Upregulated miR-374a-5p drives psoriasis pathogenesis through WIF1 downregulation and Wnt5a/NF-κB activation.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease. MicroRNAs (miRNAs) are an abundant class of non-coding RNA molecules. Recent studies have shown that multiple miRNAs are abnormally expressed in patients with psoriasis. The upregulation of miR-374a-5p has been associated with psoriasis severity. However, the specific role of miR-374a-5p in the pathogenesis of psoriasis remain unclear. METHODS: qRT-PCR was employed to validate the expression of miR-374a-5p in psoriatic lesions and in a psoriasis-like cell model constructed using a mixture of M5 (IL-17A, IL-22, OSM, IL-1α, and TNF-α). HaCaT cells were transfected with miR-374a-5p mimic/inhibitor, and assays including EdU, CCK-8, and flow cytometry were conducted to evaluate the effect of miR-374a-5p on cell proliferation. The expression of inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α was verified by qRT-PCR. Bioinformatics analysis and dual-luciferase reporter gene assay were performed to detect the downstream target genes and upstream transcription factors of miR-374a-5p, followed by validation of their expression through qRT-PCR and Western blotting. A psoriasis-like mouse model was established using imiquimod cream topical application. The psoriasis area and severity index scoring, hematoxylin-eosin histology staining, and Ki67 immunohistochemistry were employed to validate the effect of miR-374a-5p on the psoriatic inflammation phenotype after intradermal injection of miR-374a-5p agomir/NC. Additionally, the expression of pathway-related molecules and inflammatory factors such as IL-1ß, IL-17a, and TNF-α was verified by immunohistochemistry. RESULTS: Upregulation of miR-374a-5p was observed in psoriatic lesions and the psoriasis-like cell model. In vitro experiments demonstrated that miR-374a-5p not only promoted the proliferation of HaCaT cells but also upregulated the expression of inflammatory cytokines, including IL-1ß, IL-6, IL-8, and TNF-α. Furthermore, miR-374a-5p promoted skin inflammation and epidermal thickening in the Imiquimod-induced psoriasis-like mouse model. Mechanistic studies revealed that miR-374a-5p led to downregulation of WIF1, thereby activating the Wnt5a/NF-κB signaling pathway. The transcription factor p65 encoded by RELA, as a subunit of NF-κB, further upregulated the expression of miR-374a-5p upon activation. This positive feedback loop promoted keratinocyte proliferation and abnormal inflammation, thereby facilitating the development of psoriasis. CONCLUSION: Our findings elucidate the role of miR-374a-5p upregulation in the pathogenesis of psoriasis through inhibition of WIF1 and activation of the Wnt5a/NF-κB pathway, providing new potential therapeutic targets for psoriasis.

Prostate cancer-associated transcript 6 (PCAT6) promotes epithelial-mesenchymal transition and stemness and worsens prognosis in patients with colorectal cancer.

Approximately 20% of colorectal cancer (CRC) patients are first diagnosed with metastatic colorectal cancer (mCRC) because they develop symptoms at an advanced stage. Despite advancements in treatment, patients with metastatic disease still experience inferior survival rates. Our objective is to investigate the association between long noncoding RNAs (lncRNAs) and prognosis and to explore their role in mCRC. In this study, we find that elevated expression of PCAT6 is independently linked to unfavourable survival outcomes in The Cancer Genome Atlas (TCGA) data, and this finding is further confirmed in CRC samples obtained from Fudan University Shanghai Cancer Center. Cell lines and xenograft mouse models are used to examine the impact of PCAT6 on tumor metastasis. Knockdown of PCAT6 is observed to impede the metastatic phenotype of CRC, as evidenced by functional assays, demonstrating the suppression of epithelial-mesenchymal transition (EMT) and stemness. Our findings show the significance of PCAT6 in mCRC and its potential use as a prognostic biomarker.

Schwann cell-derived extracellular vesicles promote memory impairment associated with chronic neuropathic pain.

BACKGROUND: The pathogenesis of memory impairment, a common complication of chronic neuropathic pain (CNP), has not been fully elucidated. Schwann cell (SC)-derived extracellular vesicles (EVs) contribute to remote organ injury. Here, we showed that SC-EVs may mediate pathological communication between SCs and hippocampal neurons in the context of CNP. METHODS: We used an adeno-associated virus harboring the SC-specific promoter Mpz and expressing the CD63-GFP gene to track SC-EVs transport. microRNA (miRNA) expression profiles of EVs and gain-of-function and loss-of-function regulatory experiments revealed that miR-142-5p was the main cargo of SC-EVs. Next, luciferase reporter gene and phenotyping experiments confirmed the direct targets of miR-142-5p. RESULTS: The contents and granule sizes of plasma EVs were significantly greater in rats with chronic sciatic nerve constriction injury (CCI)than in sham rats. Administration of the EV biogenesis inhibitor GW4869 ameliorated memory impairment in CCI rats and reversed CCI-associated dendritic spine damage. Notably, during CCI stress, SC-EVs could be transferred into the brain through the circulation and accumulate in the hippocampal CA1-CA3 regions. miR-142-5p was the main cargo wrapped in SC-EVs and mediated the development of CCI-associated memory impairment. Furthermore, α-actinin-4 (ACTN4), ELAV-like protein 4 (ELAVL4) and ubiquitin-specific peptidase 9 X-linked (USP9X) were demonstrated to be important downstream target genes for miR-142-5p-mediated regulation of dendritic spine damage in hippocampal neurons from CCI rats. CONCLUSION: Together, these findings suggest that SCs-EVs and/or their cargo miR-142-5p may be potential therapeutic targets for memory impairment associated with CNP.

Predictive value of angiopoietin-like protein 8 in metabolic dysfunction-associated fatty liver disease and its progression: A case-control study.

BACKGROUND: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is rapidly increasing, currently affecting approximately 25% of the global population. Liver fibrosis represents a crucial stage in the development of MAFLD, with advanced liver fibrosis elevating the risks of cirrhosis and hepatocellular carcinoma. Simple serum markers are less effective in diagnosing liver fibrosis compared to more complex markers. However, imaging techniques like transient elastography face limitations in clinical application due to equipment and technical constraints. Consequently, it is imperative to identify a straightforward yet effective method for assessing MAFLD-associated liver fibrosis. AIM: To investigate the predictive value of angiopoietin-like protein 8 (ANGPTL8) in MAFLD and its progression. METHODS: We analyzed 160 patients who underwent abdominal ultrasonography in the Endocrinology Department, Xiaogan Central Hospital affiliated to Wuhan University of Science and Technology, during September 2021-July 2022. Using abdominal ultrasonography and MAFLD diagnostic criteria, among the 160 patients, 80 patients (50%) were diagnosed with MAFLD. The MAFLD group was divided into the liver fibrosis group (n = 23) and non-liver fibrosis group (n = 57) by using a cut-off fibrosis-4 index ≥ 1.45. Logistical regression was used to analyze the risk of MAFLD and the risk factors for its progression. Receiver operating characteristic curves were used to evaluate the predictive value of serum ANGPTL8 in MAFLD and its progression. RESULTS: Compared with non-MAFLD patients, MAFLD patients had higher serum ANGPTL8 and triglyceride-glucose (TyG) index (both P < 0.05). Serum ANGPTL8 (r = 0.576, P < 0.001) and TyG index (r = 0.473, P < 0.001) were positively correlated with MAFLD. Serum ANGPTL8 was a risk factor for MAFLD [odds ratio (OR): 1.123, 95% confidence interval (CI): 1.066-1.184, P < 0.001). Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD [area under the curve (AUC): 0.832 and 0.886, respectively; both P < 0.05]. Compared with MAFLD patients without fibrosis, those with fibrosis had higher serum ANGPTL8 and TyG index (both P < 0.05), and both parameters were positively correlated with MAFLD-associated fibrosis. Elevated serum ANGPTL8 (OR: 1.093, 95%CI: 1.044-1.144, P < 0.001) and TyG index (OR: 2.383, 95%CI: 1.199-4.736, P < 0.013) were risk factors for MAFLD-associated fibrosis. Serum ANGPTL8 and ANGPTL8 + TyG index predicted MAFLD-associated fibrosis (AUC: 0.812 and 0.835, respectively; both P < 0.05). CONCLUSION: The serum levels of ANGPTL8 are elevated and positively correlated with MAFLD. They can serve as predictors for the risk of MAFLD and liver fibrosis, with the ANGPTL8 + TyG index potentially exhibiting even higher predictive value.

Design, Synthesis, Biological Evaluation and Molecular Docking of Novel F-18-Labeled Focal Adhesion Kinase Inhibitors as Potential Tumor Radiotracers.

Tumor diagnosis, especially at the early stages, holds immense significance. Focal adhesion kinase (FAK) is often highly expressed across various types of tumors, making it a promising target for both therapy and diagnosis. In this study, seven novel inhibitors were designed and synthesized. The inhibitory activity of these compounds against FAK was notably potent, with an IC50 range of 1.27-1968 nM. In particular, compounds 7a and 7c, with IC50 values of 5.59 nM and 1.27 nM, respectively, were radiolabeled with F-18 and then evaluated with S-180 tumor-bearing mice. Subsequently, they exhibited moderate-to-high tumor uptake values, with [18F]7a showing 1.39 ± 0.30%ID/g at 60 min post injection and [18F]7c demonstrating 6.58 ± 0.46%ID/g at 30 min post injection. In addition, the results from docking studies revealed the binding specifics of the studied compounds. Overall, these findings hold the potential to offer valuable guidance for enhancing the development of radiotracers and enzyme inhibitors.

A method for predicting drugs that can boost the efficacy of immune checkpoint blockade.

Combination therapy is a promising therapeutic strategy to enhance the efficacy of immune checkpoint blockade (ICB); however, predicting drugs for effective combination is challenging. Here we developed a general data-driven method called CM-Drug for screening compounds that can boost ICB treatment efficacy based on core and minor gene sets identified between responsive and nonresponsive samples in ICB therapy. The CM-Drug method was validated using melanoma and lung cancer mouse models, with combined therapeutic efficacy demonstrated in eight of nine predicted compounds. Among these compounds, taltirelin had the strongest synergistic effect. Mechanistic analysis and experimental verification demonstrated that taltirelin can stimulate CD8+ T cells and is mediated by the induction of thyroid-stimulating hormone. This study provides an effective and general method for predicting and evaluating drugs for combination therapy and identifies candidate compounds for future ICB combination therapy.

Sex-specific associations between sodium and potassium intake and overall and cause-specific mortality: a large prospective U.S. cohort study, systematic review, and updated meta-analysis of cohort studies.

BACKGROUND: The impact of sodium intake on cardiovascular disease (CVD) health and mortality has been studied for decades, including the well-established association with blood pressure. However, non-linear patterns, dose-response associations, and sex differences in the relationship between sodium and potassium intakes and overall and cause-specific mortality remain to be elucidated and a comprehensive examination is lacking. Our study objective was to determine whether intake of sodium and potassium and the sodium-potassium ratio are associated with overall and cause-specific mortality in men and women. METHODS: We conducted a prospective analysis of 237,036 men and 179,068 women in the National Institutes of Health-AARP Diet and Health Study. Multivariable-adjusted Cox proportional hazard regression models were utilized to calculate hazard ratios. A systematic review and meta-analysis of cohort studies was also conducted. RESULTS: During 6,009,748 person-years of follow-up, there were 77,614 deaths, 49,297 among men and 28,317 among women. Adjusting for other risk factors, we found a significant positive association between higher sodium intake (≥ 2,000 mg/d) and increased overall and CVD mortality (overall mortality, fifth versus lowest quintile, men and women HRs = 1.06 and 1.10, Pnonlinearity < 0.0001; CVD mortality, fifth versus lowest quintile, HRs = 1.07 and 1.21, Pnonlinearity = 0.0002 and 0.01). Higher potassium intake and a lower sodium-potassium ratio were associated with a reduced mortality, with women showing stronger associations (overall mortality, fifth versus lowest quintile, HRs for potassium = 0.96 and 0.82, and HRs for the sodium-potassium ratio = 1.09 and 1.23, for men and women, respectively; Pnonlinearity < 0.05 and both P for interaction ≤ 0.0006). The overall mortality associations with intake of sodium, potassium and the sodium-potassium ratio were generally similar across population risk factor subgroups with the exception that the inverse potassium-mortality association was stronger in men with lower body mass index or fruit consumption (Pinteraction < 0.0004). The updated meta-analysis of cohort studies based on 42 risk estimates, 2,085,904 participants, and 80,085 CVD events yielded very similar results (highest versus lowest sodium categories, pooled relative risk for CVD events = 1.13, 95% CI: 1.06-1.20; Pnonlinearity < 0.001). CONCLUSIONS: Our study demonstrates significant positive associations between daily sodium intake (within the range of sodium intake between 2,000 and 7,500 mg/d), the sodium-potassium ratio, and risk of CVD and overall mortality, with women having stronger sodium-potassium ratio-mortality associations than men, and with the meta-analysis providing compelling support for the CVD associations. These data may suggest decreasing sodium intake and increasing potassium intake as means to improve health and longevity, and our data pointing to a sex difference in the potassium-mortality and sodium-potassium ratio-mortality relationships provide additional evidence relevant to current dietary guidelines for the general adult population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Identifier: CRD42022331618.

Analysis of the association between testosterone and cardiovascular disease potential risk factor apolipoprotein B in adult males without cancer: national health and nutrition examination survey 2011-2016.

Background: Over the years, there has been extensive exploration of the association between testosterone and lipid profiles, yet the precise mechanisms underlying their interaction remain incompletely elucidated. Similarly, there is a dearth of research on the correlation between serum apolipoprotein B (apoB) and serum total testosterone (TT), particularly within specific populations. Methods: We conducted a cross-sectional study to assess the relationship between serum TT concentration and serum apoB concentration. Using the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016, we employed weighted generalized linear models, weighted univariate, weighted multivariate analysis, and smooth curve fitting to assist in exploring the relationship between serum TT and apoB. Serum apoB concentration served as the independent variable, and serum TT concentration as the dependent variable. ApoB was divided into four quartiles-Q1 (<0.7g/L, N=691), Q2 (≥0.7g/L to <0.9g/L, N=710), Q3 (≥0.9g/L to <1.1g/L, N=696), and Q4 (≥1.1g/L, N=708)-thereby further solidifying the stable association between the two. Additionally, the application of smooth curve fitting will contribute to a more detailed elucidation of the specific relationship between serum TT concentration and serum apoB concentration under different factors (Drinking, Smoke, Diabetes, Hypertension, and High cholesterol level.). Results: The results indicate a negative correlation between serum TT concentration and apoB concentration (ß=-113.4; 95% CI: -146.6, -80.2; P<0.001). After adjusting for confounding variables, the negative correlation between apoB concentration and TT concentration remains significant (ß=-61.0; 95% CI: -116.7, -5.2; P=0.040). When apoB concentration was converted from a continuous variable to a categorical variable (quartiles: Q1<0.7g/L; Q2:≥0.7g/L to<0.9g/L; Q3:≥0.9g/L to <1.1g/L; Q4: ≥1.1g/L), TT level of participants in the highest quartile (≥1.1g/L) was -47.2 pg/mL (95% CI: -91.2, -3.3; P=0.045) lower than that in the lowest quartile (<0.7g/L). The smooth curve fitting diagram revealed differences in the relationship between TT concentration and apoB among individuals with different cardiovascular disease (CVD) risk factors. Conclusions: This study elucidates a robust inverse correlation between serum TT concentration and apoB concentration, maintaining statistical significance even upon adjustment for confounding factors. These findings present a promising avenue for addressing the prevention and treatment of low testosterone and CVD.

[Determination of organic acids and anions in exhaled breath by condensation collection-ion chromatography].

A non-invasive condensation collection-ion chromatography method was established for the determination of organic acids and anions including lactic acid, formic acid, acetic acid, pyruvic acid, chloride, nitrate, nitrite, and sulfate in the exhaled breath of humans. The breath exhaled was condensed and collected using a home-made exhaled breath condensation equipment. This equipment included a disposable mouthpiece as a blow-off port, one-way valve and flow meter, cold trap, disposable condensate collection tube placed in the cold trap, and gas outlet. A standard sampling procedure was used. Before collection, the collection temperature and sampling volume were set on the instrument control panel, and sampling was started when the cold-trap temperature dropped to the set value, while maintaining the balance. Subjects were required to gargle with pure water before sampling. During the sampling process, the subjects were required to inhale deeply until the lungs were full of gas and then exhale evenly through the air outlet. When the set volume was collected, the instrument made a prompt sound; then, the collection was immediately ended, the expiration time was recorded, and the average collection flow was calculated according to the expiration time and sampling volume. After collection, the disposable condensation collection tube was immediately taken out, sealed, and stored in the refrigerator at -20 ℃ away from light, and immediately used for further testing. The organic acids and anions in exhaled breath condensation (EBC) were filtered through a 0.22 µm membrane filter before injection and detected by ion chromatography with conductivity detection. Factors such as collection temperature and collection flow rate during condensation collection were optimized. The optimal cooling temperature was set at -15 ℃, and the optimal exhaled breath flow rate was set at 15 L/min. The mobile phase consisted of a mixture of sodium carbonate (1.5 mmol/L) and sodium bicarbonate (3 mmol/L). The flow rate was 0.8 mL/min, and the injection volume was 100 µL. An IC-SA3 column (250 mm×4.0 mm) was used, and the temperature was set at 45 ℃. An ICDS-40A electrodialysis suppressor was used, and the current was set at 150 mA. The linear ranges of the eight organic acids and anions were 0.1-10.0 mg/L; their correlation coefficients (r) were ≥0.9993. The limits of detection (LODs) for the eight organic acids and anions were 0.0017-0.0150 mg/L based on a signal-to-noise ratio of 3, and the limits of quantification (LOQs) were 0.0057-0.0500 mg/L based on a signal-to-noise ratio of 10. The intra-day precisions were 5.06%-6.33% (n=5), and the inter-day precisions were 5.37%-7.50% (n=5). This method was used to detect organic acids and anions in the exhaled breath of five healthy subjects. The contents of organic acids and anions in the exhaled breath were calculated. The content of lactic acid was relatively high, at 1.13-42.3 ng/L, and the contents of other seven organic acids and anions were 0.18-11.0 ng/L. During a 10 km-long run, the majority of organic acids and anions in the exhaled breath of five subjects first increased and then decreased. However, due to abnormal metabolism, the content changes of lactic acid, acetic acid, pyruvic acid and chloride in one subject were obviously different from others during exercise, showing a continuous rise. This method has the advantages of involving a simple sampling process and exhibiting good precision, few side effects, and no obvious discomfort or risk to the subjects. This study provides experimental ideas and a theoretical basis for future research on human metabolites.

Vitamin E biofortification: enhancement of seed tocopherol concentrations by altered chlorophyll metabolism.

Homogentisate Phytyltransferase (HPT) catalyzes condensation of homogentisate (HGA) and phytyl diphosphate (PDP) to produce tocopherols, but can also synthesize tocotrienols using geranylgeranyl diphosphate (GGDP) in plants engineered for deregulated HGA synthesis. In contrast to prior tocotrienol biofortification efforts, engineering enhanced tocopherol concentrations in green oilseeds has proven more challenging due to the integral role of chlorophyll metabolism in supplying the PDP substrate. This study show that RNAi suppression of CHLSYN coupled with HPT overexpression increases tocopherol concentrations by >two-fold in Arabidopsis seeds. We obtained additional increases in seed tocopherol concentrations by engineering increased HGA production via overexpression of bacterial TyrA that encodes chorismate mutase/prephenate dehydrogenase activities. In overexpression lines, seed tocopherol concentrations increased nearly three-fold, and resulted in modest tocotrienol accumulation. We further increased total tocochromanol concentrations by enhancing production of HGA and GGDP by overexpression of the gene for hydroxyphenylpyruvate dioxygenase (HPPD). This shifted metabolism towards increased amounts of tocotrienols relative to tocopherols, which was reflected in corresponding increases in ratios of GGDP/PDP in these seeds. Overall, our results provide a theoretical basis for genetic improvement of total tocopherol concentrations in green oilseeds (e.g., rapeseed, soybean) through strategies that include seed-suppression of CHLSYN coupled with increased HGA production.

Convex optimization-based high-speed and security joint optimization scheme in optical access networks.

Data rate and security are essential performance metrics for passive optical networks (PON). However, existing optical access networks lack standardized metrics to evaluate rate and security performance uniformly. This paper introduces a high-speed and security joint optimization scheme for optical access networks using convex optimization. Evaluation metrics for data rate and security performance in PON are established. According to the evaluation metrics, the security optimization objective function Us, high-speed optimization objective function GMI, and high-speed security joint-optimization objective function Hs are established. An optimization problem is formulated to maximize weighted rate and security indicators, factoring in constraints such as maximum power, probability, amplifier capacity, normalized mutual information, and key and frame lengths. An alternating optimization method is applied to iteratively address sub-problems by exploiting successive convex approximations and differences of convex functions. This transforms non-convex sub-problems into convex optimizations. Experimental results highlight notable improvements in objective function values, confirming the effectiveness of the proposed high-speed security optimization algorithm for optical access networks.

Clinical Efficacy and Mechanism of Vitamin D2 in Treating Hashimoto's Thyroiditis.

Objective: Hashimoto's thyroiditis (HT) is one of the most common autoimmune diseases, with the highest incidence rate among autoimmune thyroid disorders. Vitamin D2 may have therapeutic effects on HT. This study aimed to elucidate the molecular mechanisms underlying vitamin D2 therapy for HT. Methods: Differentially expressed genes (DEGs) associated with vitamin D2-treated HT were identified, and the DEG-associated gene enrichment pathway was explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The correlation between the hub genes and infiltrating immune cells was investigated, and the interactions among the hub genes and target drug and competing endogenous RNA (ceRNA; long non-coding RNA [lncRNA]-microRNA [miRNA]-messenger RNA [mRNA]) regulatory networks were determined. Results: GO and KEGG enrichment analyses identified a total of 102 DEGs (6 upregulated and 96 downregulated) in the vitamin D2-treated group samples. The area under the curve values of the identified 10 hub genes was as follows: CCR1(0.920), CXCL1 (0.960), CXCL8 (0.960), EGR1 (0.960), FCGR3B (0.920), FOS (1.000), FPR1 (0.840), MMP9 (0.720), PTGS2 (0.960), and TREM1 (1.000). The immune enrichment scores of the mast cell (P = 0.008), neutrophil (P = 0.016), and plasmacytoid dendritic cell (P = 0.016) were significantly decreased in the vitamin D2-treated group (P < 0.05). The hub gene/drug regulatory network included 8 hub genes, 108 molecular drugs, and 114 interaction relationship pairs. The ceRNA regulatory network included 129 lncRNAs, 145 miRNAs, mRNAs (hub genes), and 324 interaction relationship pairs. Conclusion: Vitamin D2 may play an immunomodulatory role by regulating the aforementioned immune-related molecules and immune cells, thereby improving its therapeutic effects on HT.

Dysfunctional Mitochondria Clearance in Situ: Mitophagy in Obesity and Diabetes-Associated Cardiometabolic Diseases.

Several mitochondrial dysfunctions in obesity and diabetes include impaired mitochondrial membrane potential, excessive mitochondrial reactive oxygen species generation, reduced mitochondrial DNA, increased mitochondrial Ca2+ flux, and mitochondrial dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria in physiological and pathological conditions. As a paradox, inhibition and activation of mitophagy have been observed in obesity and diabetes-related heart disorders, with both exerting bidirectional effects. Suppressed mitophagy is beneficial to mitochondrial homeostasis, also known as benign mitophagy. On the contrary, in most cases, excessive mitophagy is harmful to dysfunctional mitochondria elimination and thus is defined as detrimental mitophagy. In obesity and diabetes, two classical pathways appear to regulate mitophagy, including PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent mitophagy and receptors/adapters-dependent mitophagy. After the pharmacologic interventions of mitophagy, mitochondrial morphology and function have been restored, and cell viability has been further improved. Herein, we summarize the mitochondrial dysfunction and mitophagy alterations in obesity and diabetes, as well as the underlying upstream mechanisms, in order to provide novel therapeutic strategies for the obesity and diabetes-related heart disorders.

Aptamers targeting SARS-CoV-2 nucleocapsid protein exhibit potential anti pan-coronavirus activity.

Emerging and recurrent infectious diseases caused by human coronaviruses (HCoVs) continue to pose a significant threat to global public health security. In light of this ongoing threat, the development of a broad-spectrum drug to combat HCoVs is an urgently priority. Herein, we report a series of anti-pan-coronavirus ssDNA aptamers screened using Systematic Evolution of Ligands by Exponential Enrichment (SELEX). These aptamers have nanomolar affinity with the nucleocapsid protein (NP) of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and also show excellent binding efficiency to the N proteins of both SARS, MERS, HCoV-OC43 and -NL63 with affinity KD values of 1.31 to 135.36 nM. Such aptamer-based therapeutics exhibited potent antiviral activity against both the authentic SARS-CoV-2 prototype strain and the Omicron variant (BA.5) with EC50 values at 2.00 nM and 41.08 nM, respectively. The protein docking analysis also evidenced that these aptamers exhibit strong affinities for N proteins of pan-coronavirus and other HCoVs (-229E and -HKU1). In conclusion, we have identified six aptamers with a high pan-coronavirus antiviral activity, which could potentially serve as an effective strategy for preventing infections by unknown coronaviruses and addressing the ongoing global health threat.

A Novel Quercetin Encapsulated Glucose Modified Liposome and Its Brain-Target Antioxidative Neuroprotection Effects.

Neurodegenerative diseases (NDDs) are mainly induced by oxidative stress which produces excessive reactive oxygen species (ROS). Quercetin (QU) is a potent antioxidant with some effects on NDDs. This study prepared and characterized a novel glucose-modified QU liposome (QU-Glu-Lip), aiming not only to overcome QU's poor water solubility and bioavailability but also to deliver more QU to brain tissue to enhance its neuroprotective effect. QU-Glu-Lip possessed encapsulation efficiency (EE) of 89.9%, homogenous particle sizes (116-124 nm), small PDI value (<0.3), zeta value -1.363 ± 0.437 mV, proper pH and salt stability, and proper cytotoxicity. The glucose-modified liposome penetrated the blood-brain barrier (BBB) mediated via the glucose transporter 1 (GLUT1) and was taken by neuronal cells more efficiently than liposome without glucose, according to bEnd.3 and PC12 cell tests. QU-Glu-Lip attenuated H2O2-induced oxidative damage to PC12 with higher cell viability (88.42%) and lower intracellular ROS compared to that of QU. QU-Glu-Lip had higher brain target ability and delivered more QU to neuronal cells, effectively exerting the antioxidative neuroprotection effect. There is potential for the QU-Glu-Lip application for more effective treatment of NDDs.

Comprehensive Analysis of Phenolic Constituents, Biological Activities, and Derived Aroma Differences of Penthorum chinense Pursh Leaves after Processing into Green and Black Tea.

Penthorum chinense Pursh (Penthoraceae) is a traditional herb used in Miao medical systems that is also processed into foods (e.g., tea products) in China. Different processing methods significantly affect the volatile compounds, phenolic constituents, and biological activities. This study aimed to produce P. chinense green tea leaves (GTL), black tea leaves (BTL), and untreated leaves (UL) to investigate differences in their flavor substances, functional components, antioxidant activity, alcohol dehydrogenase (ADH) activity, and acetaldehyde dehydrogenase (ALDH) activity. The results showed that 63, 56, and 56 volatile compounds were detected in UL, GTL, and BTL, respectively, of which 43 volatile compounds were identified as differential metabolites among them. The total phenolic content (97.13-179.34 mg GAE/g DW), flavonoid content (40.07-71.93 mg RE/g DW), and proanthocyanidin content (54.13-65.91 mg CE/g DW) exhibited similar trends, decreasing in the order of UL > BTL > GTL. Fourteen phenolic compounds were determined, of which gallic acid, (-)-epicatechin, and pinocembrin 7-O-glucoside showed a sharp decrease in content from UL to BTL, while the content of pinocembrin 7-O-(3″-O-galloy-4″, 6″-hexahydroxydiphenoyl)-glucoside and pinocembrin significantly increased. GTL showed better DPPH/ABTS·+ scavenging ability and ferric-reducing ability than UL. The ADH and ALDH activities decreased in the order of GTL > UL > BTL. Therefore, tea products made with P. chinense leaves contained an abundance of functional compounds and showed satisfactory antioxidant and hepatoprotective activities, which are recommended for daily consumption.

Creation of Wood-Based Hierarchical Superstructures via In Situ Growth of ZIF-8 for Enhancing Mechanical Strength and Electromagnetic Shielding Performance.

Given the escalating prevalence of electromagnetic pollution, there is an urgent need for the development of high-performance electromagnetic interference (EMI) shielding materials. Herein, wood-based electromagnetic shielding materials have gained significant popularity due to their exceptional performance as building materials. In this study, a novel wood-based composite with electromagnetic shielding properties is developed. Through the in situ growth of zeolitic imidazolate framework-8 (ZIF-8) crystals on wood fibers, coupled with uniform integration of carbon nanotubes (CNTs), a multifunctional composite named ZIF-8/Poplar-CNT composite is synthesized via a one-step thermoforming process. The incorporation of CNTs endows the composites with excellent EMI shielding effectiveness (EMI SE). Among these elements, despite ZIF-8 crystals not possessing intrinsic electromagnetic shielding functionality, their distinctive dodecahedral structure proves adept at scattering and reflecting electromagnetic waves within the composites, further improving the electromagnetic shielding effect. Hence, the ZIF-8/Poplar-CNT composite (56.95 dB) has ≈10 dB higher EMI SE compared to that of the composites without ZIF-8 crystals. Meanwhile, ZIF-8 crystals endow the materials with excellent tensile strength (54.84 MPa, enhanced by 4 times). Moreover, the introduction of Zn2+ provides superior antibacterial properties. The potential applications of ZIF-8/Poplar-CNT composites extend to diverse areas such as building decoration, electronic products, and medical equipment.

Machine-learning-based optical spectrum feature analysis for DoS attack detection in IP over optical networks.

In this paper, we introduce a novel approach for detecting Denial of Service (DoS) attacks in software-defined IP over optical networks, leveraging machine learning to analyze optical spectrum features. This method employs machine learning to automatically process optical spectrum data, which is indicative of network security status, thereby identifying potential DoS attacks. To validate its effectiveness, we conducted both numerical simulations and experimental trials to collect relevant optical spectrum datasets. We then assessed the performance of three machine learning algorithms XGBoost, LightGBM, and the BP neural network in detecting DoS attacks. Our findings show that all three algorithms demonstrate a detection accuracy exceeding 97%, with the BP neural network achieving the highest accuracy rates of 99.55% and 99.74% in simulations and experiments, respectively. This research not only offers a new avenue for DoS attack detection but also enhances early detection capabilities in the underlying optical network through optical spectrum data analysis.