The role of silver nanoparticles alone and combined with imipenem on carbapenem-resistant Klebsiella pneumoniae.

AIMS: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections poses a significant threat to human health, necessitating urgent development of new antimicrobial agents. Silver nanoparticles (AgNPs), which are among the most widely used engineered nanomaterials, have been extensively studied. However, the impact of AgNPs on CRKP and the potential for drug resistance development remain inadequately explored. METHODS AND RESULTS: In this study, broth dilution method was used to determine the minimum inhibitory concentration (MIC) was determined using the broth dilution method. Results indicated MIC values of 93.1 ± 193.3 µg ml-1 for AgNPs, 2.3 ± 5.1 µg ml-1 for AgNO3, and 25.1 ± 48.3 µg ml-1 for imipenem (IMI). The combined inhibitory effect of AgNPs and IMI on CRKP was assessed using the checkerboard method. Moreover, after 6-20 generations of continuous culture, the MIC value of AgNPs increased 2-fold. Compared to IMI, resistance of Kl. pneumoniae to AgNPs developed more slowly, with a higher fold increase in MIC observed after 20 generations. Whole-genome sequencing revealed four nonsynonymous single nucleotide polymorphism mutations in CRKP after 20 generations of AgNP treatment. CONCLUSION: We have demonstrated that AgNPs significantly inhibit CRKP isolates and enhance the antibacterial activity of imipenem against Kl. pneumoniae. Although the development of AgNP resistance is gradual, continued efforts are necessary for monitoring and studying the mechanisms of AgNP resistance.

Mitophagy protects against silver nanoparticle-induced hepatotoxicity by inhibiting mitochondrial ROS and the NLRP3 inflammasome.

Silver nanoparticles (AgNPs) have wide clinical applications because of their excellent antibacterial properties; however, they can cause liver inflammation in animals. Macrophages are among the main cells mediating inflammation and are also responsible for the phagocytosis of nanomaterials. The NLRP3 inflammasome is a major mechanism of inflammation, and its activation both induces cytokine release and triggers inflammatory cell death (i.e., pyroptosis). In previous studies, we demonstrated that mitophagy activation plays a protective role against AgNP-induced hepatotoxicity. However, the exact molecular mechanisms underlying these processes are not fully understood. In this study, we demonstrate that AgNP exposure induces NLRP3 inflammasome activation, mitochondrial damage and pyroptosis in vivo and in vitro. NLRP3 silencing or inhibiting mitochondrial reactive oxygen species (ROS) overproduction reduces PINK1-Parkin-mediated mitophagy. Meanwhile, the inhibition of mitophagy ROS production, mitochondrial, NLRP3-mediated inflammation, and pyroptosis in RAW264.7 cells were more pronounced than in the control group. These results suggest that PINK1-Parkin-mediated mitophagy plays a protective role by reducing AgNP-induced mitochondrial ROS and subsequent NLRP3 inflammasome activation.

Hematological characteristics of COVID-19 patients with fever infected by the Omicron variant in Shanghai: A retrospective cohort study in China.

BACKGROUND: A wave of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread in Shanghai, China. Hematological abnormalities have been reported in coronavirus disease 2019 (COVID-19) patients; however, the difference in hematological parameters between COVID-19 patients with fever and patients who are febrile from other causes remains unexplored. METHODS: This retrospective cohort study enrolled 663 SARS-CoV-2 positive patients identified by RT-PCR. Clinical parameters, including age, sex, and threshold cycle values of all COVID-19 patients, and hematological parameters of COVID-19 patients in the fever clinic were abstracted for analysis. RESULTS: Overall, 60.8% of COVID-19 patients were male, and the median age was 45 years. Most of COVID-19 patients were asymptomatic, while 25.8% of patients showed fever and 10.9% of patients had other emergencies. COVID-19 patients with fever had significantly lower white blood cells (WBCs), neutrophils, lymphocytes, platelets and C-reactive protein (CRP), and significantly higher monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), and mean platelet volume-to-platelet ratio (MPR) levels, compared with those in SARS-CoV-2 negative patients with fever from other causes (p < 0.05). Neutrophil-to-lymphocyte ratio (NLR), PLR, and systemic inflammatory index (SII) levels were significantly higher in COVID-19 patients with emergencies (p < 0.05). WBCs showed the best performance with an area under the curve (0.756), followed by neutrophils (0.730) and lymphocytes (0.694) in the diagnosis of COVID-19 in the fever clinic. CONCLUSION: WBCs, neutrophils, lymphocytes, platelets, CRP and MLR, PLR, and MPR may be useful in early diagnosis of COVID-19 in the fever clinic.

Ivermectin, a potential anticancer drug derived from an antiparasitic drug.

Ivermectin is a macrolide antiparasitic drug with a 16-membered ring that is widely used for the treatment of many parasitic diseases such as river blindness, elephantiasis and scabies. Satoshi omura and William C. Campbell won the 2015 Nobel Prize in Physiology or Medicine for the discovery of the excellent efficacy of ivermectin against parasitic diseases. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. This suggests that ivermectin may be an anticancer drug with great potential. Here, we reviewed the related mechanisms by which ivermectin inhibited the development of different cancers and promoted programmed cell death and discussed the prospects for the clinical application of ivermectin as an anticancer drug for neoplasm therapy.

Neurotoxicity of metal-containing nanoparticles and implications in glial cells.

With the development of nanotechnology, metal-containing nanoparticles are used widely in the diagnosis, monitoring and treatment of central nervous system (CNS) diseases. The neurotoxicity of these nanoparticles has drawn attention. Glial cells (particularly microglial cells and astrocytes) have important functions in the CNS. Neural disorders are related to functional/histologic damage to glial cells. Dysfunctions of microglial cells or astrocytes injure the brain, and cause the neurodegeneration seen in Alzheimer's disease and Parkinson's disease. We have summarized the route of access of metal-containing nanoparticles to the CNS, as well as their neurotoxicity and potential molecular mechanisms involved in glial cells. Metal-containing nanoparticles cross or bypass the blood-brain barrier, access the CNS and cause neurotoxicity. The potential mechanisms are related to inflammation, oxidative stress, DNA and/or mitochondrial damage and cell death, all of which are mediated by microglial cell activation, inflammatory factor release, generation of reactive oxygen species, apoptosis and/or autophagy in glial cells. Moreover, these processes increase the burden of the CNS and even accelerate the occurrence or development of neurodegenerative diseases. Some important signaling pathways involved in the mechanism of neurotoxicity in glial cells caused by nanoparticles are also discussed.

Neurobehavior and neuron damage following prolonged exposure of silver nanoparticles with/without polyvinylpyrrolidone coating in Caenorhabditis elegans.

Silver nanoparticles (AgNPs) have become widespread in the environment with increasing industrial applications. But the studies about their potential health risks are far from enough, especially in neurotoxic effects. This study aimed to investigate the neurotoxic effects of longer-term exposure (prolonged exposure for 48 h and chronic exposure for 6 days) of 20nm AgNPs with/without polyvinylpyrrolidone (PVP) coating at low concentrations (0.01-10 mg·L-1 ) to Caenorhabditis elegans. The results suggested that exposure to AgNPs induced damage to nematode survival, with the longest and relative average life span reduced. Exposure to AgNPs caused neurotoxicity on locomotion behaviors (head thrashes, body bends, pharyngeal pumping frequency, and defecation interval) and sensory perception behaviors (chemotaxis assay and thermotaxis assay), as well as impaired dopaminergic, GABAergic, and cholinergic neurons, except for glutamatergic, based on the alters fluorescence intensity, in a dose- and time-dependent manner. Further investigations suggested that the low-dose AgNPs (0.01-0.1 mg·L-1 ) exposure raises receptors of GABAergic and dopamine in C. elegans at the genetic level, whereas opposite results were observed at higher doses (1-10 mg·L-1 ), which implied that AgNPs could cause neurotoxicity by impairing neurotransmitter delivery. The PVP-AgNPs could cause a higher fatality rate and neurotoxicity at the same dose. Notably, AgNPs did not cause any deleterious effect on nematodes at the lowest dose of 0.01 mg·L-1 . In general, these results suggested that AgNPs possess the neurotoxic potential in C. elegans and provided useful information to understand the neurotoxicity of AgNPs, which would offer an inspiring perspective on the safe application.

Mitophagy-lysosomal pathway is involved in silver nanoparticle-induced apoptosis in A549 cells.

With the increasing use of silver nanoparticles (AgNPs) in biological materials, the cytotoxicity caused by these particles has attracted much attention. However, the molecular mechanism underlying AgNP cytotoxicity remains unclear. In this study, we aimed to systematically investigate the toxicity induced by AgNP exposure to the lung adenocarcinoma A549 cell line at the subcellular and signaling pathway levels and elucidate the related molecular mechanism. The survival rate of cells exposed to AgNPs at 0, 20, 40, 80, and 160 µg/mL for 24 or 48 h decreased in a dose- and time-dependent manner. AgNPs induced autophagy and mitophagy, determined by the transmission electron microscopy investigation and upregulation of LC3 II/I, p62, PINK1, and Parkin expression levels. AgNP treatment induced lysosomal injury, including the decline of lysosomal membrane integrity and increase in cathepsin B level. The decreased in mitochondrial membrane potential, along with upregulation of cytochrome c, caspases 9 and 3, and BAX/BCL2, further suggested that mitochondrial injury were involved in AgNP-induced apoptosis. In addition, mitochondrial injury may further lead to excessive production of reactive oxygen species and oxidative/ antioxidant imbalance. The results suggested that AgNPs could regulate autophagy via mitochondrial and lysosome injury in A549 cells. The information of the molecular mechanism will provide an experimental basis for the safe application of nanomaterials.

Silver nanoparticles induced cytotoxicity in HT22 cells through autophagy and apoptosis via PI3K/AKT/mTOR signaling pathway.

With the widespread application and inevitable environmental exposure, silver nanoparticles (AgNPs) can be accumulated in various organs. More serious concerns are raised on the biological safety and potential toxicity of AgNPs in the central nervous system (CNS), especially in the hippocampus. This study aimed to investigate the biological effects and the role of PI3K/AKT/mTOR signaling pathway in AgNPs mediated cytotoxicity using the mouse hippocampal neuronal cell line (HT22 cells). AgNPs reduced cell viability and induced membrane leakage in a dose-dependent manner, determined by the MTT and LDH assay. In doses of 25, 50, 100 µg mL-1 for 24 h, AgNPs promoted the excessive production of reactive oxygen species (ROS) and caused the oxidative stress in HT22 cells. AgNPs induced autophagy, determined by the transmission electron microscopy observation, upregulation of LC3 II/I and downregulation of p62 expression levels. The mechanistic investigation showed that the PI3K/AKT/mTOR signaling pathway was activated by phosphorylation, which was enrolled in an AgNP-induced autophagy process. AgNPs could further trigger the apoptosis by upregulation of caspase-3 and Bax and downregulation of Bcl-2 in HT22 cells. These results revealed AgNP-induced cytotoxicity in HT22 cells, which was mediated by autophagy and apoptosis via the PI3K/AKT/mTOR signaling pathway. The study could provide the experimental evidence and explanation for the potential neurotoxicity triggered by AgNPs in vitro.

Potential health impact of environmental micro- and nanoplastics pollution.

Micro- and nanoplastics are generated from plastics and have negative impacts on the environment due to their high level of fragmentation. They can originate from various sources such as fragments, fibers and foams. The large proportion of the waste and resistance to degradation means micro- and nanoplastics have become a serious global environmental problem, but there are few studies on their potential toxicity for human health. In this review, we discussed routes of exposure and the potential effects of micro- and nanoplastics to human health. Human beings could mainly be exposed to micro- and nanoplastics orally and by inhalation. The possible toxic effects of plastic particles are due to the potential toxicity of plastics themselves, and their combined toxicity with leachable additives and adsorbed contaminants. The potential risks for human health focused on their gastrointestinal toxicity and liver toxicity. The toxic mechanisms could involve oxidative stress, inflammatory reactions and metabolism disorders. More studies are needed to carry out and explore the potential toxicological mechanisms of micro- and nanoplastics and evaluate the combined toxicity of their adsorbed contaminants.

Biodistribution and organ oxidative damage following 28 days oral administration of nanosilver with/without coating in mice.

This study evaluated the biodistribution and organ oxidative effects of silver nanoparticles (AgNPs) coated with/without polyvinylpyrrolidone (PVP) (AgNP-20 and AgNP-PVP) in mice; these were administered by gavage at a dose of 10-250 mg/kg body weight per day for 28 days. The results showed that both the AgNPs could induce subacute toxicity and oxidative damage to mice and were mainly accumulated in the liver and spleen and excreted by feces. AgNPs could be absorbed into blood and might cross the blood-brain barrier, and be distributed extensively in mice. The malondialdehyde content in the liver, lungs and kidneys increased in both AgNP groups, while the content of glutathione decreased, and the activity of superoxide dismutase increased at first and then decreased along with the increased doses. Inflammatory pathological changes in the lung and liver at high dose of both AgNPs were consistent with increases in glutamate pyruvic transaminase, glutamate oxaloacetic transaminase and the total protein in serum detection. The Ag content was detected in organs, with the highest content in the liver, followed by spleen, while the Ag content in feces was about 500 times higher than that in urine. AgNP-PVP could induce higher oxidative stress and subacute toxicity than AgNP-20 at the same dose, which might be related to the higher concentrations and more Ag+ ions released in mice after AgNP-PVP exposure. The data from this research provided information on toxicity and biodistribution of AgNPs following gavage administration in mice, and might shed light for future application of AgNPs in daily life.

Review of the effects of silver nanoparticle exposure on gut bacteria.

Gut bacteria are involved in regulating several important physiological functions in the host, and intestinal dysbacteriosis plays an important role in several human diseases, including intestinal, metabolic and autoimmune disorders. Although silver nanoparticles (AgNPs) are increasingly being incorporated into medical and consumer products due to their unique physicochemical properties, studies have indicated their potential to affect adversely the gut bacteria. In this review, we focus on the biotoxicological effects of AgNPs entering the gastrointestinal tract and the relationship of these effects with important nanoscale properties. We discuss in detail the mechanisms underlying the bactericidal toxicity effects of AgNPs and explore the relationships between AgNPs, gut bacteria and disease. Finally, we highlight the need to focus on the negative effects of AgNPs usage to facilitate appropriate development of these particles.

Genotoxic effects of silver nanoparticles with/without coating in human liver HepG2 cells and in mice.

With the rapid expansion of human exposure to silver nanoparticles (AgNPs), the genotoxicity screening is critical to the biosafety evaluation of nanosilver. This study assessed DNA damage and chromosomal aberration in the human hepatoma cell line (HepG2) as well as the effects on the micronucleus of bone marrow in mice induced by 20 nm polyvinylpyrrolidone-coated nanosilver (PVP-AgNPs) and 20 nm bare nanosilver (AgNPs). Our results showed that the two types of AgNPs, in doses of 20-160 µg/mL, could cause genetic toxicological changes on HepG2 cells. The DNA damage degree of HepG2 cells in 20 nm AgNPs was higher than that in 20 nm PVP-AgNPs, while the 20 nm PVP-AgNPs caused more serious chromosomal aberration than 20 nm AgNPs. Both kinds of AgNPs caused genetic toxicity in a dose-dependent manner in HepG2 cells. In the micronucleus test on mouse bone marrow cells, in doses of 10, 50 and 250 mg/kg body weight administered orally for 28 days once a day, the two kinds of AgNPs have no obvious inhibitory effect on the mouse bone marrow cells, and the effect of chromosome aberration could be documented at the high dose of 250 mg/kg. These results suggest that AgNPs have genotoxic effects in HepG2 cells and limited effects on bone marrow in mice; both in vitro and in vivo tests could be of great importance on the evaluation of genotoxicity of nanosilver. These findings can provide useful toxicological information that can help to assess genetic toxicity of nanosilver in vitro and in vivo.

Further evaluation of the NWF filter for the purification of Plasmodium vivax-infected erythrocytes.

BACKGROUND: Isolation of Plasmodium-infected red blood cells (iRBCs) from clinical blood samples is often required for experiments, such as ex vivo drug assays, in vitro invasion assays and genome sequencing. Current methods for removing white blood cells (WBCs) from malaria-infected blood are time-consuming or costly. A prototype non-woven fabric (NWF) filter was developed for the purification of iRBCs, which showed great efficiency for removing WBCs in a pilot study. Previous work was performed with prototype filters optimized for processing 5-10 mL of blood. With the commercialization of the filters, this study aims to evaluate the efficiency and suitability of the commercial NWF filter for the purification of Plasmodium vivax-infected RBCs in smaller volumes of blood and to compare its performance with that of Plasmodipur® filters. METHODS: Forty-three clinical P. vivax blood samples taken from symptomatic patients attending malaria clinics at the China-Myanmar border were processed using the NWF filters in a nearby field laboratory. The numbers of WBCs and iRBCs and morphology of P. vivax parasites in the blood samples before and after NWF filtration were compared. The viability of P. vivax parasites after filtration from 27 blood samples was examined by in vitro short-term culture. In addition, the effectiveness of the NWF filter for removing WBCs was compared with that of the Plasmodipur® filter in six P. vivax blood samples. RESULTS: Filtration of 1-2 mL of P. vivax-infected blood with the NWF filter removed 99.68% WBCs. The densities of total iRBCs, ring and trophozoite stages before and after filtration were not significantly different (P > 0.05). However, the recovery rates of schizont- and gametocyte-infected RBCs, which were minor parasite stages in the clinical samples, were relatively low. After filtration, the P. vivax parasites did not show apparent morphological changes. Culture of 27 P. vivax-infected blood samples after filtration showed that parasites successfully matured into the schizont stage. The WBC removal rates and iRBC recovery rates were not significantly different between the NWF and Plasmodipur® filters (P > 0.05). CONCLUSIONS: When tested with 1-2 mL of P. vivax-infected blood, the NWF filter could effectively remove WBCs and the recovery rates for ring- and trophozoite-iRBCs were high. P. vivax parasites after filtration could be successfully cultured in vitro to reach maturity. The performance of the NWF and Plasmodipur® filters for removing WBCs and recovering iRBCs was comparable.

Localized Surface Plasmon Resonance Sensor Based at Metallic Sphere Dimer Particle.

Simulated transmission spectrums of the sphere dimer nanoparticle and the nanoshell structure by the Finite-Difference time-Domain method are present. The considered structure is silver or SiO2 dimer nanoparticle and nanoshell structures, and the particle distance is 10 nm. There is little transmission dip in the transmission spectrums for the silver dimer nanoparticle and nanoshell structure in the visible wavelength range, which arisen from the excitation of the Localized Surface Plasmon Resonance. The transmission dip sensitivity with the index refractive for the silver dimer nanoparticle is about 80 nm RIU­1. Meanwhile, the electric field enhancement and localization properties of the Silver dimer nanoparticle is better than that of the SiO2 dimer nanoparticle. Meanwhile, these structures can extensively apply to biochemical sensor devices design and localized field enhancement device so on.

[Effects of dexamethasone on MRL/lpr mice with systemic lupus erythematosus complicated with cognitive dysfunction].

OBJECTIVE: To evaluate the effects of dexamethasone on systemic lupus erythematosus complicated with cognitive dysfunction.
 Methods: Ten wild type mice and 20 MRL/lpr mice were applied for the research. MRL/lpr mice were randomly assigned to a MRL/lpr group and a MRL/lpr + dexamethasone (1.5 mg/kg) group. Interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor alpha (TNF-α) in serum and hippocampus were detected. The protein phosphorylation levels of phosphoinositide 3-kinase (P-PI3K), protein kinase B (P-Akt), NF-kappa-B inhibitor alpha (P-IκBa) and nuclear transcription factor kappa-B p65 (P-NF-κB p65) were detected by Western blot, the level of P-NF-κB p65 also was detected by immunohistochemistry. 
 Results: Treatment with dexamethasone (1.5 mg/kg) alleviated the cognitive dysfunction and decreased the levels of IL-6, IL-1ß and TNF-α in serum and hippocampus, and reduced the levels of P-PI3K, P-Akt, P-IκBa and P-NF-κB p65 in hippocampus in MRL/lpr mice.
 Conclusion: Dexamethasone may play a protective role in the cognitive function by decreasing the levels of TNF-α and IL-1ß in the hippocampus of MRL/lpr lupus mice.

[In vitro Effect of Hypericin against Toxoplasma gondii Tachyzoites].

Objective: To investigate the killing effect of hypericin on tachyzoites of Toxoplasma gondii RH strain in vitro. Methods: Normal saline （group A） and different concentrations of hypericin (5 µg/ml, group B; 50 µg/ml, group C; 500 µg/ml, group D） were added to T. gondii tachyzoites in 24-well plate（1×10(6)/well）. The tachyzoites were harvested after 2, 4 and 6 h, and underwent the following treatment: trypan blue staining to calculate the dyeing rate, Giemsa staining to observe the morphological and structural alterations of tachyzoites, and transmission electron microscopy to observe the ultrastructure of tachyzoites. In addition, flow cytometry was performed to calculate the survival rate of YFP-carrying Toxoplasma with the same treatment. Results: The trypan blue dyeing rate at 2 h after treatment in groups B, C and D was（11.0±3.6）%, （25.0±6.3）% and（40.0±2.7）% respectively, with a significant difference of group D versus B and C （P<0.01）, and groups C and D versus group A ［（6.0±3.0）%）］. The dyeing rate at 4 h and 6 h in group D was（97.0±2.0）% and （98.0±1.7）%, respectively, both significantly higher than that of groups C ［（30.0±7.2）%, （42.7±5.5）%ï¼½, B ［（20.0±3.0）%, （34.0±6.6）%ï¼½ and A ［（10.0±1.0）%, （19.3±4.9）%］（P<0.01）. Giemsa staining showed gradual end swelling and necrosis of tachyzoites with increased treatment duration and dosage. Transmission electron microscopy showed swelling of worm body, gap between cell membrane and matrix, increase and enlargement of vacuoles inside worm body, disruption of cell membrane, and dissolving of inner structures, with increased treatment duration. Flow cytometry showed significant difference of tachyzoite survival rate at 2, 4 and 6 h after hypericin treatment with that of the control group（P<0.01）. The survival rate of group C at 2 h after hypericin treatment was（7.9±1.9）%, significantly lower than that of groups B ［（38.1±5.5）%ï¼½ and A ［（81.8±6.0）%ï¼½ （P<0.01）. No tachyzoite was found to survive in group D at 2 h and in group C at 4 h. The survival rate of group B at 4 and 6 h after hypericin treatment was（14.3±7.9）% and （1.4±1.8）%, respectively, both significantly lower than that of group A［（73.8±11.3）% and（64.1±14.4）%, respectivelyï¼½ （P<0.01）. Conclusion: Hypericin has a remarkable killing effect on T. gondii tachyzoites, and the efficacy positively correlates with the dose and treatment duration.

Exosomes derived from vMIP-II-Lamp2b gene-modified M2 cells provide neuroprotection by targeting the injured spinal cord, inhibiting chemokine signals and modulating microglia/macrophage polarization in mice.

Inflammation is one of the key injury factors for spinal cord injury (SCI). Exosomes (Exos) derived from M2 macrophages have been shown to inhibit inflammation and be beneficial in SCI animal models. However, lacking targetability restricts their application prospects. Considering that chemokine receptors increase dramatically after SCI, viral macrophage inflammatory protein II (vMIP-II) is a broad-spectrum chemokine receptor binding peptide, and lysosomal associated membrane protein 2b (Lamp2b) is the key membrane component of Exos, we speculated that vMIP-II-Lamp2b gene-modified M2 macrophage-derived Exos (vMIP-II-Lamp2b-M2-Exo) not only have anti-inflammatory properties, but also can target the injured area by vMIP-II. In this study, using a murine contusive SCI model, we revealed that vMIP-II-Lamp2b-M2-Exo could target the chemokine receptors which highly expressed in the injured spinal cords, inhibit some key chemokine receptor signaling pathways (such as MAPK and Akt), further inhibit proinflammatory factors (such as IL-1ß, IL-6, IL-17, IL-18, TNF-α, and iNOS), and promote anti-inflammatory factors (such as IL-4 and Arg1) productions, and the transformation of microglia/macrophages from M1 into M2. Moreover, the improved histological and functional recoveries were also found. Collectively, our results suggest that vMIP-II-Lamp2b-M2-Exo may provide neuroprotection by targeting the injured spinal cord, inhibiting some chemokine signals, reducing proinflammatory factor production and modulating microglia/macrophage polarization.

Hepatitis C virus genotype diversity in Shanghai, China.

We studied 67 hepatitis C virus (HCV) isolates from 64 hospitalized patients in Shanghai, China. Genotype 1 was prevalent, and genotypes 2, 3, 6 were found for the first time in Shanghai. A rare mixed infection with three subtypes (1a, 1b, 2a) was found. The complete genome sequence of a subtype 3b isolate was determined and analyzed.

Design, synthesis and biological evaluation of novel 7-mercaptocoumarin derivatives as α(1)-adrenoceptor antagonists.

Study on the pharmacophore model of α(1)-adrenoceptor (α(1)-AR) antagonists led to design a series of novel 7-mercaptocoumarin derivatives as α(1)-AR antagonists. All designed compounds have been synthesized and biologically evaluated. The results showed that most of them exhibited strong antagonistic activity. Especially compound 6 showed excellent activity, which was better than that of the reference compound prazosin. Structure-activity relationship studies revealed that small hydrophobic group at the terminal heterocyclic ring and ortho substituents on the phenyl ring of phenylpiperazine moiety were the essential structural factors for α(1)-AR antagonistic activity. The pharmacophore modeling studies further clarified their structural contributions to antagonistic activity and also demonstrated that 7-mercaptocoumarin moiety could be a useful scaffold for design of α(1)-AR antagonists.

Development and validation of a machine learning model for differential diagnosis of malignant pleural effusion using routine laboratory data.

BACKGROUND: The differential diagnosis of malignant pleural effusion (MPE) and benign pleural effusion (BPE) presents a clinical challenge. In recent years, the use of artificial intelligence (AI) machine learning models for disease diagnosis has increased. OBJECTIVE: This study aimed to develop and validate a diagnostic model for early differentiation between MPE and BPE based on routine laboratory data. DESIGN: This was a retrospective observational cohort study. METHODS: A total of 2352 newly diagnosed patients with pleural effusion (PE), between January 2008 and March 2021, were eventually enrolled. Among them, 1435, 466, and 451 participants were randomly assigned to the training, validation, and testing cohorts in a ratio of 3:1:1. Clinical parameters, including age, sex, and laboratory parameters of PE patients, were abstracted for analysis. Based on 81 candidate laboratory variables, five machine learning models, namely extreme gradient boosting (XGBoost) model, logistic regression (LR) model, random forest (RF) model, support vector machine (SVM) model, and multilayer perceptron (MLP) model were developed. Their respective diagnostic performances for MPE were evaluated by receiver operating characteristic (ROC) curves. RESULTS: Among the five models, the XGBoost model exhibited the best diagnostic performance for MPE (area under the curve (AUC): 0.903, 0.918, and 0.886 in the training, validation, and testing cohorts, respectively). Additionally, the XGBoost model outperformed carcinoembryonic antigen (CEA) levels in pleural fluid (PF), serum, and the PF/serum ratio (AUC: 0.726, 0.699, and 0.692 in the training cohort; 0.763, 0.695, and 0.731 in the validation cohort; and 0.722, 0.729, and 0.693 in the testing cohort, respectively). Furthermore, compared with CEA, the XGBoost model demonstrated greater diagnostic power and sensitivity in diagnosing lung cancer-induced MPE. CONCLUSION: The development of a machine learning model utilizing routine laboratory biomarkers significantly enhances the diagnostic capability for distinguishing between MPE and BPE. The XGBoost model emerges as a valuable tool for the diagnosis of MPE.