Kaempferol inhibits SARS-CoV-2 invasion by impairing heptad repeats-mediated viral fusion.

BACKGROUND: The continuous evolution of SARS-CoV-2 has underscored the development of broad-spectrum prophylaxis. Antivirals targeting the membrane fusion process represent promising paradigms. Kaempferol (Kae), an ubiquitous plant flavonol, has been shown efficacy against various enveloped viruses. However, its potential in anti-SARS-CoV-2 invasion remains obscure. PURPOSE: To evaluate capabilities and mechanisms of Kae in preventing SARS-CoV-2 invasion. METHODS: To avoid interference of viral replication, virus-like particles (VLPs) constructed with luciferase reporter were applied. To investigate the antiviral potency of Kae, human induced pluripotent stem cells (hiPSC)-derived alveolar epithelial cells type II (AECII) and human ACE2 (hACE2) transgenic mice were utilized as in vitro and in vivo models, respectively. Using dual split protein (DSP) assays, inhibitory activities of Kae in viral fusion were determined in Alpha, Delta and Omicron variants of SARS-CoV-2, as well as in SARS-CoV and MERS-CoV. To further reveal molecular determinants of Kae in restricting viral fusion, synthetic peptides corresponding to the conserved heptad repeat (HR) 1 and 2, involved in viral fusion, and the mutant form of HR2 were explored by circular dichroism and native polyacrylamide gel electrophoresis. RESULTS: Kae inhibited SARS-CoV-2 invasion both in vitro and in vivo, which was mainly attributed to its suppressive effects on viral fusion, but not endocytosis, two pathways that mediate viral invasion. In accordance with the proposed model of anti-fusion prophylaxis, Kae functioned as a pan-inhibitor of viral fusion, including three emerged highly pathogenic coronaviruses, and the currently circulating Omicron BQ.1.1 and XBB.1 variants of SARS-CoV-2. Consistent with the typical target of viral fusion inhibitors, Kae interacted with HR regions of SARS-CoV-2 S2 subunits. Distinct from previous inhibitory fusion peptides which prevent the formation of six-helix bundle (6-HB) by competitively interacting with HRs, Kae deformed HR1 and directly reacted with lysine residues within HR2 region, the latter of which was considered critical for the preservation of stabilized S2 during SARS-CoV-2 invasion. CONCLUSIONS: Kae prevents SARS-CoV-2 infection by blocking membrane fusion and possesses a broad-spectrum anti-fusion ability. These findings provide valuable insights into potential benefits of Kae-containing botanical products as a complementary prophylaxis, especially during the waves of breakthrough infections and re-infections.

Repetitive Transcranial Magnetic Stimulation Improves Mild Cognitive Impairment Associated with Alzheimer's Disease in Mice by Modulating the miR-567/NEUROD2/PSD95 Axis.

BACKGROUND: Mild cognitive impairment (MCI) is a typical symptom of early Alzheimer's disease (AD) and is driven by the dysfunction of microRNAs (miRs). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique for handling neuropsychiatric disorders and has universally effects on the functions of miRs. In the current study, the improvement effects of rTMS on MCI associated with AD were explored by focusing on miR-567/NEUROD2/PSD95 axis. METHODS: MCI was induced in mice using scopolamine and was treated with rTMS of two frequencies (1 Hz and 10 Hz). The changes in cognitive function, brain structure, neurotrophic factor levels, and activity of miR-567/NEUROD2/PSD95 axis were assessed. The interaction between rTMS and miR-567 was further verified by inducing the level of miR-567 in AD mice. RESULTS: The administrations of rTMS improved the cognitive function of AD mice and attenuated brain tissue destruction, which were associated with the restored production of BDNF and NGF. Additionally, rTMS administrations suppressed the expression of miR-567 and up-regulated the expressions of NEUROD2 and PSD95, which contributed to the improved condition in central nerve system. With the induced level of miR-567, the effects of rTMS were counteracted: the learning and memorizing abilities of mice were impaired, the brain neuron viability was suppressed, and the production of neurotrophic factors was suppressed even under the administration of rTMS. The changes in brain function and tissues were associated with the inhibited expressions of NEUROD2 and PSD95. CONCLUSION: The findings outlined in the current study demonstrated that rTMS treatment could protect brain against AD-induced MCI without significant side effects, and the function depended on the inhibition of miR-567.

Broad Anti-Viral Capacities of Lian-Hua-Qing-Wen Capsule and Jin-Hua-Qing-Gan Granule and Rational use Against COVID-19 Based on Literature Mining.

The novel coronavirus disease 2019 (COVID-19) has become a matter of international concern as the disease is spreading exponentially. Statistics showed that infected patients in China who received combined treatment of Traditional Chinese Medicine and modern medicine exhibited lower fatality rate and relatively better clinical outcomes. Both Lian-Hua-Qing-Wen Capsule (LHQWC) and Jin-Hua-Qing-Gan Granule (JHQGG) have been recommended by China Food and Drug Administration for the treatment of COVID-19 and have played a vital role in the prevention of a variety of viral infections. Here, we desired to analyze the broad-spectrum anti-viral capacities of LHQWC and JHQGG, and to compare their pharmacological functions for rational clinical applications. Based on literature mining, we found that both LHQWC and JHQGG were endowed with multiple antiviral activities by both targeting viral life cycle and regulating host immune responses and inflammation. In addition, from literature analyzed, JHQGG is more potent in modulating viral life cycle, whereas LHQWC exhibits better efficacies in regulating host anti-viral responses. When translating into clinical applications, oral administration of LHQWC could be more beneficial for patients with insufficient immune functions or for patients with alleviated symptoms after treatment with JHQGG.

Transdermal Delivery of Therapeutic Compounds With Nanotechnological Approaches in Psoriasis.

Psoriasis is a chronic, immune-mediated skin disorder involving hyperproliferation of the keratinocytes in the epidermis. As complex as its pathophysiology, the optimal treatment for psoriasis remains unsatisfactorily addressed. Though systemic administration of biological agents has made an impressive stride in moderate-to-severe psoriasis, a considerable portion of psoriatic conditions were left unresolved, mainly due to adverse effects from systemic drug administration or insufficient drug delivery across a highly packed stratum corneum via topical therapies. Along with the advances in nanotechnologies, the incorporation of nanomaterials as topical drug carriers opens an obvious prospect for the development of antipsoriatic topicals. Hence, this review aims to distinguish the benefits and weaknesses of individual nanostructures when applied as topical antipsoriatics in preclinical psoriatic models. In view of specific features of each nanostructure, we propose that a proper combination of distinctive nanomaterials according to the physicochemical properties of loaded drugs and clinical features of psoriatic patients is becoming a promising option that potentially drives the translation of nanomaterials from bench to bedside with improved transdermal drug delivery and consequently therapeutic effects.

Application of Functional Biocompatible Nanomaterials to Improve Curcumin Bioavailability.

Curcumin is a lipophilic natural product extracted from turmeric and commonly used as a dietary spice. Being multi-functional, curcumin has been proposed in the prevention and treatment of a broad spectrum of diseases. However, due to unsatisfactory aqueous solubility and hence low bioavailability, clinical application of curcumin has been greatly restrained. To break these limitations, biocompatible nanoformulation, such as liposomes, nanoparticles, micelles, nanoemulsions and conjugates has been employed as alternatives to improve in vivo delivery of curcumin. In this scenario, in order to enhance bioavailability of curcumin, the choice of effective molecules as facilitators is of prominence. In this review, we focus on functional biocompatible materials, including polymers, protein molecules, polysaccharide, surface stabilizers and phospholipid complexes, and decipher their potential applications as how they assist to promote medicinal performance of curcumin.

Corrigendum: Construction of SARS-CoV-2 Virus-Like Particles by Mammalian Expression System.

[This corrects the article DOI: 10.3389/fbioe.2020.00862.].

Construction of SARS-CoV-2 Virus-Like Particles by Mammalian Expression System.

Virus-like particle (VLP) is a self-assembled nanostructure incorporating key viral structural proteins. VLP resembles molecular and morphological features of authentic viruses but is non-infectious and non-replicating due to lack of genetic materials. Successful applications of VLP has been shown in vaccinological and virological research. As an accessibly safe and relevant substitute of naturally pathogenic viruses, the construction of SARS-CoV-2 VLPs is much in demand in the ongoing fight against 2019 Coronavirus disease (COVID-19) pandemics. In the current study, using mammalian expression system, which is advantageous in maintaining correct protein glycosylation patterns, we efficiently constructed SARS-CoV-2 VLPs. We showed that among four SARS-CoV-2 structural proteins, expression of membrane protein (M) and small envelope protein (E) are essential for efficient formation and release of SARS-CoV-2 VLPs. Moreover, the corona-like structure presented in SARS-CoV-2 VLPs from Vero E6 cells is more stable and unified, as compared to those from HEK-293T cells. Our data demonstrate that SARS-CoV-2 VLPs possess molecular and morphological properties of native virion particles, which endow such VLPs with a promising vaccine candidate and a powerful tool for the research of SARS-CoV-2.

[A study on risk factors and perceptions of diabetes among urban and suburban residents from six provinces in China].

OBJECTIVE: To study the epidemiological status of diabetes' risk factors among urban and suburban residents and their perceptions of their own health status and risk of diabetes. METHODS: Stratified multi-stage sampling method was used to conduct the survey among 18-60 years old residents from Zhejiang, Jiangsu, Shanxi, Henan, Yunnan, and Qinghai provinces in China from March to May in 2013. The Questionnaire of Health Literacy of Diabetes Mellitus of the Public in China was used to conduct the survey, and then the data were analyzed. The main contents of the questionnaire included diabetes mellitus knowledge, diabetes mellitus risk factors and diabetes mellitus risk self-assessment. The results of the survey were standardized by the 6(th) national census data. RESULTS: A total of 4 416 respondents were surveyed, and 4 282 valid questionnaires were successfully collected during the survey and the response rate was 97.0%. After weighted adjustment, the overweight and obesity rate of the residents in 6 provinces was 35.3%, abdominal obesity rate was 54.7%. 77.8% of the residents without diabetes had more than one risk factor, but only 8.5% thought they might got diabetes. The residents with high risk behavior possessing rates of diabetes were in eastern areas (79.7%), urban areas (80.7%), men (84.1%), aged from 45 to 60(100.0%), below primary school education level (83.4%) and enterprise personnel (79.7%). The residents with high risk consciousness of getting diabetes were in eastern areas (11.0%), urban areas (9.7%), men (9.7%), aged from 45 to 60 (12.3%), over college education level (12.7%) and the offices (14.7%). The results of logistic regression showed that residents in the middle areas (OR = 2.148, 95% CI: 1.633-2.920), urban residents (OR = 2.100, 95% CI: 1.611-2.738), male (OR = 2.488, 95% CI: 1.962-3.154), the older (OR = 1.102, 95% CI: 1.090-1.115) had a higher risk behavior rate of diabetes mellitus. Urban residents (OR = 2.784, 95% CI: 1.497-5.175), male (OR = 1.522, 95% CI: 1.152-2.011), the older (OR = 1.022, 95% CI: 1.009-1.035), college educational level (OR = 1.685, 95% CI: 1.033-2.749), with a higher score of health awareness(OR = 1.090, 95% CI: 1.061-1.120)had a higher risk consciousness to being diabetes mellitus. CONCLUSION: The urban and suburban residents in China had a high risk behavior possessing rates of diabetes, and a low risk consciousness of being diabetes.

[An analysis of health literacy about diabetes prevention and control and its influencing factors among the residents in six provinces in China].

OBJECTIVE: To investigate the health literacy about diabetes prevention and control and its influencing factors among the public in China. METHODS: A multistage stratified random sampling method was applied to investigate urban and rural residents aged 18-60 years among six provinces in China during March and May, 2013. The Questionnaire of Health Literacy of Diabetes Mellitus of the Public in China was used to conduct the survey. The influencing factors of health literacy about diabetes prevention and control were analyzed by logistic regression. The results of the survey were standardized by the 6(th) national census data. RESULTS: A total of 4 416 persons were interviewed. A total of 4 282 valid questionnaires including 1 986 males (46.4%) and 2 296 females (53.6%) were obtained. The efficiency rate was 97.0%. The level of health literacy about diabetes prevention and control among the public in China was 32.7% (1 036/2 399). And this rate was 40.5%, 36.5% and 15.4% in east, middle and west of China, respectively. Take the west region as reference, the health literacy about diabetes prevention and control in east China was high (OR = 2.510, 95% CI: 1.931-3.263), central China was in the second place (OR = 2.083, 95% CI: 1.579-2.749). The health literacy about diabetes prevention and control among males was lower than that in females (OR = 0.488, 95% CI: 0.402-0.593). The higher education level the respondents had, the higher the health lireracy level about diabetes prevention and control. Taking the primary school and below education level as reference, the health lireracy level about diabetes prevention and control of respondents with a secondary education was higher (OR = 1.103, 95% CI: 0.812-1.499), and that of college or above degree was the highest (OR = 2.029, 95% CI: 0.460-0.870). The health literacy about diabetes prevention and control among civil servants and institution staff was high, the enterprise personnel was in the second place (OR = 0.632, 95% CI: 0.460-0.870), the literacy level among the rural residents was very low (OR = 0.339, 95% CI: 0.234-0.491). The health literacy about diabetes prevention and control among people who have a family history of diabetes was relatively higher (OR = 1.570, 95% CI: 1.222-2.018 ). The health literacy about diabetes prevention and control among people who considered that they have diabetes risk was higher than that among people who considered they didn't (OR = 1.821, 95% CI: 1.317-2.517). CONCLUSION: The east region, females, a high educational level, civil servants and public officers, having a family history of diabetes, self-assessed risk of getting diabetes were protective factors of health literacy about diabetes prevention and control.

[The study of diabetes-related behavior status and affecting factors among urban and suburban residents in six provinces in China].

OBJECTIVE: To explore the status of diabetes-related behaviors and affecting factors among urban and suburban residents in China. METHODS: A sample of 18-60 years old residents from Zhejiang, Jiangsu, Shanxi, Henan, Yunnan and Qinghai provinces was investigated by using stratified cluster random sampling method from March to May in 2013, and 4 282 residents were recruited. The Questionnaire of Health Literacy of Diabetes Mellitus of the Public in China was used to conduct the survey. χ(2) test was used to compare the different risk behavior characteristics of diabetes. The results of the survey were standardized by the 6th national census data. Multiple regression analysis was used to understand the affecting factors to related behaviors. RESULTS: After data standardization, 14.3% sat more than 6 hours every day, 57.6% exercised less than 3 times every week, 21.3% had no regularly daily diet, 58.7% paid no attention to diet control, 15.7% and 7.8% residents preferred salty and oily diet, 51.4% had physical examination less than 1 time every year, 29.7% were smokers, and 9.2% often drank. Urban residents spent much more time on sitting (18.2%) than rural residents (8.4%) (P < 0.05), and the rates of lack of physical exercise(52.7%), irregular diet (17.2%), paying no attention to diet control (51.9%), smokers (23.6%) among urban residents were lower than rural residents (60.1%, 21.4%, 62.5% and 32.1% respectively) (P < 0.05). The rates of irregular diet (24.6%), paying no attention to diet control (63.5%), high-salt and high-fat diet (30.1%), smokers (57.7%), drinking (18.7%) among men were higher than those in females (15.5%, 52.1%, 23.2%, 2.2%, and 0.8% respectively) (P < 0.05); regions, genders, educational levels, occupations were related to relative behaviors of diabetes, residents in rural areas (t = 7.829, P < 0.01), males (t = -21.760, P < 0.01), lower education level (t = 0.771, P < 0.01), as well as institution personnel (t = -4.240, P < 0.01) had lower behavior scores, which meant they had more risk behaviors related to diabetes. CONCLUSION: There were diabetes-related risk behaviors among both urban and suburban residents in China, such as insufficient physical exercise, no diet control and regular medical examinations. These risk behaviors happened more in rural areas than in urban areas, men than women, older age group than lower age group.

[The status of diabetes prevention awareness among Chinese residents in six provinces].

OBJECTIVE: To explore the status of diabetes prevention awareness among Chinese residents in order to provide the scientific basis for making intervention strategy. METHODS: A sample of 18-60 years old residents in six provinces was investigated from March to April in 2013. RESULTS: Totally, 17.8% of respondents answered all questions correctly about the awareness of diabetes. As for "Diabetes is a common chronic disease" got highest recognition rate (86.2%), and "Diabetes can be cured" got the lowest rate, 48.3%. 50.6% of respondents answered all questions correctly about the diabetes symptoms; and "thirsty, drink more water" got the highest recognition rate (75.3%). 17.8% of respondents answered all questions correctly about the complications of diabetes; and "causes of diabetes ketoacidosis" got the lowest rate of 31.6%. 12.3% of respondents answered all questions correctly about the diabetes high-risk group; the correct recognition rate for "family history" was the highest (75.1%); and the "macrosomia" got the lowest rate of 20.4%. 74.2% of respondents answered all questions correctly about the diabetes preventive measure;the correct cognition rate of a reasonable diet was the highest (92.0%), and the weight control was the lowest (81.5%). In addition, there are significant differences of knowledge score between different areas and genders. City residents' knowledge score about diabetes related views (6.2 ± 1.8), typical symptoms (2.9 ± 1.4), complication (4.1 ± 2.3), high-risk groups (3.4 ± 1.7), prevention measures (3.7 ± 0.9) were higher than rural residents (respectively 5.2 ± 2.2, 2.7 ± 1.5, 3.2 ± 2.3, 2.9 ± 1.8, 3.3 ± 1.2) (P < 0.05). Female residents' knowledge score about diabetes related views (5.7 ± 2), typical symptoms (2.9 ± 1.4), complication (3.8 ± 2.3), high-risk groups (3.1 ± 1.8), prevention measures (3.5 ± 1) were higher than male residents (respectively 5.5 ± 2.1, 2.7 ± 1.5, 3.5 ± 2.4, 3.1 ± 1.8, 3.4 ± 1.2, 18.1 ± 6.8) (P < 0.05). CONCLUSION: The public is lack of diabetes prevention awareness, and city residents' knowledge score is higher than rural residents', females are higher than males.