In the last few decades, RNA-based drugs have emerged as a promising candidate to specifically target and modulate disease-relevant genes to cure genetic defects. The key to applying RNA therapy in ...clinical trials is developing safe and effective delivery systems. Exosomes have been exploited as a promising vehicle for drug delivery due to their nanoscale size, high stability, high biocompatibility, and low immunogenicity. We reviewed and summarized the progress in the strategy and application of exosome-mediated RNA therapy. The challenges of exosomes as a carrier for RNA drug delivery are also elucidated in this article. RNA molecules can be loaded into exosomes and then delivered to targeted cells or tissues via various biochemical or physical approaches. So far, exosome-mediated RNA therapy has shown potential in the treatment of cancer, central nervous system disorders, COVID-19, and other diseases. To further exploit the potential of exosomes for RNA delivery, more efforts should be made to overcome both technological and logistic problems.
Introduction Vascular endothelial growth factor (VEGF) is key to wet age-related macular degeneration (wAMD). Anti-VEGF drugs are the main treatment in clinics. This study assessed ocular adverse ...events (AE) from anti-VEGF drugs in VigiAccess, WHO’s database, and compared adverse drug reaction (ADR) profiles of four drugs to aid personalized treatment choices for optimal benefit and safety. Methods The design was a descriptive retrospective study. We observed four anti-VEGF drugs commonly used in the clinical treatment of wAMD, and their ADR reports came from WHO-VigiAccess. The collected data included the age group, gender, and regional data, as well as the data of disease systems and symptoms caused by ADR recorded in the annual ADR reports and reports received by the WHO. We observed the overall characteristics of the ADR reports of these drugs, then explored the distribution of 27 SOCs of these drugs. Subsequently, we compared the most common ocular ADRs of the drugs. Finally, we compared the commonalities and differences of ocular ADRs related to the drugs. Results Overall, 57,779 AE associated with the four anti-VEGF drugs were reported. The results showed that the number of females experiencing ADRs (67.83%) was significantly higher than males (32.17%), the age group with the highest reported incidence was over 75 years old. More than half of the ADR reports came from the Americas (50.86%). The five most common types of AE were: eye disorders (43.56%), general disorders and administration site conditions (34.47%), injury poisoning and procedural complications (13.36%), infections and infestations (11.61%), nervous system disorders (9.99%). Compared with the other three inhibitors, brolucizumab had a significantly higher rate of ocular ADR reports. The most common ocular ADRs of these four anti-VEGF drugs were mostly related to visual impairment, vision blurred, and blindness. However, there is still a disparity of ADRs between different drugs. Conclusion The presence of ocular AEs when using anti-VEGF drugs to treat wAMD in clinical practice should attract clinical attention. Clinicians should use these expensive drugs more rationally based on the characteristics of ADRs and develop personalized treatment plans for patients.
For ultrathin semiconductor channels, the surface and interface nature are vital and often dominate the bulk properties to govern the field-effect behaviors. High-performance thin-film transistors ...(TFTs) rely on the well-defined interface between the channel and gate dielectric, featuring negligible charge trap states and high-speed carrier transport with minimum carrier scattering characters. The passivation process on the back-channel surface of the bottom-gate TFTs is indispensable for suppressing the surface states and blocking the interactions between the semiconductor channel and the surrounding atmosphere. We report a dielectric layer for passivation of the back-channel surface of 20 nm thick tin monoxide (SnO) TFTs to achieve ambipolar operation and complementary metal oxide semiconductor (CMOS) like logic devices. This chemical passivation reduces the subgap states of the ultrathin channel, which offers an opportunity to facilitate the Fermi level shifting upward upon changing the polarity of the gate voltage. With the advent of n-type inversion along with the pristine p-type conduction, it is now possible to realize ambipolar operation using only one channel layer. The CMOS-like logic inverters based on ambipolar SnO TFTs were also demonstrated. Large inverter voltage gains (>100) in combination with wide noise margins are achieved due to high and balanced electron and hole mobilities. The passivation also improves the long-term stability of the devices. The ability to simultaneously achieve field-effect inversion, electrical stability, and logic function in those devices can open up possibilities for the conventional back-channel surface passivation in the CMOS-like electronics.
Early stage detection of biofilm formation is an important aspect of microbial research because once formed, biofilms show serious tolerance to antibiotics in contrast to the free-floating bacteria, ...which significantly increases the difficulty for clinical treatment of bacterial infections. The early stage detection technology is desired to improve the efficiency of medical treatments. In this work, we present a biosensor consisting of a magnesium zinc oxide (MZO) dual gate thin-film transistor (DGTFT) as the actuator and an MZO nanostructure (MZOnano) array coated conducting pad as the extended sensing gate for the early stage detection of Staphylococcus epidermidis (S. epidermidis) biofilm formation. S. epidermidis bacteria were cultured in vitro on the nanostructure modified sensing pad. Charge transfer occurs between microbial cells and the MZOnano during the initial bacterial adhesion stage. Such electrical signals, which represent the onset of biofilm formation, were dynamically detected by the DGTFT where the top gate electrode was connected to the extended MZOnano sensing pad and the bottom gate was used for biasing the device into the optimum characteristic region for high sensitivity and stable operation. The testing results show that a current change of ~80% is achieved after ~200 min of bacterial culturing. A crystal violet staining-based assay shows that tiny bacterial microcolonies just start to form at 200 min, and that it would take approximately 24 h to form matured biofilms. This technology enables medical professionals to act promptly on bacterial infection before biofilms get fully established.
•The biosensor is used for the early stage detection of bacterial biofilm formation.•An MZO nanostructured film is deposited as a modification layer on the sensing pad.•The device's sensitivity is improved by using MZOnano comparing with ZnOnano.•Dual gate structure of TFT is implemented to optimize the operation conditions.•The sensing gate is separated from the dual gate TFT to ensure stable operation.
Malignant glioma is the most common type of primary brain tumor in adults, characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. Alterations in the activity of the ...26S proteasome have been associated with malignant glioma cells, although the specific defects have not been identified. Recently, microRNA-326 (miR-326) was shown to play an important role in glioblastoma and breast cancer, but the underlying molecular mechanisms remain unclear. In the present study, the human Nin one binding protein (NOB1) was identified as a direct target of miR-326 and a potential oncogene in human glioma. Similar to NOB1 silencing by shRNA, overexpression of miR-326 in human glioma cell lines (A172 and U373) caused cell cycle arrest at the G1 phase, delayed cell proliferation and enhanced apoptosis. MiR-326 inhibited colony formation in soft agar and decreased growth of a xenograft tumor model, suggesting that miR-326 and NOB1 are required for tumorigenesis in vitro and in vivo. Furthermore, these processes were shown to involve the MAPK pathway. NOB1 overexpression in human glioma samples was detected by Affymetrix array analysis, and NOB1 mRNA and protein levels were shown to be increased in high-grade glioma compared to low-grade glioma and normal brain tissue. Furthermore, high levels of NOB1 were associated with unfavorable prognosis of glioma patients. Taken together, these results indicate that miR-326 and NOB1 may play an important role in the development of glioma.
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•Single-cell RNA sequence analysis revealed the heterogeneity of fibroblast of hearts in diabetic mouse for the first time.•The number of cluster 4 fibroblasts were higher and we ...reveal the up-regulation of Lox in diabetic mouse group.•We validate that the up-regulation of Lox is associated with the decreased cardiac function, increased interstitial fibrosis, higher expression of HYP and the amounts of collagen in the DM group.•Upregulation of Lox might be involved in the development of diabetic myocardial fibrosis and cardiac dysfunction via activation of TGF-β1-Smad2/3 signaling pathway.•Inhibition of Lox could improve cardiac function and fibrosis, which may indicate a potential target for the treatment of diabetic cardiomyopathy.
Myocardial fibrosis and cardiac dysfunction are the main characteristics of diabetic heart disease. However, the molecular mechanisms underlying diabetic myocardial fibrosis remain unclear.
This study aimed to investigate the heterogeneity of cardiac fibroblasts in diabetic mice and its possible mechanism in the development of diabetic myocardial fibrosis.
We established a diabetic mouse model by injecting mice with streptozotocin. The overall cell profiles in diabetic hearts were analyzed using single-cell RNA transcriptomic techniques. Cardiac function was evaluated by echocardiography. Cardiac fibrosis was assessed by Masson’s trichrome and Sirius red staining. Protein expression was analyzed using Western blotting and immunofluorescence staining.
A total of 11,585 cells were captured in control (Ctrl) and diabetic (DM) hearts. Twelve cell types were identified in this study. The number of fibroblasts was significantly higher in the DM hearts than in the Ctrl group. The fibroblasts were further re-clustered into nine subsets. Interestingly, cluster 4 fibroblasts were significantly increased in diabetic hearts compared with other fibroblast clusters. Lysyl oxidase (Lox) was highly expressed in DM fibroblasts (especially in cluster 4). Beta-aminopropionitrile, a Lox inhibitor, inhibited collagen expression and alleviated cardiac dysfunction in the diabetic group. Lysyl oxidase inhibition also reduced high glucose-induced collagen protein upregulation in primary fibroblasts. Moreover, a TGF-β receptor inhibitor not only prevented an increase in Lox and Col I but also inhibited the phosphorylation of Smad2/3 in fibroblasts.
This study revealed the heterogeneity of cardiac fibroblasts in diabetic mice for the first time. Fibroblasts with high expression of Lox (cluster 4 fibroblasts) were identified to play a crucial role in fibrosis in diabetic heart disease. The findings of this study may provide a possible therapeutic target for interstitial fibrosis.
Abstract MicroRNAs control a wide array of biological processes including cell differentiation, proliferation, and apoptosis whose dysregulation is a hallmark of cancer. MicroRNA-21 (miR-21) is ...overexpressed in many cancers including glioblastoma and contributes to tumor resistance to chemotherapy. We investigated whether miR-21 mediated chemoresistance to the chemotherapeutic agent VM-26 in glioblastoma cells and sought to identify the candidate target genes for miR-21 by gene expression profiling. Here we report that miR-21 was involved in mediating chemoresistance to VM-26 in glioblastoma cells. Suppression of miR-21 by specific antisense oligonucleotides in glioblastoma cell U373 MG led to enhanced cytotoxicities of VM-26 against U373 MG cells. We further identified and validated LRRFIP1, whose product is an inhibitor of NF-κB signaling, as a direct target gene of miR-21. Our findings suggest that miR-21 represents a promising target for therapeutic manipulation to increase the efficacy of chemotherapeutic agents in treating glioblastoma, a highly lethal type of cancer.
Background and purpose
The efficacy of temozolomide (TMZ) in recurrent glioblastoma multiforme (GBM) has been evaluated by several clinical trials. A meta‐analysis to assess the overall efficacy of ...TMZ in the treatment of recurrent GBM was carried out by the authors.
Methods
Medline, EMBASE database and the Cochrane Library were searched for relevant studies. Eligible studies were clinical trials of recurrent GBMs assigned to TMZ with data on efficacy including tumor response, progression‐free survival (PFS) or overall survival (OS) available. The overall efficacy was calculated using a random‐effects or fixed‐effects model, depending on the heterogeneity of the included trials.
Results
A total of 15 phase II clinical trials including 902 recurrent GBMs were analyzed. The overall clinical benefit rate was 50.5% (95% CI: 44.3–56.7%) with significant difference between metronomic and standard schedules of TMZ (61.4% vs. 46.3%, P = 0.037). The overall 6‐month PFS (PFS‐6) rate was found to be 27.8% (95% CI: 22.7–33.5%) with significant difference between metronomic and standard schedules (33.1% vs. 20.1%, P < 0.001). In addition, significant difference in PFS‐6 was detected between high (average daily dose >100 mg/m2) and low (average daily dose ≤100 mg/m2) dose metronomic schedules (RR = 1.57, 95% CI: 1.17–2.09, P = 0.002). The overall 6‐month OS (OS‐6) and 12‐month OS (OS‐12) rates were 65.0% (95% CI: 57.4–71.9%) and 36.4% (95% CI: 26.9–47.1%) separately. There was no significant difference in OS‐6 between metronomic and standard schedules (P = 0.266); however, a trend was noted favoring the metronomic schedule for OS‐12 (P = 0.089).
Conclusions
Temozolomide is effective for recurrent GBMs, and its efficacy may be increased with metronomic schedule and high average daily dose (>100 mg/m2).
Background/Aims: Cyclin D1 (CCND1) is frequently overexpressed in malignant gliomas. We have previously shown ectopic overexpression of CCND1 in human malignant gliomas cell lines. Methods: ...Quantitative reverse transcriptase PCR (qRT-PCR) and Western Blot (WB) was performed to investigate the expression of CCND1 in glioma tissues and cell lines. The biological function of CCND1 was also investigated through knockdown and overexpression of BCYRN1 in vitro. Results: Here we reported that CCND1 expression was positively associated with the pathological grade and proliferative activity of astrocytomas, as the lowest expression was found in normal brain tissue (N = 3) whereas the highest expression was in high-grade glioma tissue (N = 25). Additionally, we found that the expression level of CCND1 was associated with IC50 values in malignant glioma cell lines. Forced inhibition of CCND1 increased temozolomide efficacy in U251 and SHG-44 cells. After CCND1 overexpression, the temozolomide efficacy decreased in U251 and SHG-44 cells. Colony survival assay and apoptosis analysis confirmed that CCND1 inhibition renders cells more sensitive to temozolomide treatment and temozolomide-induced apoptosis in U251 and SHG-44 cells. Inhibition of P-gp (MDR1) by Tariquidar overcomes the effects of CCND1 overexpression on inhibiting temozolomide-induced apoptosis. Inhibition of CCND1 inhibited cell growth in vitro and in vivo significantly more effectively after temozolomide treatments than single temozolomide treatments. Finally, inhibition of CCND1 in glioma cells reduced tumor volume in a murine model. Conclusion: Taken together, these data indicate that CCND1 overexpression upregulate P-gp and induces chemoresistance in human malignant gliomas cells and that inhibition of CCND1 may be an effective means of overcoming CCND1 associated chemoresistance in human malignant glioma cells.
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