Recombinant Human Heavy Chain Ferritin Nanoparticles Serve as ROS Scavengers for the Treatment of Ischemic Stroke.

Purpose: Ischemic stroke is a high-incidence disease that threatens human well-being. The potent neuroprotective effects render reactive oxygen species (ROS) scavengers potential agents for acute ischemic stroke therapy. Challenges such as inadequate permeability across the blood-brain barrier (BBB), limited half-life, and adverse effects hinder the widespread utilization of small molecule and inorganic ROS scavengers. Thus, there is an urgent demand for efficacious neuroprotective agents targeting ischemic stroke. Our study discovered the superoxide dismutase (SOD)-mimetic activity of recombinant human heavy chain ferritin (rHF) nanoparticles expressed from Escherichia coli (E. coli). Subsequent investigations delved into the ROS-scavenging proficiency of rHF within neural cells, its therapeutic efficacy against ischemic stroke, and the elucidation of its neuroprotective mechanisms. Methods: rHF protein nanoparticles were expressed in E. coli and purified via size-exclusion chromatography. The superoxide anion (•O2-) scavenging SOD-mimetic activity of rHF nanoparticles was measured using a SOD detection kit. The ROS scavenging ability and protection effects against oxidative damage of rHF nanoparticles were studied in H2O2-induced PC12 cells. Therapeutic effects and neuroprotective mechanisms of rHF against ischemic stroke were investigated with transient middle cerebral artery occlusion (MCAO) reperfusion mice model. Results: rHF nanoparticles can eliminate excessive ROS in nerve cells and alleviate oxidative damage. The results of animal experiments demonstrated that rHF nanoparticles passed across BBB, reduced infarct areas in brain tissue, and lowered the neurological deficit score of ischemia-reperfusion model mice. Additionally, rHF nanoparticles mitigated neuronal apoptosis and ferroptosis, suppressed microglial activation, maintained oxygen homeostasis, and exhibited negligible organ toxicity. Conclusion: rHF nanoparticle could be developed as a new ROS scavenger for nerve cells and has therapeutic potential as a drug for cerebral ischemia-reperfusion injury.

An Intranasal Multivalent Epitope-Based Nanoparticle Vaccine Confers Broad Protection against Divergent Influenza Viruses.

The development of a universal influenza vaccine to control public health threats from circulating and emerging influenza viruses is highly desirable. Here we report an intranasal multivalent epitope-based nanoparticle vaccine with broad protection against divergent influenza A and B viruses. Three highly conserved epitopes consisting of the A α-helix of hemagglutinin (H), the ectodomain of matrix protein 2 (M) and the HCA-2 of neuraminidase (N) are presented on a self-assembling recombinant human heavy chain ferritin cage (F) to generate the HMNF nanoparticle. Intranasal immunization of mice with HMNF mobilized potent immune responses, including high levels of antigen-specific antibodies and T cell-mediated responses, which exhibited cross-reactivity to various antigen mutations. Vaccination with HMNF conferred full protection against lethal challenge with divergent influenza A and B viruses. The broad protection of HMNF nanoparticles could be attributed to the synergistic function of antibodies and T cells. Moreover, the induced immune responses are long-lasting, and protection is maintained six months after vaccination. Our constructed HMNF nanoparticle can serve as a promising candidate for a universal influenza vaccine.

Non-hepatitis-associated mixed cryoglobulinemia with polyclonal plasma cells disease and alcoholic cirrhosis: A rare case report.

Mixed cryoglobulinemia refers to the serum presence of a variety of cryoglobulins, which are defined as immunoglobulins that precipitate at temperatures of < 37°C. The most common cause of mixed cryoglobulinemia is hepatitis C virus (HCV), while other infections, including hepatitis B virus (HBV) and HIV infections, and lymphoproliferative and autoimmune disorders have also been associated with the disease. We reported a rare case of type II-III mixed cryoglobulinemia caused by alcoholic cirrhosis. We need to increase the awareness of and facilitate the early identification of mixed cryoglobulinemia in our clinical study when encountering a patient with liver cirrhosis combined with renal impairment so that treatment can begin early to improve the success rate of therapy and reduce the fatality rate in a potentially life-saving therapy.

Self-Assembling Nanovaccine Confers Complete Protection Against Zika Virus Without Causing Antibody-Dependent Enhancement.

The Zika virus (ZIKV) epidemic poses a substantial threat to the public, and the development of safe and effective vaccines is a demanding challenge. In this study, we constructed a kind of self-assembling nanovaccine which confers complete protection against ZIKV infection. The ZIKV envelop protein domain III (zEDIII) was presented on recombinant human heavy chain ferritin (rHF) to form the zEDIII-rHF nanoparticle. Immunization of mice with zEDIII-rHF nanoparticle in the absence of an adjuvant induced robust humoral and cellular immune responses. zEDIII-rHF vaccination conferred complete protection against lethal infection with ZIKV and eliminated pathological symptoms in the brain. Importantly, the zEDIII-rHF nanovaccine induced immune response did not cross-react with dengue virus-2, overcoming the antibody-dependent enhancement (ADE) problem that is a safety concern for ZIKV vaccine development. Our constructed zEDIII-rHF nanovaccine, with superior protective performance and avoidance of ADE, provides an effective and safe vaccine candidate against ZIKV.

Acupoint selection rules of acupuncture and moxibustion for stroke-related pneumonia / 中国针灸

Using data mining technology, the rules of acupoint selection of acupuncture and moxibustion were explored in treatment of stroke-related pneumonia. The clinical articles of acupuncture and moxibustion in treatment of stroke-related pneumonia were retrieved from CNKI, SinoMed, Wanfang and VIP databases from their inception through to January l 2021, and then, the acupuncture-moxibustion prescription database was set up for stroke-related pneumonia. SPSS Modeler 18.0 Apriori algorithm was adopted to analyze the association rules of acupoints and draw complex network diagrams. SPSS26.0 was used in clustering analysis of acupoints. Finally, a total of 44 articles were included, with 51 acupoint prescriptions and 82 acupoints extracted. The total frequency of acupoints was 340 times. The high-frequency acupoints in treatment with acupuncture and moxibustion for stroke-related pneumonia were Feishu (BL 13), Fenglong (ST 40), Hegu (LI 4), etc. These acupoints were mainly distributed on the limbs and back and mostly from yang meridians. Of these extracted acupoints, the five-shu points, convergent points and back-shu points were selected specially. Regarding acupoint combination, the association of Quchi (LI 11) had the highest support with Hegu (LI 4) and Zusanli (ST 36). The core prescription of acupuncture-moxibustion treatment for stroke-related pneumonia could be composed of Quchi (LI 11), Hegu (LI 4), Zusanli (ST 36), Fenglong (ST 40) and Taichong (LR 3).

Quchi (LI 11) for treatment of allergic diseases based on coincidence of key therapeutic characteristics of acupoints and pathogenesis of allergic diseases / 中国针灸

According to the etiology, allergic diseases are related to wind and heat; according to the pathogenesis, most of allergic diseases are

Analysis on specific effect of acupoints at the upper arms in treatment of scrofula and goiter / 中国针灸

Through analyzing the indication distribution of the different acupoints located at the upper limbs recorded in

Modified and simplified clinically important deterioration: multidimensional indices of short-term disease trajectory to predict future exacerbations in patients with chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: Various prediction indices based on the single time point observation have been proposed in chronic obstructive pulmonary disease (COPD), but little was known about disease trajectory as a predictor of future exacerbations. Our study explored the association between disease trajectory and future exacerbations, and validated the predictive value of the modified and simplified short-term clinically important deterioration (CID). METHODS: This study was a multicenter, prospective observational study. Patients with COPD were recruited into our study and followed up for 18 months. The modified CID (CID-C) was defined as a decrease of 100 mL in forced expiratory volume in 1 second (FEV1), or suffering exacerbations, or increase of 2 units in COPD Assessment Test (CAT) during the first 6 months follow-up. Simplified CID was defined when excluding CAT from the CID-C model. RESULTS: A total of 127 patients were enrolled in our final analysis. Compared with patients without exacerbations during the period of the 6th to the 18th month, patients with exacerbations were more likely to have frequent short-term exacerbations in the first 6 months (2.14 versus 0.21, p < 0.001). The short-term exacerbations were the best predictor for future exacerbations [odds ratio (OR): 13.25; 95% confidence interval: 5.62-34.67; p < 0.001], followed by the history of exacerbation before study entry, short-term changes in FEV1 and CAT. CID-C and Simplified CID were both significantly associated with exacerbations (OR: 7.14 and 9.74, both p < 0.001). The receiver operating characteristic curves showed that the Simplified CID had slightly better predictive capacity for future exacerbation than CID-C (0.754 versus 0.695, p = 0.02). CONCLUSION: Disease trajectory, including both the CID-C and the Simplified CID had significant predictive value for future exacerbations.The reviews of this paper are available via the supplemental material section.

Targeted ferritin nanoparticle encapsulating CpG oligodeoxynucleotides induces tumor-associated macrophage M2 phenotype polarization into M1 phenotype and inhibits tumor growth.

Tumor-associated macrophages (TAM) are primarily of the M2 type that facilitates tumor growth, metastasis, and immunosuppression. Therefore, repolarizing the TAMs to the pro-inflammatory M1 type is a promising therapeutic strategy against cancer. Toll-like receptor (TLR) agonists like CpG oligodeoxynucleotides (CpG ODNs) can induce anti-tumor macrophages, however, their applications in vivo are limited by the lack of effective delivery approaches. Naked CpG ODNs fail to penetrate cell membranes and are easily cleared by nucleases, which can potentially trigger an inflammatory response in serum by systemic administration. Nanoparticles can deliver TLR agonists to the target TAMs following systemic administration and selectively accumulate in tumors and macrophages, and eventually trigger TLR signaling and M1 polarization. In this study, we developed a nanoparticle vector for the targeted delivery of CpG ODNs to M2 type TAMs by encapsulating the CpG ODNs inside human ferritin heavy chain (rHF) nanocages surface modified with a murine M2 macrophage-targeting peptide M2pep. These M2pep-rHF-CpG nanoparticles repolarized M2 TAMs to the M1 type and inhibited tumor growth in 4T1 tumor-bearing mice after intravenous injection. Furthermore, M2pep-rHF-CpG also reversed the phenotype of cultured human macrophages in vitro. Interestingly, the empty M2pep-rHF nanoparticles lacking CpG ODNs also exhibited anti-tumor ability. Taken together, M2pep-rHF nanoparticles offer a novel anti-cancer therapeutic strategy via targeted delivery of CpG ODNs to M2 type TAMs, and M2pep-rHF-CpG or M2pep-rHF nanoparticles may become promising medicines for tumor immunotherapy.

Characteristics of Patients with Chronic Obstructive Pulmonary Disease Exposed to Different Environmental Risk Factors: A Large Cross-Sectional Study.

Purpose: Tobacco smoking, biomass smoke, and occupational exposure are the main risk factors for chronic obstructive pulmonary disease (COPD). The present study analyzes data on exposure to these factors in a cohort of patients with COPD and assesses their differences in demographic and clinical characteristics. Patients and Methods: The cross-sectional observational study was conducted from November 2016 to December 2019. Inclusion criteria were patients aged over 40 years old with post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <0.7. At baseline, demographic features and exposure history were recorded. Moreover, respiratory symptoms were assessed by the COPD Assessment Test (CAT) and modified Medical Research Council scale (mMRC). A generalized linear mixed model was used to adjust for potential confounders. Results: A total of 5183 patients with COPD were included in the final analysis. The results demonstrate that exposure to tobacco combined with other risk factors resulted in significantly higher CAT scores (16.0 ± 6.7 vs 15.3 ± 6.3, P = 0.003) and more severe dyspnea (patients with mMRC ≥ 2, 71.5% vs 61.6%, P < 0.001) than exposure to tobacco alone. In addition, COPD patients with biomass smoke exposure alone had higher CAT scores than patients with only tobacco or occupational exposure (17.5 ± 6.3 vs 15.3 ± 6.3, and 15.2 ± 6.3, respectively, P < 0.05 for each comparison) and were more likely to be female and older. In addition, COPD patients who suffered from occupational exposure developed more severe dyspnea than those exposed to tobacco alone (70.8% vs 61.6%, P < 0.05), as did those exposed to biomass smoke alone (74.2% vs 61.6%, P < 0.05). This difference remained strong even after adjustment for potential confounders. Conclusion: There are significant demographic and clinical differences among COPD patients with tobacco smoking, biomass smoke, and occupational exposures.

Enterovirus A71 Oncolysis of Malignant Gliomas.

Malignant gliomas, the most lethal type of primary brain tumor, continue to be a major therapeutic challenge. Here, we found that enterovirus A71 (EV-A71) can be developed as a novel oncolytic agent against malignant gliomas. EV-A71 preferentially infected and killed malignant glioma cells relative to normal glial cells. The virus receptor human scavenger receptor class B, member 2 (SCARB2), and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)-mediated cell death were involved in EV-A71-induced oncolysis. In mice with implanted subcutaneous gliomas, intraneoplastic inoculation of EV-A71 caused significant tumor growth inhibition. Furthermore, in mice bearing intracranial orthotopic gliomas, intraneoplastic inoculation of EV-A71 substantially prolonged survival. By insertion of brain-specific microRNA-124 (miR124) response elements into the viral genome, we improved the tumor specificity of EV-A71 oncolytic therapy by reducing its neurotoxicity while maintaining its replication potential and oncolytic capacity in gliomas. Our study reveals that EV-A71 is a potent oncolytic agent against malignant gliomas and may have a role in treating this tumor in the clinical setting.

Intranasal Nanovaccine Confers Homo- and Hetero-Subtypic Influenza Protection.

Cross-protective and non-invasively administered vaccines are attractive and highly desired for the control of influenza. Self-assembling nanotechnology provides an opportunity for the development of vaccines with superior performance. In this study, an intranasal nanovaccine is developed targeting the conserved ectodomain of influenza matrix protein 2(M2e). 3-sequential repeats of M2e (3M2e) is presented on the self-assembling recombinant human heavy chain ferritin (rHF) cage to form the 3M2e-rHF nanoparticle. Intranasal vaccination with 3M2e-rHF nanoparticles in the absence of an adjuvant induces robust immune responses, including high titers of sera M2e-specific IgG antibodies, T-cell immune responses, and mucosal secretory-IgA antibodies in mice. The 3M2e-rHF nanoparticles also confer complete protection against a lethal infection of homo-subtypic H1N1 and hetero-subtypic H9N2 virus. An analysis of the mechanism of protection underlying the intranasal immunization with the 3M2e-rHF nanoparticle indicates that M2e-specific mucosal secretory-IgA and T-cell immune responses may play critical roles in the prevention of infection. The results suggest that the 3M2e-rHF nanoparticle is a promising, needle-free, intranasally administered, cross-protective influenza vaccine. The use of self-assembling nanovaccines could be an ideal strategy for developing vaccines with characteristics such as high immunogenicity, cross-protection, and convenient administration, as well as being economical and suitable for large-scale production.

In Vivo Targeting and Imaging of Atherosclerosis Using Multifunctional Virus-Like Particles of Simian Virus 40.

Atherosclerosis is a leading cause of death globally. Targeted imaging and therapeutics are desirable for the detection and treatment of the disease. In this study, we developed trifunctional Simian virus 40 (SV40)-based nanoparticles for in vivo targeting and imaging of atherosclerotic plaques. These novel trifunctional SV40-based nanoparticles encapsulate near-infrared quantum dots and bear a targeting element and a drug component. Using trifunctional SV40-based nanoparticles, we were able to noninvasively fluorescently image atherosclerotic plaques in live intact ApoE(-/-) mice. Near-infrared quantum dots encapsulated in the SV40 virus-like particles showed prominent optical properties for in vivo imaging. When different targeting peptides for vascular cell adhesion molecule-1, macrophages, and fibrin were used, early, developmental, and late stages of atherosclerosis could be targeted and imaged in live intact ApoE(-/-) mice, respectively. Targeted SV40 virus-like particles also delivered an increased concentration of the anticoagulant drug Hirulog to atherosclerosis plaques. Our study provides novel SV40-based nanoparticles with multivalency and multifunctionality suitable for in vivo imaging, molecular targeting, and drug delivery in atherosclerosis.

Morphometric studies of genus Placocheilus (Teleostei: Cypriniformes) from Red River, China.

It is practically difficult to differentiate Placocheilus robustus and Placocheilus caudofasciatus from Red River drainage of China. Without stated reasons, P. robustus has been assumed as the synonyms of P. caudofasciatus. The present study aims to decipher the morphological differences between two species so as to provide reliable clues for their classification by multivariate morphometry. A total of 72 specimens of two species in genus Placocheilus were examined. Besides morphological character comparisons, 10 anatomic landmarks were utilized and 23 frame structures and 15 general characters measured. The scatter plot results of principal component analysis showed that all specimens were clustered together and could not be defined as two distinct species. No significant morphological differences existed in four diagnostic characters between P. robustus and P. caudofasciatus. Thus the results of the present study fail to support P. robustus as a valid and independent species.

Advances in the study of aldehyde oxidases / 药学学报

Aldehyde oxidase (AOX), a highly conserved molybdoflavoenzyme in mammal cytoplasm, has broad substrate specificity and ability to catalyze the oxidation of aldehydes and nitrogen, oxygen-containing heterocyclic rings. AOX was found to widely distribute with the individual differences in vivo and plays an important role in phase I metabolism of drugs and xenobiotics. The biological characteristics of AOX and its contributions in drug metabolism are introduced briefly in this review.