ABSTRACT
Background: Unusual site deep vein thrombosis (DVT) was defined as venous thromboembolism (VTE) occurring outside the conventional deep veins of the lower extremity or pulmonary arteries. However, the optimal anticoagulation therapy for unusual site DVT remained unclear. This study aims to evaluate the efficacy and safety of rivaroxaban in unusual site DVT. Methods: This retrospective cohort study enrolled consecutive patients at Nanjing Drum Tower Hospital between January 2011 and December 2021 who were diagnosed with unusual site DVT. Patients were divided into two groups based on their ultimate medication choice: the warfarin group and the rivaroxaban group. The demographic characteristics were recorded for all enrolled patients. Clinical outcomes included recurrent VTE, bleeding complications and major bleeding. Results: A total of 1,088 patients were divided into warfarin (n = 514) and rivaroxaban (n = 574) groups. After the stabilized inverse probability of treatment weighting, Hazard Ratios for warfarin vs. rivaroxaban of recurrent VTE, bleeding complications and major bleeding were 0.52(95% CI: 0.25-1.08), 0.30(95% CI: 0.14-0.60), and 0.33 (95% CI, 0.13-0.74), respectively. Risk of clinical outcomes in specified subgroups for age, gender, renal function, thrombosis sites and diagnosis were assessed. The interaction of gender and treatment on major bleeding was significant (P for interaction = 0.062). Otherwise, there was no significant interaction between the other subgroups and the treatment group in terms of clinical outcomes. Conclusion: Compared with warfarin, rivaroxaban exhibited comparable efficacy for the anticoagulant treatment of unusual site DVT, associated with a lower risk of bleeding complications and major bleeding.
ABSTRACT
Background: The European League of Rheumatology(EULAR)guidelines recommend Janus kinase (JAK) inhibitors for patients with moderate to severe rheumatoid arthritis (RA) who are insensitive or under-responsive to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). But there was no recommendation for which one was preferred in five currently approved JAK inhibitors. The objective of this network meta-analysis study was to evaluate the efficacy of five JAK inhibitors as monotherapy and combination therapy in patients with moderate-to-severe active rheumatoid arthritis. Methods: The randomized controlled trials (RCTs) of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy or combined with csDMARD in the treatment of active RA were searched in database of PubMed, Embase, Web of Science and Cochrane Library, up to December 2023. The control group included placebo or csDMARD. Outcome indicators included American College of Rheumatology 20% response (ACR20), ACR50, ACR70 and the percentage of patients achieving 28-joint disease activity score using C-reactive protein (DAS28(CRP))<2.6 at 12 weeks and 24 weeks. The statistical analysis was performed by Stata14 and RevMan5.4. Data processing, network evidence plots, surface under the cumulative ranking curve (SUCRA) ranking, league plots and funnel plots were generated. Risk ratio (RR) and 95% confidence interval (95%CI) as effect sizes to analyze the statistics. Results: This study included thirty-six RCTs with 16,713 patients. All JAK inhibitors were more effective than placebo in ACR20 (RRs ranging between 1.74 and 3.08), ACR50 (RRs ranging between 2.02 and 7.47), ACR70 (RRs ranging between 2.68 and 18.13), DAS28(CRP) < 2.6 (RRs ranging between 2.70 and 7.09) at 12 weeks. Upadacitinib 30 mg and upadacitinib 15 mg showed relatively good efficacy according to their relative SUCRA ranking. All JAK inhibitors were more effective than csDMARD or placebo in ACR20 (RRs ranging between 1.16 and 1.86), ACR50 (RRs ranging between 1.69 and 2.84), ACR70 (RRs ranging between 1.50 and 4.47), DAS28(CRP) < 2.6 (RRs ranging between 2.28 and 7.56) at 24 weeks. Upadacitinib 15 mg + csDMARD and baricitinib 4 mg + csDMARD showed relatively good efficacy according to their relative SUCRA ranking. The safety analysis results such as serious infection, malignancy, major adverse cardiovascular event (MACE), and venous thromboembolic events (VTE) showed no statistical difference. Conclusion: This NMA study indicated that all JAK inhibitors performed better than placebo. Based on the results of this study, upadacitinib 30 mg, upadacitinib 15 mg, upadacitinib 15 mg + csDMARD and baricitinib 4 mg + csDMARD were recommended treatment options with relatively good efficacy and safety. However, attention should be paid to monitoring the occurrence of adverse events in high-risk RA patients with medication. Combination therapy with csDMARD might be more suitable for the maintenance of long-term efficacy. However, in clinical practice, it is still necessary to select the appropriate therapeutic regimen based on the actual clinical situation.
ABSTRACT
Soft actuators, pivotal for converting external energy into mechanical motion, have become increasingly vital in a wide range of applications, from the subtle engineering of soft robotics to the demanding environments of aerospace exploration. Among these, electrochemically-driven actuators (EC actuators), are particularly distinguished by their operation through ion diffusion or intercalation-induced volume changes. These actuators feature notable advantages, including precise deformation control under electrical stimuli, freedom from Carnot efficiency limitations, and the ability to maintain their actuated state with minimal energy use, akin to the latching state in skeletal muscles. This review extensively examines EC actuators, emphasizing their classification based on diverse material types, driving mechanisms, actuator configurations, and potential applications. It aims to illuminate the complicated driving mechanisms of different categories, uncover their underlying connections, and reveal the interdependencies among materials, mechanisms, and performances. We conduct an in-depth analysis of both conventional and emerging EC actuator materials, casting a forward-looking lens on their trajectories and pinpointing areas ready for innovation and performance enhancement strategies. We also navigate through the challenges and opportunities within the field, including optimizing current materials, exploring new materials, and scaling up production processes. Overall, this review aims to provide a scientifically robust narrative that captures the current state of EC actuators and sets a trajectory for future innovation in this rapidly advancing field.
ABSTRACT
Objective: To systematically evaluate the efficacy and safety of a new hypoglycemic drug, tirzepatide, for treating obesity based on indicators such as BMI, waist circumference, and body weight. Methods: A search formula was written using search terms such as "tirzepatide," "overweight," and "obesity." A comprehensive search was conducted on databases such as PubMed, Cochrane Library, Embase, and Web of Science using a computer. Random controlled trial (RCT) literature was selected based on inclusion and exclusion criteria. After extracting the data, literature bias risk assessment and meta-analysis were conducted using RevMan 5.4 software. The search deadline is from the establishment of each database to May 2023. Results: A total of 12 randomized controlled trials were included, with a total of 11,758 patients. Meta analysis results showed that compared with the glucagon like peptide-1 receptor agonist (GLP-1 RAs), placebo and insulin groups, tirzepatide could significantly reduce the BMI (body mass index) of patients [MD = -1.71, 95% CI (-2.46, -0.95), p < 0.00001], [MD = -3.99, 95% CI (-3.69, -2.45), p < 0.00001], [MD = -4.02, 95% CI (-4.72, -3.31), p < 00.00001]. In terms of decreasing waist circumference, tirzepatide has a more significant advantage [MD = -4.08, 95% CI (-5.77, -2.39), p < 0.00001], [MD = -7.71, 95% CI (-10.17, -5.25), p < 0.00001], [MD = -9.15, 95% CI (-10.02, -8.29), p < 0.00001]. In the analysis of body weight, tirzepatide showed a more significant reduction effect compared to the control group [MD = -5.65, 95% CI (-7.47, -3.82), p < 0.001], [MD = -10.06, 95% CI (-12.86, -7.25), p < 0.001], [MD = -10.63, 95% CI (-12.42, -8.84), p < 0.001]. In comparison with placebo, tirzepatide had a prominent advantage in weight loss ≥20% and ≥25% [RR = 30.43, 95% CI (19.56, 47.33), p < 0.00001], [RR = 37.25, 95% CI (26.03, 53.30), p < 0.00001]. Subgroup analysis showed a dose-dependent therapeutic effect. In terms of safety, compared with the placebo and insulin groups, the incidence of gastrointestinal adverse reactions was markedly higher in the tirzepatide group, slightly higher to the GLP-1 RAs group. The hypoglycemic (<70 mg/dL) risk of tirzepatide was slightly higher to that of placebo and GLP-1 RAs, but significantly lower than that of the insulin group [RR = 0.46, 95% CI (0.36, 0.58), p < 0.001]. The incidence of other adverse events, including pancreatitis, cholecystitis, major adverse cardiovascular events-4, hypersensitivity reactions, and neoplasms did not show significant statistical differences compared to the control group (p > 0.05). Conclusion: Tirzepatide, as a weight loss drug, significantly reduces BMI, waist circumference and body weight while gastrointestinal adverse reactions need to be vigilant. Overall, its efficacy is significant and its safety is high.
Subject(s)
Gastric Inhibitory Polypeptide , Glucagon-Like Peptide-2 Receptor , Insulins , Obesity , Humans , Body Weight , Glucagon-Like Peptide 1/adverse effects , Glucagon-Like Peptide 1/therapeutic use , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Insulins/therapeutic use , Obesity/drug therapy , Randomized Controlled Trials as TopicABSTRACT
Background: Age-related macular degeneration (AMD) stands as the foremost cause of irreversible central vision impairment, marked by choroidal neovascularization (CNV). The prevailing clinical approach to AMD treatment relies on intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs. However, this method is encumbered by diverse complications, prompting exploration of non-invasive alternatives such as ocular administration via eye drops for anti-VEGF therapy. Methods: Two complexes, 5-FITC-CPP-Ranibizumab (5-FCR) and 5-FITC-CPP-Conbercept (5-FCC), were synthesized by incorporating the anti-VEGF drugs Ranibizumab (RBZ) or Conbercept (CBC) with cell-penetrating peptide (CPP). Circular dichroism spectrum (CD) facilitated complexes characterization. Eye drops was utilized to address laser-induced CNV in mice. Fluorescein fundus angiography (FFA) observe the CNV lesion, while FITC-dextran and IB4 dual fluorescent staining, along with hematoxylin-eosin (HE) staining, assessed in lesion size. Tissue immunofluorescence examined CD31 and VEGF expression in choroidal/retinal pigment epithelial (RPE) tissues. Biocompatibility and biosafety of 5-FCR and 5-FCC was evaluated through histological examination of various organs or cell experiments. Results: Both 5-FCR and 5-FCC exhibited favorable biocompatibility and safety profiles. VEGF-induced migration of Human umbilical vein endothelial cells (HUVECs) significantly decreased post-5-FCR/5-FCC treatment. Additionally, both complexes suppressed VEGF-induced tube formation in HUVECs. FFA results revealed a significant improvement in retinal exudation in mice. Histological examination unveiled the lesion areas in the 5-FCR and 5-FCC groups showed a significant reduction compared to the control group. Similar outcomes were observed in histological sections of the RPE-choroid-sclera flat mounts. Conclusion: In this study, utilizing the properties of CPP and two anti-VEGF drugs, we successfully synthesized two complexes, 5-FCR and 5-FCC, through a straightforward approach. Effectively delivering the anti-VEGF drugs to the target area in a non-invasive manner, suppressing the progression of laser-induced CNV. This offers a novel approach for the treatment of wet AMD.
Subject(s)
Cell-Penetrating Peptides , Choroidal Neovascularization , Macular Degeneration , Humans , Animals , Mice , Fluorescein-5-isothiocyanate , Ranibizumab , Vascular Endothelial Growth Factor A , Choroidal Neovascularization/drug therapy , Human Umbilical Vein Endothelial Cells , Ophthalmic SolutionsABSTRACT
Pathological neovascularization is a pivotal biological process in wet age-related macular degeneration (AMD), retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), in which macrophages (Mφs) play a key role. Tip cell specialization is critical in angiogenesis; however, its interconnection with the surrounding immune environment remains unclear. Succinate is an intermediate in the tricarboxylic acid (TCA) cycle and was significantly elevated in patients with wet AMD by metabolomics. Advanced experiments revealed that SUCNR1 expression in Mφ and M2 polarization was detected in abnormal vessels of choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) models. Succinate-induced M2 polarization via SUCNR1, which facilitated vascular endothelial cell (EC) migration, invasion, and tubulation, thus promoting angiogenesis in pathological neovascularization. Furthermore, evidence indicated that succinate triggered the release of RBP4 from Mφs into the surroundings to regulate endothelial sprouting and pathological angiogenesis via VEGFR2, a marker of tip cell formation. In conclusion, our results suggest that succinate represents a novel class of vasculature-inducing factors that modulate Mφ polarization and the RBP4/VEGFR2 pathway to induce pathological angiogenic signaling through tip cell specialization.
Subject(s)
Choroidal Neovascularization , Retinopathy of Prematurity , Infant, Newborn , Humans , Animals , Succinic Acid/metabolism , Eye/metabolism , Choroidal Neovascularization/metabolism , Retinopathy of Prematurity/metabolism , Macrophages/metabolism , Disease Models, Animal , Retinol-Binding Proteins, Plasma/metabolismABSTRACT
Purpose: To investigate changes in corneal densitometry (CD) and visual quality following small incision lenticule extraction (SMILE) and laser epithelial keratomileusis (LASEK) in patients with mild-to-moderate myopia. Methods: A retrospective analysis was performed on 24 and 25 patients (46 eyes each) who underwent SMILE and LASEK, respectively, for mild-to-moderate myopia. The visual quality and CD values were recorded. Using the Pentacam Scheimpflug system, CD values were collected in three concentric optical zones at the depths of the anterior, central, and posterior layers. Efficacy, safety, predictability, corneal wavefront aberrations, and QoV scores were measured to evaluate visual quality. A correlation analysis was performed between changes in CD and clinical characteristics. Results: There were no statistical differences in efficacy and safety indices between the two groups. At 3 months postoperatively, a pronounced reduction in several zones was observed in the LASEK group (p < 0.05), whereas no obvious change was observed in the SMILE group. There were obvious changes in the CD values in several zones in the SMILE and LASEK groups (p < 0.05) after 1 year. The magnitude of the CD changes in the anterior and central corneal layers was smaller in the SMILE group than in the LASEK group (all p < 0.05). Lower HOAs, spherical aberration, and horizontal comas of the anterior and whole corneal surfaces were observed in the SMILE group. QoV scores were similar between the two groups. Conclusion: CD decreased in the SMILE and LASEK groups after 1 year; there was a smaller reduction in SMILE than in LASEK. SMILE and LASEK did not differ significantly in terms of safety and effectiveness in correcting mild-to-moderate myopia.
Subject(s)
Corneal Wavefront Aberration , Keratectomy, Subepithelial, Laser-Assisted , Keratomileusis, Laser In Situ , Myopia , Surgical Wound , Humans , Corneal Stroma/surgery , Retrospective Studies , Visual Acuity , Lasers, Excimer/therapeutic use , Prospective Studies , Myopia/surgery , Corneal Wavefront Aberration/surgery , Densitometry , Refraction, OcularABSTRACT
Dry eye disease (DED) is the most common disease affecting vision and quality of life. PM2.5 was a potential risk of DED. Herein, we conducted animal exposure and cell-based studies to evaluate the pathogenic effect of PM2.5 exposure on the ocular surface and DED etiological mechanisms. C57 mice were exposed to filtered air and PM2.5 aerosol. We assessed health conditions and inflammation of the ocular surface by corneal fluorescein staining and immunohistochemistry. In parallel, cultured human corneal epithelial cells (HCETs) were treated with PM2.5, followed by characterization of cell viability, intracellular ATP level, mitochondrial activities, and expression level of DED relevant mRNA and proteins. In mice, PM2.5 exposure induced severe superficial punctate keratopathy and inflammation in their cornea. In HCETs, cell proliferation and ROS generation followed dose-response and time-dependent manner; meanwhile, mitochondrial ROS (mtROS) level increased and mitochondrial membrane potential (MMP) level decreased. Inflammation cascade was triggered even after short-term exposure. The reduction of ATP production was alleviated with Nrf2 overexpression, NF-κB P65 knockdown, or ROS clearance. Nrf2 overexpression and P65 knockdown reduced inflammatory reaction through decreasing expression of P65 and increasing of Nrf2, respectively. They partly alleviated changes of ROS/mtROS/MMP. This research proved that PM2.5 would cause DED-related inflammation reaction on corneal epithelial cells and further explored its mechanism: ROS from mitochondrial dysfunctions of corneal epithelial cells after PM2.5 exposure partly inhibited the expression of anti-inflammatory protein Nrf2 led the activation of inflammatory protein P65 and its downstream molecules, which finally caused inflammation reaction.
Subject(s)
Dry Eye Syndromes , Particulate Matter , Humans , Animals , Mice , Particulate Matter/toxicity , Particulate Matter/metabolism , Reactive Oxygen Species , NF-E2-Related Factor 2 , Quality of Life , Dry Eye Syndromes/chemically induced , Dry Eye Syndromes/metabolism , Dry Eye Syndromes/pathology , Inflammation , Mitochondria/metabolism , Adenosine TriphosphateABSTRACT
One of the central issues in cognition is identifying universal and culturally specific patterns of thought. In this study, we examined how one aspect of culture, a linguistic part of speech known asclassifiers, are related to categorization of solid objects. In Experiment 1, we used a numeral classifier elicitation task to examine the classifiers used by speakers of Hmong, Japanese, and Mandarin Chinese (N = 34) with 135 nouns that referred to solid objects. In Experiment 2, adult speakers of English, Japanese, Mandarin Chinese, and Hmong (N = 64) rated the similarity of 39 pictured objects that depicted a subset of the nouns. All groups classified the objects into natural kinds and artifacts, with the category of humans anchoring both divisions. The main difference that emerged from the study was that speakers of Japanese and English rated humans and animals as more similar to each other than Hmong speakers; Mandarin speakers' ratings of the similarity between humans and animals fell in between those of Hmong and English speakers. However, the pattern of categorization of humans and animals found among speakers of the classifier languages contradicted their patterns of classifier use. The findings help to tease apart the effects of language from other cultural factors that impact cognition.
Subject(s)
Cross-Cultural Comparison , Language , Adult , Humans , Cognition , SpeechABSTRACT
Correlations in gene expression are used to infer functional and regulatory relationships between genes. However, correlations are often calculated across different cell types or perturbations, causing genes with unrelated functions to be correlated. Here, we demonstrate that correlated modules can be better captured by measuring correlations of steady-state gene expression fluctuations in single cells. We report a high-precision single-cell RNA-seq method called MALBAC-DT to measure the correlation between any pair of genes in a homogenous cell population. Using this method, we were able to identify numerous cell-type specific and functionally enriched correlated gene modules. We confirmed through knockdown that a module enriched for p53 signaling predicted p53 regulatory targets more accurately than a consensus of ChIP-seq studies and that steady-state correlations were predictive of transcriptome-wide response patterns to perturbations. This approach provides a powerful way to advance our functional understanding of the genome.
Subject(s)
Gene Regulatory Networks , Tumor Suppressor Protein p53 , Tumor Suppressor Protein p53/genetics , Gene Expression Profiling , Transcriptome , Signal Transduction , Single-Cell Analysis/methodsABSTRACT
Proliferative vitreoretinopathy (PVR) is an intractable condition after rhegmatogenous retinal detachment (RD), which is the primary cause of failure in retinal reattachment surgery. This study aimed to investigate the effects of chicken ovalbumin upstream promoter transcriptional factor 1 (COUP-TF1) in the development of proliferative vitreoretinopathy (PVR) both in vitro and in vivo. Adult retinal pigment epithelium cell line was used for in-vitro experiments. Immunocytochemistry assay, real-time quantitative polymerase chain reaction, and Western blot were used to measure the expression of COUP-TF1, alpha-smooth muscle actin (α-SMA), and E-cadherin. Epithelial-mesenchymal transition (EMT) was observed through cell counting kit-8 assay, wound healing tests, and the expression changes of related proteins. PVR rabbit models were established and evaluated by the images of fundus and vitreous cavity, pathological sections, and COUP-TF1 expression. As shown by our results, the proliferation and migration of the COUP-TF1 knockdown cells were reduced compared with the control cells with or without transforming growth factor-ß1 (TGF-ß1) treatment. After TGF-ß1 treatment, α-SMA expression was upregulated in ARPE-19 cells but kept the same in COUP-TF1 knockdown cells. E-cadherin expression was down-regulated in all the groups but the extent of the decrease in COUP-TF1 knockdown cells was smaller. EMT was attenuated in ARPE-19 cells after COUP-TF1 was knocked down. In the in-vivo experiment, PVR severity was attenuated and the retinal detachment rate decreased on the 14th and 28th day in COUP-TF1 knockdown group. In conclusion, COUP-TF1 is related to the development of PVR, and COUP-TF1 knockdown attenuates the progression of PVR. This suggests that COUP-TF1 can be a promising candidate for the treatment of PVR.
Subject(s)
Retinal Detachment , Vitreoretinopathy, Proliferative , Animals , Rabbits , Vitreoretinopathy, Proliferative/genetics , Vitreoretinopathy, Proliferative/metabolism , Vitreoretinopathy, Proliferative/pathology , Epithelial-Mesenchymal Transition/genetics , Transforming Growth Factor beta1/metabolism , Chickens/metabolism , Ovalbumin/metabolism , Ovalbumin/pharmacology , Retinal Detachment/metabolism , Retinal Detachment/pathology , Retinal Pigment Epithelium/metabolism , Cell Movement/genetics , Cells, Cultured , Cadherins/genetics , Cadherins/metabolismABSTRACT
Background: Nasopharynx carcinoma (NPC) is the most common malignant tumor of the nasopharynx. Many studies have shown some factors related with the prognosis of NPC patients. Our study aims to evaluate the differences of prognosis between initial and second primary NPC. Material and methods: The Surveillance, Epidemiology, and End Results (SEER) program was used to perform the population-based analysis in NPC patients who were newly diagnosed between 2004 and 2015. Kaplan-Meier and Cox regressions were used to evaluate the effects of primary site on the overall survival (OS), as well as the cancer-specific survival (CSS). Results: Our study included 5,012 NPC patients: 4,474 initial primary NPC patients and 5,38 s primary NPC patients. Significant differences were observed in sex, age at diagnosis, race, median household income, histological type, American Joint Committee on Cancer (AJCC) stage, N-stage, radiation treatment and chemotherapy between patients with initial and second NPC (P < 0.05). Moreover, the patients with second NPC had longer survival months. In addition, radiation and chemotherapy were recommended both in first and second primary NPC patients. Conclusion: Worse prognosis was observed in patients with second primary NPC compared with those with primary NPC in all subgroups of AJCC stage and age at diagnosis.
ABSTRACT
Aim: Chronic inflammation is crucial for age-related macular degeneration (AMD) pathogenesis. However, the mechanism involved in activating inflammation remains unclear. This study is aimed at investigating whether nuclear factor erythrocyte-associated factor 2 (Nrf2) negatively regulated the Nod-like receptor protein 3 (NLRP3) inflammasomes through the thioredoxin 1 (Trx1)/thioredoxin interaction protein (TXNIP) complex. Methods: We determined the optimal hydrogen peroxide (H2O2) concentration, time, and changes in reactive oxygen species (ROS) levels. We also constructed animal models using blue LED irradiation. Then, the expression of Nrf2, TXNIP, Trx1, NLRP3, and inflammation-related factors and proteins, along with the changes in retinal thickness and functional status, was analyzed. Results: The oxidative stress model was established after 1 h intervention with 100 µM H2O2. Nrf2 reduced ROS production, protected the ultrastructure of mitochondria, increased the thickness of the ONL layer, and increased the amplitude of a- and b-wave amplitudes in ERG. Trx1 knockdown increased the production of ROS, damaged the ultrastructure of mitochondria, reduced the thickness of the other ONL layer, and reduced the amplitudes of a- and b-waves in the electroretinogram (ERG). Thus, TXNIP in the cytoplasm activated the inflammasomes. Conclusions: Nrf2 showed antioxidant and anti-inflammatory activity in the H2O2-induced cell stress model and blue LED-induced retinal light damage model. TXNIP transferred from the nucleus to the cytoplasm, activated NLRP3, and aggravated the retinal injury in both the cell stress model and the animal blue LED model. In contrast, Trx1 knockout promoted this process. This study revealed the possible role of the thioredoxin system in developing AMD while also providing newer insights for the future treatment of AMD.
Subject(s)
Carrier Proteins , Macular Degeneration , NF-E2-Related Factor 2 , Thioredoxins , Animals , Humans , Mice , Carrier Proteins/genetics , Carrier Proteins/metabolism , Disease Models, Animal , Down-Regulation , Hydrogen Peroxide , Inflammasomes , Inflammation , Macular Degeneration/genetics , Macular Degeneration/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein , Oxidative Stress , Reactive Oxygen Species , Retinal Diseases/genetics , Retinal Diseases/metabolism , Thioredoxins/genetics , Thioredoxins/metabolismABSTRACT
Senescent cells have been demonstrated to have lower cellular NAD+ levels and are involved in the development of various age-related diseases, including age-related macular degeneration (AMD). Sodium iodate (NaIO3) has been primarily used as an oxidant to establish a model of dry AMD. Results of previous studies have showed that NaIO3 induced retinal tissue senescence in vivo. However, the role of NaIO3 and the mechanism by which it induces retinal pigment epithelium (RPE) senescence remains unknown. In this study, RPE cell senescence was confirmed to be potentially induced by NaIO3. The results showed that the number of senescence-associated-ß-galactosidase (SA-ß-gal-)-positive cells and the protein levels of p16 and p21 increased after NaIO3 treatment. Additionally, the senescent RPE cells underwent oxidative stress and NAD+ depletion. Furthermore, significant DNA damage and mitochondrial dysfunction were also detected in senescent RPE cells. The antioxidant N-acetylcysteine (NAC) could alleviate cellular senescence only by a minimal degree, whereas supplementation with nicotinamide mononucleotide (NMN) strongly ameliorated RPE senescence through the alleviation of DNA damage and the maintenance of mitochondrial function. The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling. Moreover, both the expression of senescence markers of RPE and subretinal inflammatory cell infiltration were decreased by NMN treatment in vivo. Our results indicate that RPE senescence induced by NaIO3 acquired several key features of AMD. More importantly, NMN may potentially be used to treat RPE senescence and senescence-associated pre-AMD changes by restoring the NAD+ levels in cells and tissues.
Subject(s)
Macular Degeneration , Retinal Pigment Epithelium , Cellular Senescence , Humans , Inflammation/metabolism , Iodates , Macular Degeneration/metabolism , NAD/metabolism , Nicotinamide Mononucleotide/metabolism , Nicotinamide Mononucleotide/pharmacology , Oxidative Stress , Retinal Pigment Epithelium/metabolismABSTRACT
The crucial effect of vascular endothelial growth factor (VEGF)-induced vascular angiogenesis has been well known in corneal neovascularization (CNV). This research aimed to determine the underlying value and mechanism of Meg3 on CNV in vivo and in vitro. In an alkali-burned mouse model, length and area of new vessels were increased along with thinning of corneal epithelium, accompanied by the overexpression of Meg3. Notably, subconjunctival injection of shMeg3 suppressed the degree of injury in cornea, causing expression of the angiogenesis markers--VEGF-A and CD31 decreased. In VEGF-induced human umbilical vein endothelial cells (HUVECs), knockdown of Meg3 antagonized the enhancement of viability, proliferation, wound healing ability and angiogenesis by VEGF. The proteins expression of VEGF-A, CD31, SDF-1/CXCR4 as well as phosphoraylation-Smad2/3 pathways, which were related to angiogenesis, were reduced with Meg3 deficiency. Overall, knockdown of Meg3 alleviated formation of neovascularization in alkali-burned corneas and reduced VEGF-induced angiogenesis by inhibiting SDF-1/CXCR4 and Smad2/3 signaling in vitro.
Subject(s)
Corneal Neovascularization , RNA, Long Noncoding , Alkalies/adverse effects , Animals , Corneal Injuries , Corneal Neovascularization/metabolism , Eye Burns , Human Umbilical Vein Endothelial Cells , Humans , Mice , Neovascularization, Pathologic , Neovascularization, Physiologic , RNA, Long Noncoding/genetics , Receptors, CXCR4 , Smad2 Protein/metabolism , Smad3 Protein , Vascular Endothelial Growth Factors/adverse effectsABSTRACT
Bacterial endophthalmitis (BE) is an acute eye infection and potentially irreversible blinding ocular disease. The empirical intravitreous injection of antibiotic is the primary treatment once diagnosed as BE. However, the overuse of antibiotic contributes to the drug resistance of pathogens and the retinal toxicity of antibiotic limits its application in clinic. Herein, a cationic aggregation-induced emission luminogens named with triphenylamine thiophen pyridinium (TTPy) is reported for photodynamic treatment of BE. TTPy can selectively discriminate and kill bacteria efficiently over normal ocular cells. More importantly, TTPy shows excellent antibacterial ability in BE rat models infected by Staphylococcus aureus. Meanwhile, the bacterial killing behavior triggered by TTPy induces innate immune response at an early stage of infection, limiting subsequent robust inflammation and protecting retina from bacterial toxins and inflammation-induced bystander damage. In addition, TTPy performs better antibacterial ability than commercially used Rose Bengal, suggesting its excellent capability of vision salvage in acute BE. This study exhibits an efficient photodynamic antibacterial treatment to BE, which induces an early intraocular immune response and saves useful vision, endowing TTPy a promising potential for clinical application of ocular infections.
Subject(s)
Endophthalmitis , Eye Infections, Bacterial , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Endophthalmitis/drug therapy , Endophthalmitis/microbiology , Eye Infections, Bacterial/drug therapy , Eye Infections, Bacterial/microbiology , Immunity , Inflammation , RatsABSTRACT
Stretching a coiled carbon nanotube (CNT) yarn can provide large, reversible electrochemical capacitance changes, which convert mechanical energy to electricity. Here, it is shown that the performance of these "twistron" harvesters can be increased by optimizing the alignment of precursor CNT forests, plastically stretching the precursor twisted yarn, applying much higher tensile loads during precoiling twist than for coiling, using electrothermal pulse annealing under tension, and incorporating reduced graphene oxide nanoplates. The peak output power for a 1 and a 30 Hz sinusoidal deformation are 0.73 and 3.19 kW kg-1 , respectively, which are 24- and 13-fold that of previous twistron harvesters at these respective frequencies. This performance at 30 Hz is over 12-fold that of other prior-art mechanical energy harvesters for frequencies between 0.1 and 600 Hz. The maximum energy conversion efficiency is 7.2-fold that for previous twistrons. Twistron anode and cathode yarn arrays are stretched 180° out-of-phase by locating them in the negative and positive compressibility directions of hinged wine-rack frames, thereby doubling the output voltage and reducing the input mechanical energy.
ABSTRACT
Aim: We aimed to establish and validate a simple and sensitive UPLC-MS/MS method for the determination of UNC1999, a dual inhibitor against EZH1 and EZH2 in plasma samples. Materials & methods: UNC1999 in rat plasma was processed with protein precipitation method and then separated on a C18 column and detected under positive ionization mode. The method presented good linearity over the range of 1.0-2000 ng/ml with good accuracy and precision. UNC1999 was absorbed slowly and achieved a maximum concentration of 118.8 ± 12.0 ng/ml 1.5 h after oral administration. Conclusion: The method provides a favorable character in selectivity, linearity, accuracy, precision, recovery, matrix effects and stabilities and was suitable for describing the pharmacokinetic profile of UNC1999.
Subject(s)
Benzamides/therapeutic use , Chromatography, High Pressure Liquid/methods , Indazoles/therapeutic use , Piperazines/therapeutic use , Pyridones/therapeutic use , Tandem Mass Spectrometry/methods , Animals , Benzamides/pharmacology , Indazoles/pharmacology , Male , Piperazines/pharmacology , Pyridones/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Bacterial keratitis (BK) is an acute infection of the cornea, accompanied by uneven epithelium boundaries with stromal ulceration, potentially resulting in vision loss. Topical antibiotic is the regular treatment for BK. However, the incidence rate of multidrug-resistant bacteria limits the application of traditional antibiotics. Therefore, a cationic aggregation-induced emission luminogens (AIEgens) named TTVP is utilized for the treatment of BK. TTVP showed no obvious cytotoxicity in maintaining the normal cell morphology and viability under a limited concentration, and revealed the ability to selectively combine with bacteria in normal ocular environment. After light irradiation, TTVP produced reactive oxygen species (ROS), thus exerting efficient antibacterial ability in vitro. What's more, in rat models of Staphylococcus aureus (S. aureus) infection, the therapeutic intervention of TTVP lessens the degree of corneal opacity and inflammatory infiltration, limiting the spread of inflammation. Besides, TTVP manifested superior antibacterial efficacy than levofloxacin in acute BK, endowing its better vision salvage ability than conventional method. This research demonstrates the efficacy and advantages of TTVP as a photodynamic drug in the treatment of BK and represents its promise in clinical application of ocular infections.
ABSTRACT
Age-related macular degeneration (AMD) is a multifactor disease, which is primarily characterized by retinal pigment epithelium (RPE) cell loss. Since the retina is the most metabolically active tissue, RPE cells are exposed to consistent oxidative environment. So, oxidation-induced RPE cell death has long been considered a contributor to the onset of AMD. Here, we applied a retinal degeneration (RD) rat model induced by blue light-emitting diode (LED) and a cell model constructed by H2O2 stimulus to mimic the prooxidant environment of the retina. We detected that the expression of miR-27a was upregulated and the expression of FOXO1 was downregulated in both models. So, we furtherly investigated the role of miR-27a-FOXO1 axis in RPE in protesting against oxidants. Lentivirus-mediated RNA was injected intravitreally into rats to modulate the miR-27a-FOXO1 axis. Retinal function and histopathological changes were evaluated by electroretinography (ERG) analysis and hematoxylin and eosin (H&E) staining, respectively. Massive photoreceptor and RPE cell death were examined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The damage to the retina was aggravated in the FOXO1 gene-knockdown and miR-27a-overexpression groups after exposure to LED but was alleviated in the FOXO1 gene-overexpression or miR-27a-knockdown groups. Dual luciferase assay was used to detect the binding site of miR-27a and FOXO1. Upregulated miR-27a inhibited the expression of FOXO1 by directly binding to the FOXO1 mRNA 3'UTR and decreased the autophagy activity of ARPE-19 cells, resulting in the accumulation of reactive oxygen species (ROS) and decrease of cell viability. The results suggest that miR-27a is a negative regulator of FOXO1. Also, our data emphasize the prominent role of miR-27a/FOXO1 axis in modulating ROS accumulation and cell death in RPE cell model under oxidative stress and influencing the retinal function in the LED-induced RD rat model.