hole mobilities increase by factors of 4 and 11 along the π-π stacking and the backbone directions. Intriguingly, we observe a synergistic effect between the gel matrix and the ionic liquid that produces markedly enhanced templating effect than either component alone. Molecular dynamics simulations suggest that complementary multivalent interactions facilitated by template reconfigurability underlie the observed synergy. We further demonstrate field-effect transistors both templated and gated by ion gels with average mobility exceeding 7 cm2 V-1 s-1.

Understanding Film-To-Stripe Transition of Conjugated Polymers Driven by Meniscus Instability.

Meniscus instability during meniscus-guided solution coating and printing of conjugated polymers has a significant impact on the deposit morphology and the charge-transport characteristics. The lack of quantitative investigation on meniscus-instability-induced morphology transition for conjugated polymers hindered the ability to precisely control conjugated polymer deposition for desired applications. Herein, we report a film-to-stripe morphology transition caused by stick-and-slip meniscus instability during solution coating seen in multiple donor-acceptor polymer systems. We observe the coexistence of film and stripe morphologies at the critical coating speed. Surprisingly, higher charge-carrier mobility is measured in transistors fabricated from stripes despite their same deposition condition as the films at the critical speed. To understand the origin of the morphology transition, we further construct a generalizable surface free energy model to validate the hypothesis that the morphology transition occurs to minimize the system surface free energy. As the system surface free energy varies during a stick-and-slip cycle, we focus on evaluating the maximum surface free energy at a given condition, which corresponds to the sticking state right before slipping. Indeed, we observe the increase of the maximum system surface free energy with the increase in coating speed prior to film-to-stripe morphology transition and an abrupt drop in the maximum system surface free energy post-transition when the coating speed is further increased, which is associated with the reduced meniscus length during stripe deposition. Such an energetic change originates from the competition between pinning and depinning forces on a partial wetting substrate which underpins the film-to-stripe transition. This work establishes a quantitative approach for understanding meniscus-instability-induced morphology transition during solution coating. The mechanistic understanding may further facilitate the use of meniscus instability for lithography-free patterning or to suppress instability for highly homogeneous thin film deposition.

Evaluation of Serum Trace Element Levels and Superoxide Dismutase Activity in Patients with Inflammatory Bowel Disease: Translating Basic Research into Clinical Application.

The relationship of minerals and trace elements with inflammatory bowel disease (IBD) is complex. Alterations in their metabolism can be induced by the diseases and their complications. To study the role of trace elements in IBD patients' serum zinc and copper and their related enzymes, including superoxide dismutase (SOD), activity were measured in patients with IBD patients as well as in healthy subjects. In addition, the correlation between serum trace element levels, albumin, total protein, urea level, copper/zinc ratio, and disease activity (DA) was determined in these subjects. Serum samples were obtained from 35 patients (19 ulcerative colitis (UC) and 16 Crohn's disease (CD)) in the active phase of the disease and 30 healthy control subjects. Serum levels of zinc, copper, SOD activity, albumin, total protein, and urea were measured. The results were compared between the two groups using independent Student's t test in statistical analysis. Serum levels of zinc, SOD activity, albumin, and total protein were significantly lower (P < 0.05) in patients than controls, while serum urea level was significantly higher in patients compared to controls. Copper concentrations did not differ between patients with IBD (mean ± SD, 58.8 ± 20.7 µg/d) and controls (55.57 ± 12.6 µg/d). Decreased levels of zinc and SOD activity are associated with increased inflammatory processes indicating inappropriate antioxidant system in patients with IBD. Additionally, lower levels of albumin and total protein with higher level of urea reflect metabolic problems in liver system.

Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats.

INTRODUCTION: Oxidative stress is a common factor in cataract. Considering the antioxidant properties of hesperidin as a flavanone glycoside from the flavonoid family with radioprotective effect, this study aimed to determine the protective effect of this flavanone glycoside on reducing oxidative stress in the eye lens tissue of mature rats caused by gamma irradiation. MATERIALS AND METHODS: A total of 48 adult rats were randomly divided into six groups, namely, control, Dimethyl sulfoxide (DMSO), hesperidin, radiation, radiation + DMSO, and radiation + hesperidin. 15 Gy irradiation was carried out using Cobalt-60 teletherapy instrument with a source-to-surface distance of 80 cm at a dose rate of 98.5 cGy/min. 2 days following irradiation, we removed the rats' lenses and analyzed them to determine the effects of hesperidin. RESULTS: The comparison of control and intervention groups after irradiation showed that malondialdehyde (MDA) level in the lens tissue was significantly higher in the irradiation groups than the control group. Furthermore, a significant difference between radiation and radiation + hesperidin groups were observed. The level of glutathione (GSH) in the lens tissue was significantly lower in the irradiation groups compared to the control group. Nonetheless, significant elevation of GSH in the radiation + hesperidin group compared to radiation group was seen. CONCLUSIONS: Radiation exposure reduced GSH and enhanced MDA levels in the lens tissue. However, GSH and MDA levels were modulated after hesperidin consumption. These results show the antioxidative properties of hesperidin in the lens and demonstrated that radiation complications such as cataract can be reduced by hesperidin through reducing oxidative stress.

Understanding Interfacial Alignment in Solution Coated Conjugated Polymer Thin Films.

Domain alignment in conjugated polymer thin films can significantly enhance charge carrier mobility. However, the alignment mechanism during meniscus-guided solution coating remains unclear. Furthermore, interfacial alignment has been rarely studied despite its direct relevance and critical importance to charge transport. In this study, we uncover a significantly higher degree of alignment at the top interface of solution coated thin films, using a donor-acceptor conjugated polymer, poly(diketopyrrolopyrrole-co-thiophene-co-thieno[3,2-b]thiophene-co-thiophene) (DPP2T-TT), as the model system. At the molecular level, we observe in-plane π-π stacking anisotropy of up to 4.8 near the top interface with the polymer backbone aligned parallel to the coating direction. The bulk of the film is only weakly aligned with the backbone oriented transverse to coating. At the mesoscale, we observe a well-defined fibril-like morphology at the top interface with the fibril long axis pointing toward the coating direction. Significantly smaller fibrils with poor orientational order are found on the bottom interface, weakly aligned orthogonal to the fibrils on the top interface. The high degree of alignment at the top interface leads to a charge transport anisotropy of up to 5.4 compared to an anisotropy close to 1 on the bottom interface. We attribute the formation of distinct interfacial morphology to the skin-layer formation associated with high Peclet number, which promotes crystallization on the top interface while suppressing it in the bulk. We further infer that the interfacial fibril alignment is driven by the extensional flow on the top interface arisen from increasing solvent evaporation rate closer to the meniscus front.

Dynamic-template-directed multiscale assembly for large-area coating of highly-aligned conjugated polymer thin films.

Solution processable semiconducting polymers have been under intense investigations due to their diverse applications from printed electronics to biomedical devices. However, controlling the macromolecular assembly across length scales during solution coating remains a key challenge, largely due to the disparity in timescales of polymer assembly and high-throughput printing/coating. Herein we propose the concept of dynamic templating to expedite polymer nucleation and the ensuing assembly process, inspired by biomineralization templates capable of surface reconfiguration. Molecular dynamic simulations reveal that surface reconfigurability is key to promoting template-polymer interactions, thereby lowering polymer nucleation barrier. Employing ionic-liquid-based dynamic template during meniscus-guided coating results in highly aligned, highly crystalline donor-acceptor polymer thin films over large area (>1 cm2) and promoted charge transport along both the polymer backbone and the π-π stacking direction in field-effect transistors. We further demonstrate that the charge transport anisotropy can be reversed by tuning the degree of polymer backbone alignment.