Dopamine and its precursor levodopa inactivate SARS-CoV-2 main protease by forming a quinoprotein.

Many studies show either the absence, or very low levels of, SARS-CoV-2 viral RNA and/or antigen in the brain of COVID-19 patients. Reports consistently indicate an abortive infection phenomenon in nervous cells despite the fact that they contain the SARS-CoV-2 receptor, ACE2. Dopamine levels in different brain regions are in the range of micromolar to millimolar concentrations. We have shown that sub-micromolar to low micromolar concentrations of dopamine or its precursor (levodopa) time- and dose-dependently inhibit the activity of SARS-CoV-2 main protease (Mpro), which is vital for the viral life cycle, by forming a quinoprotein. Thiol detection coupled with the assessment of Mpro activity suggests that among the 12 cysteinyl thiols, the active site, Cys145-SH, is preferentially conjugated to the quinone derived from the oxidation of dopamine or levodopa. LC-MS/MS analyses show that the Cys145-SH is covalently conjugated by dopamine- or levodopa-o-quinone. These findings help explain why SARS-CoV-2 causes inefficient replication in many nerve cell lines. It is well recognized that inhaled pulmonary drug delivery is the most robust therapy pathway for lung diseases. CVT-301 (orally inhaled levodopa) was approved by the FDA as a drug for Parkinson's patients prior to the outbreak of COVID-19 in 2018. Based on the fact that SARS-CoV-2 causes inefficient replication in the CNS with abundant endogenous Mpro inhibitor in addition to the current finding that levodopa has an Mpro-inhibitory effect somewhat stronger than dopamine, we should urgently investigate the use of CVT-301 as a lung-targeting, COVID-19, Mpro inhibitor.

Effect of Dexmedetomidine on Intraoperative Hemodynamics and Blood Loss in Patients Undergoing Spine Surgery: A Systematic Review and Meta-Analysis.

Objective Dexmedetomidine (Dex) is a highly selective α2 adrenoceptor agonist that reduces blood pressure and heart rate. However, its ability to provide stable hemodynamics and a clinically significant reduction in blood loss in spine surgery is still a matter of debate. This study aimed to investigate the effects of Dex on intraoperative hemodynamics and blood loss in patients undergoing spine surgery.Methods The Web of Science, MEDLINE, EMBASE, and the Cochrane Library were searched up to February 2023 for randomized controlled trials (RCTs) including patients undergoing spine surgeries under general anaesthesia and comparing Dex and saline. A fixed- or random-effect model was used depending on heterogeneity.Results Twenty-one RCTs, including 1388 patients, were identified. Dex added the overall risk of intraoperative hypotension (odds ratio [OR]: 2.11; 95% confidence interval [CI]: 1.24 - 3.58; P=0.006) and bradycardia (OR: 2.48; 95%CI: 1.57 - 3.93; P=0.0001). The use of a loading dose of Dex led to significantly increased risks of intraoperative hypotension (OR: 2.00; 95%CI: 1.06 - 3.79; P=0.03) and bradycardia (OR: 2.28; 95%CI: 1.42 - 3.66; P=0.0007). For patients receiving total intravenous anesthesia, there was an increased risk of hypotension (OR: 2.90; 95%CI: 1.24 - 6.82; P=0.01) and bradycardia (OR: 2.66; 95%CI: 1.53 - 4.61; P=0. 0005). For patients in the inhalation anesthesia group, only an increased risk of bradycardia (OR: 4.95; 95%CI: 1.41 - 17.37; P=0.01) was observed. No significant increase in the risk of hypotension and bradycardia was found in the combined intravenous-inhalation anesthesia group. The incidence of severe hypotension (OR: 2.57; 95%CI: 1.05 - 6.32; P=0.04), but not mild hypotension, was increased. Both mild (OR: 2.55; 95%CI: 1.06 - 6.15; P=0.04) and severe (OR: 2.45; 95%CI: 1.43 - 4.20; P=0.001) bradycardia were associated with a higher risk. The overall analyses did not reveal significant reduction in intraoperative blood loss. However, a significant decrease in blood loss was observed in total inhalation anesthesia subgroup (mean difference [MD]: -82.97; 95%CI: -109.04 - -56.90; P<0.001).Conclusions Dex increases the risks of intraoperative hypotension and bradycardia in major spine surgery. The administration of a loading dose of Dex and the utilization of various anesthesia maintenance methods may potentially impact hemodynamic stability and intraoperative blood loss.

Effects of different extraction methods on the structural and biological properties of Hericium coralloides polysaccharides.

In current study, polysaccharides from Hericium coralloides were extracted by heat reflux, acid-assisted, alkali-assisted, enzyme-assisted, ultrasonic-assisted, cold water, pressurized hot water, hydrogen peroxide/ascorbic acid system and acid-chlorite delignification methods, which were named as HRE-P, ACE-P, AAE-P, EAE-P, UAE-P, CWE-P, PHE-P, HAE-P, and ACD-P, respectively. Their physicochemical properties, structural characteristics, and antioxidant activities were investigated and compared. Experimental outcomes indicated notable variations in the extraction yields, chemical compositions, monosaccharide constituents and molecular weights of the obtained nine polysaccharides. HRE-P demonstrated the highest activity against ABTS and OH radicals, CWE-P against ABTS, DPPH, and superoxide radicals, and UAE-P against DPPH radicals. In addition, UAE-P, CWE-P, and HAE-P exhibited better protective effects on L929 cells, when compared to the other obtained polysaccharides. Additionally, correlation analysis indicated that monosaccharide composition and total polyphenol content were two prominent variables influencing the bioactivity of H. coralloides polysaccharides.

EGCG oxidation-derived polymers induce apoptosis in digestive tract cancer cells via regulating the renin-angiotensin system.

Green tea polyphenol (-)-Epigallocatechin-3-gallate (EGCG) has been well studied for its biological activities in the prevention of chronic diseases. However, the biological activities of EGCG oxidation-derived polymers remain unclear. Previously, we found that these polymers accumulated in intraperitoneal tissues after intraperitoneal injection and gained an advantage over native EGCG in increasing insulin sensitivity via regulating the renin-angiotensin system (RAS) in type 2 diabetic mice. The present study determined the pro-apoptosis activities and anticancer mechanisms of the EGCG oxidation-derived polymer preparation (the >10 kDa EGCG polymers) in digestive tract cancer cells. Upon incubation of the >10 kDa EGCG polymers with CaCo2 colon cancer cells, these polymers coated the cell surface and regulated multiple components of the RAS in favor of cancer inhibition, including the downregulation of angiotensin-converting enzyme (ACE), angiotensin-II (AngII) and AngII receptor type 1 (AT1R) in the pro-tumor axis, as well as the upregulation of angiotensin-converting enzyme 2 (ACE2) and angiotensin1-7 (Ang(1-7)) in the anti-tumor axis. The treatment also markedly increased angiotensinogen (AGT), which is the precursor of the angiotensin peptides. The regulation of these RAS components occurred prior to apoptosis. Similar pro-apoptotic mechanisms of the >10 kDa EGCG polymers, were also observed in TCA8113 oral cancer cells. The >10 kDa EGCG polymers exhibited compromised activities in scavenging or initiating reactive oxygen species compared to EGCG, but gained a higher reactivity toward sulfhydryl groups, including protein cysteine thiols. We propose that the polymers bind onto the cell surface and regulate multiple RAS components by reacting with the sulfhydryl groups on the ectodomains of transmembrane proteins.

Ocular dominance in cataract surgery: research status and progress.

Ocular dominance (OD), a commonly used concept in clinical practice, plays an important role in optometry and refractive surgery. With the development of refractive cataract surgery, the refractive function of the intraocular lens determines the achievement of the postoperative full range of vision based on the retinal defocus blur suppression and binocular monovision principle. Therefore, OD plays an important role in cataract surgery. OD is related to the visual formation of the cerebral cortex, and its plasticity suggests that visual experience can influence the visual system. Cataract surgery changes the visual experience and transforms the dominant eye, which confirms the plasticity of the visual system. Based on the concept and mechanism of OD, this review summarizes the application of OD in cataract surgery.

Single-cell sequencing of head and neck carcinoma: Transcriptional landscape and prognostic model based on malignant epithelial cell features.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and the development of novel therapeutic strategies for HNSCC requires a profound understanding of tumor cells and the tumor microenvironment (TME). Additionally, HNSCC has a poor prognosis, necessitating the use of genetic markers for predicting clinical outcomes in HNSCC. In this study, we performed single-cell sequencing analysis on tumor tissues from seven HNSCC patients, along with one adjacent normal tissue. Firstly, the analysis of epithelial cell clusters revealed two clusters of malignant epithelial cells, characterized by unique gene expression patterns and dysregulated signaling pathways compared to normal epithelial cells. Secondly, the examination of the TME unveiled extensive crosstalk between fibroblasts and malignant epithelial cells, potentially mediated through ligand-receptor interactions such as COL1A1-SDC1, COL1A1-CD44, and COL1A2-SDC1. Furthermore, transcriptional heterogeneity was observed in immune cells present in the TME, including macrophages and dendritic cells. Finally, leveraging the gene expression profiles of malignant epithelial cells, we developed a prognostic model comprising six genes, which we validated using two independent datasets. These findings shed light on the heterogeneity within HNSCC tumors and the intricate interplay between malignant cells and the TME. Importantly, the developed prognostic model demonstrates high efficacy in predicting the survival outcomes of HNSCC patients.

Nucleophilic aromatization of monoterpenes from isoprene under nickel/iodine cascade catalysis.

As a large number of organic compounds possessing two isoprene units, monoterpenes and monoterpenoids play important roles in pharmaceutical, cosmetic, agricultural, and food industries. In nature, monoterpenes are constructed from geranyl pyrophosphate (C10) via various transformations. Herein, the bulk C5 chemical-isoprene, is used for the creation of various monoterpenoids via a nucleophilic aromatization of monoterpenes under cascade catalysis of nickel and iodine. Drugs and oil mixtures from conifer and lemon can be convergently transformed to the desired monoterpenoid. Preliminary mechanistic studies are conducted to get insights about reaction pathway. Two types of cyclic monoterpenes can be respectively introduced onto two similar heterocycles via orthogonal C-H functionalization. And various hybrid terpenyl indoles are programmatically assembled from abundant C5 or C10 blocks. This work not only contributes a high chemo-, regio-, and redox-selective transformation of isoprene, but also provides a complementary approach for the creation of unnatural monoterpenoids.

Deep skin diseases diagnostic system with Dual-channel Image and Extracted Text.

Background: Due to the lower reliability of laboratory tests, skin diseases are more suitable for diagnosis with AI models. There are limited AI dermatology diagnostic models combining images and text; few of these are for Asian populations, and few cover the most common types of diseases. Methods: Leveraging a dataset sourced from Asia comprising over 200,000 images and 220,000 medical records, we explored a deep learning-based system for Dual-channel images and extracted text for the diagnosis of skin diseases model DIET-AI to diagnose 31 skin diseases, which covers the majority of common skin diseases. From 1 September to 1 December 2021, we prospectively collected images from 6,043 cases and medical records from 15 hospitals in seven provinces in China. Then the performance of DIET-AI was compared with that of six doctors of different seniorities in the clinical dataset. Results: The average performance of DIET-AI in 31 diseases was not less than that of all the doctors of different seniorities. By comparing the area under the curve, sensitivity, and specificity, we demonstrate that the DIET-AI model is effective in clinical scenarios. In addition, medical records affect the performance of DIET-AI and physicians to varying degrees. Conclusion: This is the largest dermatological dataset for the Chinese demographic. For the first time, we built a Dual-channel image classification model on a non-cancer dermatitis dataset with both images and medical records and achieved comparable diagnostic performance to senior doctors about common skin diseases. It provides references for exploring the feasibility and performance evaluation of DIET-AI in clinical use afterward.

Chlorogenic acid as an indispensible partner of caffeic acid in coffee via selective regulation of prooxidative actions of caffeic acid.

Chlorogenic acid (CGA) and caffeic acid (CA) are two major phenolic acids in coffee. Though the International Agency for Research on Cancer has classified CA as a Group2B carcinogen, coffee consumption seems generally safe within the usual levels of intake and is more likely to benefit health than to harm it. We thus speculated that CGA may effectively suppress the carcinogenic potential of CA. In a molar ratio achievable in vivo, this study shows that CGA can inhibit (i) copper reduction caused by CA, (ii) CA oxidation caused by copper, (iii) the formation of hydroxyl radicals by CA and copper, and (iv) DNA damage induced by CA, quercetin or (-)-epigallocatechin-3-gallate in the presence of copper. CA tends to undergo autoxidation to produce hydrogen peroxide and quinone, which further reacts with proteins to form quinoproteins. This autoxidation at a tolerable level normally induces beneficial adaptive responses. This study shows that CGA is less efficient than CA in producing hydrogen peroxide and quinoprotein; however, together they synergistically produce hydrogen peroxide and quinoprotein in vitro at a molar ratio achievable in vivo. In conclusion, CGA can selectively regulate the prooxidant activities of CA depending on whether copper is involved or not. CGA could be viewed as an indispensable partner of CA in coffee, given its dual role in suppressing the carcinogenic potential of CA and boosting CA autoxidation which is beneficial for disease prevention.

Clinical utility of the pan-immune-inflammation value in breast cancer patients.

Background: The newly discovered pan-immune-inflammation value (PIV) has been illustrated to have good prognostic value for cancer patient prognosis. However, the prognostic usefulness of PIV in breast cancer patients is unknown. As a result, to aid the clinic in providing a distinctive and trustworthy biomarker to better assess breast cancer patient's prognosis, we conducted this meta-analysis to investigate the relationship between PIV and the survival of breast cancer patients. Methods: We conducted a systematic search of Pubmed, Embase, the Cochrane Library, and the CNKI databases to screen for eligible studies published up to April 2023. Outcomes included overall survival (OS), progression-free survival (PFS), and pathological complete response (pCR). The hazard ratio (HR) and the corresponding 95% confidence interval (CI) were used as the indicators. STATA 15.0 software was used to perform meta-analysis, sensitivity analysis, and publication bias analysis. Results: A total of eight articles, involving 2953 patients, met the inclusion criteria and were included in this meta-analysis. The results showed that patients with higher PIV levels had a significantly shorter OS (HR: 2.045, 95% CI: 1.355-3.086, P = 0.001) and PFS (HR: 1.466, 95% CI: 1.163-1.848, P = 0.001). Besides, the PIV value was negatively correlated with the efficacy of neoadjuvant chemotherapy. Sensitivity analysis showed that the results of this study were reliable and stable. Conclusions: PIV has a good prognostic value in breast cancer patients and is expected to be a prognostic biomarker for breast cancer.

Integrative Identification by Hi-C Revealed Distinct Advanced Structural Variations in Lung Adenocarcinoma Tissue.

Advanced three-dimensional structure variations of chromatin in large genome fragments, such as conversion of A/B compartment, topologically associated domains (TADs) and chromatin loops are related closely to occurrence of malignant tumors. However, the structural characteristics of lung cancer still remain uncovered. In this study, we used high-throughput chromosome (Hi-C) conformation capture technology to detect the advanced structural variations in chromatin of two non-smoking lung adenocarcinoma (LUAD) tumor and paired normal tissues. The results indicate that significant chromatin variations are detected in tumor tissues compared with normal tissues. At compartment scale, the main conversion type of compartment is A → B in tumor tissues, which are concentrated mainly on chromosome 3 (Chr3) (33.6%). A total of 216 tumor-specific TADs are identified in tumor tissues, which are distributed mainly in Chr1 (19), Chr2 (15) and Chr3 (17). Forty-one distinct enhancer-promoter loops are observed in tumor tissue, which are associated closely to tumor-related pathways including mitogen-activated protein kinase (MAPK), Phosphatidylinositol-3-kinase-Protein kinase B (PI3K-AKT), Ras, Wnt and Ras1. The most important observation in this study is that we identify five important genes (SYT16, NCEH1, NXPE3, MB21D2, and DZIP1L), which are detected in both A → B compartment, TADs and chromatin loops in tumor samples, and four of these genes (NCEH1, NXPE3, MB21D2, and DZIP1L) locate on q arm of Chr3. Further gene expression and invasion experiment analysis show that NCEH1, MB21D2 and SYT16 are involved in the tumor development. Thus, we provide a comprehensive overview of advanced structures in LUAD for the first time and provide a basis for further research on the genetic variation of this tumor.

Strong and ductile titanium-oxygen-iron alloys by additive manufacturing.

Titanium alloys are advanced lightweight materials, indispensable for many critical applications1,2. The mainstay of the titanium industry is the α-ß titanium alloys, which are formulated through alloying additions that stabilize the α and ß phases3-5. Our work focuses on harnessing two of the most powerful stabilizing elements and strengtheners for α-ß titanium alloys, oxygen and iron1-5, which are readily abundant. However, the embrittling effect of oxygen6,7, described colloquially as 'the kryptonite to titanium'8, and the microsegregation of iron9 have hindered their combination for the development of strong and ductile α-ß titanium-oxygen-iron alloys. Here we integrate alloy design with additive manufacturing (AM) process design to demonstrate a series of titanium-oxygen-iron compositions that exhibit outstanding tensile properties. We explain the atomic-scale origins of these properties using various characterization techniques. The abundance of oxygen and iron and the process simplicity for net-shape or near-net-shape manufacturing by AM make these α-ß titanium-oxygen-iron alloys attractive for a diverse range of applications. Furthermore, they offer promise for industrial-scale use of off-grade sponge titanium or sponge titanium-oxygen-iron10,11, an industrial waste product at present. The economic and environmental potential to reduce the carbon footprint of the energy-intensive sponge titanium production12 is substantial.

PLCG2 can exist in eccDNA and contribute to the metastasis of non-small cell lung cancer by regulating mitochondrial respiration.

Extrachromosomal circular DNAs (eccDNAs) participate in tumorigenesis and tumor progression. However, the role and mechanism of eccDNAs have yet to be elucidated in non-small cell lung cancer (NSCLC). In our research, three surgically matched NSCLC tissue samples, NSCLC cell lines (H1299, A549, and H460), and a normal lung cell line (MRC-5) were used as study objects. High-throughput eccDNA sequencing and bioinformatics analysis were performed to study the distribution pattern and level of eccDNA expression. The upregulated candidate eccDNA-encoding PLCG2 was validated by routine PCR. Plasmid transfection, RNA interference, qRT‒PCR and western blotting experiments were used to verify the expression level of PLCG2. Our results showed that the chromosome distribution, length distribution, and genomic annotation of the eccDNAs were comparable between the NSCLC and normal groups. Nevertheless, there were no significant differences in eccDNAs between NSCLC tissues and matched normal lung tissues. The eccDNA derived from PLCG2 was upregulated in NSCLC cells. TCGA analysis and immunohistochemistry showed that PLCG2 was highly expressed in lung cancer tissues and tended to be associated with poor outcome. We also demonstrated that PLCG2 can promote metastasis through the regulation of mitochondrial respiration. These results suggested that PLCG2 identified by eccDNA sequencing acts as an oncogene and might be a new biomarker for NSCLC diagnosis and prognosis evaluation.

Dietary cysteine drives body fat loss via FMRFamide signaling in Drosophila and mouse.

Obesity imposes a global health threat and calls for safe and effective therapeutic options. Here, we found that protein-rich diet significantly reduced body fat storage in fruit flies, which was largely attributed to dietary cysteine intake. Mechanistically, dietary cysteine increased the production of a neuropeptide FMRFamide (FMRFa). Enhanced FMRFa activity simultaneously promoted energy expenditure and suppressed food intake through its cognate receptor (FMRFaR), both contributing to the fat loss effect. In the fat body, FMRFa signaling promoted lipolysis by increasing PKA and lipase activity. In sweet-sensing gustatory neurons, FMRFa signaling suppressed appetitive perception and hence food intake. We also demonstrated that dietary cysteine worked in a similar way in mice via neuropeptide FF (NPFF) signaling, a mammalian RFamide peptide. In addition, dietary cysteine or FMRFa/NPFF administration provided protective effect against metabolic stress in flies and mice without behavioral abnormalities. Therefore, our study reveals a novel target for the development of safe and effective therapies against obesity and related metabolic diseases.

Construction and validation of an angiogenesis-related lncRNA prognostic model in lung adenocarcinoma.

Background: There is increasing evidence that long non-coding RNAs (lncRNAs) can be used as potential prognostic factors for cancer. This study aimed to develop a prognostic model for lung adenocarcinoma (LUAD) using angiogenesis-related long non-coding RNAs (lncRNAs) as potential prognostic factors. Methods: Transcriptome data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to identify aberrantly expressed angiogenesis-related lncRNAs in LUAD. A prognostic signature was constructed using differential expression analysis, overlap analysis, Pearson correlation analysis, and Cox regression analysis. The model's validity was assessed using K-M and ROC curves, and independent external validation was performed in the GSE30219 dataset. Prognostic lncRNA-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) networks were identified. Immune cell infiltration and mutational characteristics were also analyzed. The expression of four human angiogenesis-associated lncRNAs was quantified using quantitative real-time PCR (qRT-PCR) gene arrays. Results: A total of 26 aberrantly expressed angiogenesis-related lncRNAs in LUAD were identified, and a Cox risk model based on LINC00857, RBPMS-AS1, SYNPR-AS1, and LINC00460 was constructed, which may be an independent prognostic predictor for LUAD. The low-risk group had a significant better prognosis and was associated with a higher abundance of resting immune cells and a lower expression of immune checkpoint molecules. Moreover, 105 ceRNA mechanisms were predicted based on the four prognostic lncRNAs. qRT-PCR results showed that LINC00857, SYNPR-AS1, and LINC00460 were significantly highly expressed in tumor tissues, while RBPMS-AS1 was highly expressed in paracancerous tissues. Conclusion: The four angiogenesis-related lncRNAs identified in this study could serve as a promising prognostic biomarker for LUAD patients.

Enhanced photothermal-ferroptosis effects based on RBCm-coated PDA nanoparticles for effective cancer therapy.

Ferroptosis, a type of programmed cell death induced by the iron-dependent lipid hydroperoxide pathway, has attracted widespread attention. However, Fenton response-dependent ferroptosis has many limitations, such as insufficient reaction conditions in the tumor micro-environment. Here, we propose an all-in-one phototherapy nanoplatform consisting of iron-polydopamine (Fe-PDA), a folic acid-modified red blood cell membrane (FA-RBCm), and epirubicin (EPI), namely, Fe-PDA-EPI@FA-RBCm NPs, to achieve enhanced photothermal-ferroptosis effects via overcoming the limitations of the Fenton-like reaction. The results showed that the synthesized biomimetic nanoparticles could decompose hydrogen peroxide (H2O2) to generate hydroxyl radicals (˙OH), and further induce the non-apoptotic ferroptosis pathway. After irradiation with near-infrared (NIR) light, the uptake of Fe-PDA-EPI@FA-RBCm NPs by cells could be effectively promoted, and it presented impressive in vitro and in vivo photothermal properties. In vitro and in vivo results showed that laser irradiation could enhance ferroptosis by promoting the production of reactive oxygen species (ROS) and lipid peroxides, down-regulating the expression of glutathione peroxidase 4 (GPX4), and reducing the mitochondrial membrane potential. Furthermore, the photothermal-promoted ferroptosis and apoptosis pathways (photothermal therapy and chemotherapy) exhibited outstanding synergistic antitumor efficacy in vitro and in vivo, with an in vivo tumor inhibition rate as high as 76.95%. In conclusion, the construction of tumor-targeted biomimetic nanocarriers utilizing the advantageous properties of RBCm has been investigated as a potential anticancer strategy.