Targeted reprogramming of tumor-associated macrophages for overcoming glioblastoma resistance to chemotherapy and immunotherapy.

The resistance of glioblastoma multiforme (GBM) to standard chemotherapy is primarily attributed to the existence of tumor-associated macrophages (TAMs) in the GBM microenvironment, particularly the anti-inflammatory M2 phenotype. Targeted modulation of M2-TAMs is emerging as a promising strategy to enhance chemotherapeutic efficacy. However, combination TAM-targeted therapy with chemotherapy faces substantial challenges, notably in terms of delivery efficiency and targeting specificity. In this study, we designed a pH-responsive hierarchical brain-targeting micelleplex loaded with temozolomide (TMZ) and resiquimod (R848) for combination chemo-immunotherapy against GBM. This delivery system, termed PCPA&PPM@TR, features a primary Angiopep-2 decoration on the outer layer via a pH-cleavable linker and a secondary mannose analogue (MAN) on the middle layer. This pH-responsive hierarchical targeting strategy enables effective BBB permeability while simultaneous GBM- and TAMs-targeting delivery. GBM-targeted delivery of TMZ induces alkylation and triggers an anti-GBM immune response. Concurrently, TAM-targeted delivery of R848 reprograms their phenotype from M2 to pro-inflammatory M1, thereby diminishing GBM resistance to TMZ and amplifying the immune response. In vivo studies demonstrated that targeted modulation of TAMs using PCPA&PPM@TR significantly enhanced anti-GBM efficacy. In summary, this study proposes a promising brain-targeting delivery system for the targeted modulation of TAMs to combat GBM.

Cathepsin B-Responsive Programmed Brain Targeted Delivery System for Chemo-Immunotherapy Combination Therapy of Glioblastoma.

Tumor-associated macrophages (TAMs) are closely related to the progression of glioblastoma multiform (GBM) and its development of therapeutic resistance to conventional chemotherapy. TAM-targeted therapy combined with conventional chemotherapy has emerged as a promising strategy to combat GBM. However, the presence of the blood-brain barrier (BBB) severely limits the therapeutic efficacy. Meanwhile, the lack of ability to distinguish different targeted cells also poses a challenge for precise therapy. Herein, we propose a cathepsin B (CTSB)-responsive programmed brain-targeted delivery system (D&R-HM-MCA) for simultaneous TAM-targeted and GBM-targeted delivery. D&R-HM-MCA could cross the BBB via low density lipoprotein receptor-associated protein 1 (LRP1)-mediated transcytosis. Upon reaching the GBM site, the outer angiopep-2 modification could be detached from D&R-HM-MCA via cleavage of the CTSB-responsive peptide, which could circumvent abluminal LRP1-mediated efflux. The exposed p-aminophenyl-α-d-mannopyranoside (MAN) modification could further recognize glucose transporter-1 (GLUT1) on GBM and macrophage mannose receptor (MMR) on TAMs. D&R-HM-MCA could achieve chemotherapeutic killing of GBM and simultaneously induce TAM polarization from anti-inflammatory M2 phenotype to pro-inflammatory M1 phenotype, thus resensitizing the chemotherapeutic response and improving anti-GBM immune response. This CTSB-responsive brain-targeted delivery system not only can improve brain delivery efficiency, but also can enable the combination of chemo-immunotherapy against GBM. The effectiveness of this strategy may provide thinking for designing more functional brain-targeted delivery systems and more effective therapeutic regimens.

Bitter Peptides in Fermented Soybean Foods - A Review.

Fermented soybean foods with a long history are popular worldwide because of rich nutrition. However, many traditional fermented soybean foods have unacceptable bitterness, which mostly comes from the bitter peptides produced from the hydrolysis of soybean proteins. In this review, the bitter peptides in fermented soybean foods is briefly reviewed. The structural properties of bitter receptors and bitter peptides were reviewed. Bitterness is perceived through the binding between bitter compounds and specific sites of bitter receptors (25 hTAS2Rs), which further activate the downstream signal pathway mediated by G-protein. And it converts chemical signals into electrical signals, and transmit them to the brain. In addition, the influencing factors of bitter peptides in fermented soybean foods were summarized. The bitterness of fermented soybean foods primarily results from the raw materials, microbial metabolism during fermentation, unique techniques, and interactions of various flavor compounds. Moreover, the structure-bitterness relationship of bitter peptides was also discussed in this review. The bitterness degree of the bitter peptide is related to the polypeptide hydrophobicity, amino acids in the peptide, peptide molecular weight and polypeptide spatial structure. Studying the bitter peptides and their bitter characteristics in fermented soybean foods is beneficial for improving the sensory quality of fermented soybean foods and prompting more consumers accept them.

Patterns of mental health problems before and after easing COVID-19 restrictions: Evidence from a 105248-subject survey in general population in China.

BACKGROUND: The COVID-19 pandemic has alarming implications for individual and population level mental health. Although the future of COVID-19 is unknown at present, more countries or regions start to ease restrictions. The findings from this study have provided the empirical evidence of prevalence and patterns of mental disorders in Chinese general population before and after easing most COVID-19 restrictions, and information of the factors associated with these patterns. METHODS: A cross-sectional population-based online survey was carried out from February to March 2020 in the general population across all provinces in China. The 12-item General Health Questionnaire (GHQ-12) was incorporated in the survey. Latent class analyses were performed to investigate the patterns of mental disorders and multinomial logistic regressions were used to examine how individual and regional risk factors can predict mental disorder patterns. RESULTS: Four distinctive patterns of mental health were revealed in the general population. After the ease of most COVID-19 restrictions, the prevalence of high risk of mental disorders decreased from 25.8% to 20.9% and prevalence of being high risk of unhappiness and loss of confidence decreased from 10.1% to 8.1%. However, the prevalence of stressed, social dysfunction and unhappy were consistently high before and after easing restrictions. Several regional factors, such as case mortality rate and healthcare resources, were associated with mental health status. Of note, healthcare workers were less likely to have mental disorders, compared to other professionals and students. CONCLUSIONS: The dynamic management of mental health and psychosocial well-being is as important as that of physical health both before and after the ease of COVID-19 restrictions. Our findings may help in mental health interventions in other countries and regions while easing COVID-19 restrictions.

Unpacking the Mental Health of Nurses during COVID-19: Evidence from Pakistan.

The prime objective of the present study is to test the effect of COVID-19 fear on the mental condition of nurses in the public health sector of Pakistan. This study seeks to measure the psychological distress, anxiety, and psychological well-being of nurses due to fear of COVID-19 and exposure to COVID-19. This research further reveals the moderating role of "social support" in the link between COVID-19 fear, exposure and mental health. Through a convenient sampling technique, 250 sample contributors were chosen from 12 public hospitals. The results were obtained by applying multiple regression and moderation analysis by SPSS and the Hayes process. The outcomes indicated that fear of exposure to COVID-19 affects the mental health of nurses. The findings also discovered that social support is not very constructive in the pandemic. However, we suggested that social support is the best weapon to encourage nurses to relieve their fear and minimize negative emotions.

COVID-19 and Mental Health: A Study of Stress, Resilience, and Depression among the Older Population in Pakistan.

Extending studies of the adverse effects of SARS-2 coronavirus on general health consequences, this research explores complexities related to the mental health of the elderly as a result of pandemic-related stress. The study addresses this issue by using resilience theory to examine the effects of fear and exposure related to COVID-19 and depression. Besides, our study examines the moderating effects of self-efficacy in order to provide an understanding of how the coping abilities of the elderly may mitigate the effect of stress levels on mental health during pandemics. Our model is tested by analysing the survey data collected from Rawalpindi, a metropolitan city in Pakistan. The main results of the study confirm the positive association of pandemic-related fear and exposure virus with depression. However, self-efficacy shows a negative direct effect on depression, and the findings also confirm the moderation effect of self-efficacy on the fear of COVID-19 and depression, but the moderation effect of self-efficacy on COVID-19 exposure and depression is not supported. Based on the outcomes, some severe geriatric care policies that could weaken the pandemic-related fear, exposure to the virus, and depression are recommended.