Innovative freeze-drying technique in the fabrication of dissolving microneedle patch: Enhancing transdermal drug delivery efficiency.

Microneedle patch (MNP) has become a hot research topic in the field of transdermal drug delivery due to its ability to overcome the stratum corneum barrier. Among the various types of microneedles, dissolving microneedles represent one of the most promising transdermal delivery methods. However, the most used method for preparing dissolving microneedles, namely microfabrication, suffers from issues such as long drying time, susceptibility to humidity, and large batch-to-batch variability, which limit the development of dissolving microneedles. In this study, we report for the first time a method for preparing dissolving microneedles using freeze-drying technology. We screened substrates suitable for freeze-dried microneedle patch (FD-MNP) and used coating technology to enhance the mechanical strength of FD-MNP, allowing them to meet the requirements for skin penetration. We successfully prepared FD-MNP using hyaluronic acid as the substrate and insulin as the model drug. Scanning electron microscopy revealed that the microneedles had a porous structure. After coating, the mechanical strength of the microneedles was 0.61 N/Needle, and skin penetration rate was 97%, with a penetration depth of 215 µm. The tips of the FD-MNP dissolved completely within approximately 60 s after skin penetration, which is much faster than conventional MNP (180 s). In vitro transdermal experiments showed that the FD-MNP shortened the lag time for transdermal delivery of rhodamine 123 and insulin compared to conventional MNP, indicating a faster transdermal delivery rate. Pharmacological experiments showed that the FD-MNP lowered mouse blood glucose levels more effectively than conventional MNP, with a relative pharmacological availability of 96.59 ± 2.84%, higher than that of conventional MNP (84.34 ± 3.87%), P = 0.0095. After storage under 40℃ for two months, the insulin content within the FD-MNP remained high at 95.27 ± 4.46%, which was much higher than that of conventional MNP (58.73 ± 3.71%), P < 0.0001. In conclusion, freeze-drying technology is a highly valuable method for preparing dissolving microneedles with potential applications in transdermal drug delivery.

Revisiting the Immigrant Health Advantage: Self-Reported Health and Smoking Among Sexual Minority Immigrants.

This study aims to examine how the immigrant health advantage (IHA) may differ by sexual orientation. Using data from the 2015-2019 National Health Interview Survey, we examined general health status (n = 131,635) and smoking behavior (n = 131, 658) for US-born and foreign-born heterosexual and sexual minority adults, as well as how the duration of stay in the U.S. may influence sexual minority immigrants' health. Logistic regression models were adopted to examine the health outcomes of immigration in different immigrant groups divided by sexual orientation. Findings show a weaker immigrant health advantage among sexual minorities than heterosexual persons, which disappears or turns into a disadvantage for several subpopulations (i.e., foreign-born homosexual individuals who stayed for 10-15 or 15 + years in the U.S.). Foreign-born homosexual individuals having stayed in the U.S. for a decade or more have substantially higher odds of reporting poor/fair health and smoking currently than their US-born counterparts. Although immigrants' health advantage overall attenuates over time, sexual minority immigrants' health erodes more with time spent in the U.S. The disparities in immigrants' health advantages suggest a segmented health acculturation (or even marginalization) process and entail higher sexual orientation-based health disparities among immigrants than among US-born individuals, likely reinforcing the preexisting health disparities in the country. The findings call for policies to address the multifaceted barriers to health equity at the intersection of social disadvantages.

Expectations Regarding Reciprocity of Flows of Intergenerational Support in China: Does Gender or Birth Order Matter?

This study investigates the flows of downward intergenerational transfer to adult children of different gender and birth order, and their influence on parental expectations towards old-age care and financial support, using data from the 2015-2016 China Health and Retirement Longitudinal Study (CHARLS). Based on the analytic sample of 1218 parents and 3237 adult children, we found that in multi-child families, sons are more likely to be expected by their parents as future caregivers if both they and their siblings received parental housing support, while it is the case for daughters when only they themselves received parental housing support. Parents' downward housing support shows a stronger effect on care expectations than on expectations of future financial support. This study contributes to our understanding of intergenerational transfer norms and expectations from parents' perspective and has important implications for old-age care policies in contemporary China.

Tacrolimus nanocrystals microneedle patch for plaque psoriasis.

Plaque psoriasis is characterized by an abnormal thickening of the epidermis, which causes great difficulties for traditional topical drug delivery. Microneedles can pierce the thickened epidermis and deliver drugs to the skin for psoriasis treatment. Tacrolimus is a poorly water-soluble immunosuppressant used for the treatment of psoriasis. In this study, tacrolimus (TAC) nanocrystals (NCs) were produced using a bottom-up technique that dispersed TAC into a sodium hyaluronate-based microneedle patch (MNP), and its therapeutic efficacy was evaluated. The average particle size of the TAC NCs was 259.6 ± 2.3 nm. The mechanical strength of the microneedles was 0.41 ± 0.06 N/needle, which was sufficient to penetrate psoriatic skin. Microneedles were detached from the substrate 10 min after insertion into the psoriasis skin with an insertion depth of 258.8 ± 14.4 µm. The intradermal retention of the MNP (8.40 ± 0.33 µg/cm2) was six times that of the commercial ointment (1.40 ± 0.12 µg/cm2). In pharmacodynamic experiments, results indicated improvement in the phenotypic and histopathological features and reduction in the level of TNF-α, IL-17A, and IL-23 of psoriatic skin treated with TAC NCs MNP. Therefore, MNP loaded with TAC NCs may be a promising approach for psoriasis treatment.

Will Downward Intergenerational Housing Support Increase Parents' Expectations for Old-Age Care from Adult Children? Evidence from China.

Toward a background of young people's decreasing housing affordability and parents' increasing involvement in intergenerational housing support, this study investigates how such support influences parents' expectation of future care from adult children. Using data from the China Health and Retirement Longitudinal Study, we found that, in general, middle-aged/older adults who provided adult children financial housing support were more likely to expect old-age care from them. The help-receiving child was more likely to be an expected caregiver than the other children in multi-children families. Moreover, the reciprocal relationship was most prominent among the 1950s cohort, compared with the pre-1950s and the post-1950s cohorts. Our study broadly contributes to understanding how modernization reshapes intergenerational relationships and family members' expectations of commitments toward each other. It also informs the design of a comprehensive multi-level care system for older adults in China.

Astragalus Polysaccharide Protects Against Cadmium-Induced Autophagy Injury Through Reactive Oxygen Species (ROS) Pathway in Chicken Embryo Fibroblast.

Cadmium (Cd) is a harmful heavy metal pollutant, which can cause oxidative stress in the body and induce cell damage. Reactive oxygen species (ROS) is a general term for substances that contain oxygen and are active in the body. However, excessive ROS can damage the body. Cadmium poisoning can cause a large amount of ROS in cells and autophagy. Astragalus polysaccharide (APS) is a plant polysaccharide with biological functions, such as antioxidant and anti-stress activities. In this study, chicken embryo fibroblasts (CEF) were used to determine the relationship between ROS and autophagy damage of Cd-infected cells and the mechanism of APS on cadmium-induced autophagy damage. The results showed that a 10-µL dose of 10 µmol/L cadmium chloride (CdCl2) can induce CEF autophagy and damage when CEF was added for 36 h. Cadmium induced CEF autophagy damage by increasing ROS production. APS could significantly reduce ROS production and LC3-II and Beclin-1 protein expression, increase the expression of mTOR and the level of antioxidation, and restore the viability and morphological damage of CEF exposed to Cd. Our study suggests that APS can alleviate Cd-induced CEF autophagy damage by reducing the production of ROS.

Effects of Fungal Polysaccharide on Oxidative Damage and TLR4 Pathway to the Central Immune Organs in Cadmium Intoxication in Chickens.

Cadmium (Cd) can cause animal organism damage, but there have been few studies on the damage of cadmium to the immune organs of birds. Most fungal polysaccharide has antioxidant and immunomodulatory effects. The experimental study investigated the effects of fungal polysaccharide (Agaricus blazei Murill polysaccharide and Ganoderma luciduccharide) on the oxidative damage of central immune organs (thymus and bursa of Fabricius) and on the Toll-like receptor 4 (TLR4) pathway in cadmium-poisoned chickens. The results showed that Agaricus blazei polysaccharide and Ganoderma lucidum polysaccharide can reduce cadmium content, TLR4 expression, inflammatory factor (IL-1ß, IL-6, TNF-α) content, and lipid peroxidation product MDA content and increase the activity of antioxidant enzymes SOD and GSH-Px in thymus and bursa of cadmium poisoning chickens. Ganoderma lucidum polysaccharide could decrease the expression of TLR4, IL-1ß, and IL-6 in cadmium poisoning peripheral blood lymphocytes of chicken, and TLR4 inhibitor had the same effect. The results demonstrated the protective effects of Agaricus blazei Murill polysaccharide and Ganoderma lucidum polysaccharides on the damage of the central immune organs of chickens caused by cadmium poisoning were closely related to the TLR4 signaling pathway and oxidative stress.

Agaricus blazei Murill Polysaccharides Protect Against Cadmium-Induced Oxidative Stress and Inflammatory Damage in Chicken Spleens.

Agaricus blazei Murill polysaccharide (ABP) has exhibited antioxidant and immunoregulatory activity. The aim of this study was to investigate the effect of ABP on cadmium (Cd)-induced antioxidant functions and inflammatory damage in chicken spleens. In this study, groups of 7-day-old chickens were fed with normal saline (0.2 mL single/day), CdCl2 (140 mg/kg/day), ABP (30 mg/mL, 0.2 mL single/day), and Cd + ABP (140 mg/kg/day + 0.2 mL ABP). Spleens were separated on the 20th, 40th, and 60th day for each group. The Cd contents, expression of melanoma-associated differentiation gene 5 (MDA5) and its downstream signaling molecules (interferon promoter-stimulating factor 1 (IPS-1), transcription factors interferon regulatory factor 3 (IRF3), and nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB)), the content of cytokines (interleukin 1ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and beta interferon (IFN-ß)), protein levels of heat shock proteins (HSPs), levels of malondialdehyde (MDA), activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), and histopathological changes of spleens were detected on the 20th, 40th, and 60th day. The results showed that ABP significantly reduced the accumulation of Cd in the chicken spleens and reduced the expression of MDA5, IPS-1, IRF-3, and NF-κB; their downstream inflammatory cytokines, IL-1ß, IL-6, TNF-α, and IFN-ß; and the protein levels of HSPs (HSP60, HSP70, and HSP90) in spleens. The activities of antioxidant enzymes (SOD and GSH-Px) significantly increased, and the level of MDA decreased in the ABP + Cd group. The results indicate that ABP has a protective effect on Cd-induced damage in chicken spleens.

Astragalus Polysaccharide Protect against Cadmium-Induced Cytotoxicity through the MDA5/NF-κB Pathway in Chicken Peripheral Blood Lymphocytes.

Cadmium (Cd) is a known environmental pollutant that is associated with inflammation, oxidative stress, and cell apoptosis. Astragalus polysaccharide (APS) is a major component of Astragalus membranaceus, a vital qi-reinforcing herb medicine with favorable immuneregulation properties. To study the effect of APS on the inhibition of the cadmium-induced injury of peripheral blood lymphocytes (PBLs) in chickens through the MDA5/NF-κB signaling pathway, PLBs acquired from 15-day-old chickens were divided into control group, Cd group, APS + Cd group, anti-MDA5 mAb + Cd group, BAY 11-7082 (a nuclear factor kappa-light chain-enhancer of activated B cells [NF-κB] inhibitor) +Cd group, APS group, anti-MDA5 mAb group, and BAY 11-7082 group. The transcription levels of melanoma differentiation-associated gene 5 (MDA5), interferon promoter-stimulating factor 1 (IPS-1), NF-κB, and inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were measured by quantitative real-time PCR. MDA5 protein expression was measured by western blotting. Levels of malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were measured by corresponding antioxidant kit. The morphological change of PBLs was measured by transmission electron microscopy. The results showed that Cd significantly increased the expression of MDA5, IPS-1, NF-κB, and their downstream cytokines, IL-1ß and TNF-α, IL-6 in PLBs. In addition, a high level of MDA was observed in the Cd treatment group; the activities of GSH-Px and SOD were significantly lower in the Cd treatment group than those in controls (p < 0.05). Ultrastructural changes of PBLs showed that Cd promoted autophagy, apoptosis, and necrosis in PBLs. However, APS can efficiently improve Cd-induced cell damage by decreasing the activation of the MDA5 signaling pathway. The effect is consistent with that of anti-MDA5 mAb or/and BAY. The results indicated that APS inhibited Cd-induced cytotoxicity through the regulation of MDA5/NF-κB signaling.

Just Like in Their Home Country? A Multinational Perspective on Living Arrangements of Older Immigrants in the United States.

Older immigrants are more likely to share residence with their adult children and other family members than are U.S.-born older adults. Because socioeconomic factors only partially explain these differences and direct measures of cultural preferences are seldom available, the persistently high rates of intergenerational coresidence among the older foreign-born are often interpreted as driven by cultural preferences and/or a lack of assimilation. To challenge this interpretation, this study investigates the extent to which older immigrants' living arrangements deviate from those of older adults in their home countries. The analysis combines data on immigrants from the 2008-2012 American Community Survey (ACS) with census data from three major immigrant-sending countries: Mexico, the Dominican Republic, and Vietnam. Despite persistent differences from U.S.-born whites, coresidence in later life is significantly less common than in the sending countries among the older foreign-born who migrated as young adults, and especially among those who migrated as children. The older foreign-born who migrated after age 50, however, are more likely to coreside and less likely to live independently than the older adults in their home countries. The similarity of these patterns across the three immigrant subgroups suggests that the unusually high coresidence among late-life immigrants is driven by U.S. family reunification policy and not simply by cultural influences.

A chimeric alphavirus RNA replicon gene-based vaccine for human parainfluenza virus type 3 induces protective immunity against intranasal virus challenge.

Parainfluenza virus type 3 (PIV3) infections continue to be a significant health risk for infants, young children, and immunocompromised adults. We describe a gene-based vaccine strategy against PIV3 using replication-defective alphavirus vectors. These RNA replicon vectors, delivered as virus-like particles and expressing the PIV3 hemagglutinin-neuraminidase glycoprotein, were shown to be highly immunogenic in mice and hamsters, inducing PIV3-specific neutralizing antibody responses. Importantly, the replicon particle-based vaccine administered intramuscularly or intranasally protected against mucosal PIV3 challenge in hamsters, preventing virus replication in both nasal turbinates and lungs. These data suggest that the alphavirus replicon platform can be useful for a PIV3 vaccine and possibly other respiratory viruses.

An alphavirus replicon particle chimera derived from venezuelan equine encephalitis and sindbis viruses is a potent gene-based vaccine delivery vector.

Alphavirus replicon particle-based vaccine vectors derived from Sindbis virus (SIN), Semliki Forest virus, and Venezuelan equine encephalitis virus (VEE) have been shown to induce robust antigen-specific cellular, humoral, and mucosal immune responses in many animal models of infectious disease and cancer. However, since little is known about the relative potencies among these different vectors, we compared the immunogenicity of replicon particle vectors derived from two very different parental alphaviruses, VEE and SIN, expressing a human immunodeficiency virus type 1 p55(Gag) antigen. Moreover, to explore the potential benefits of combining elements from different alphaviruses, we generated replicon particle chimeras of SIN and VEE. Two distinct strategies were used to produce particles with VEE-p55(gag) replicon RNA packaged within SIN envelope glycoproteins and SIN-p55(gag) replicon RNA within VEE envelope glycoproteins. Each replicon particle configuration induced Gag-specific CD8(+) T-cell responses in murine models when administered alone or after priming with DNA. However, Gag-specific responses varied dramatically, with the strongest responses to this particular antigen correlating with the VEE replicon RNA, irrespective of the source of envelope glycoproteins. Comparing the replicons with respect to heterologous gene expression levels and sensitivity to alpha/beta interferon in cultured cells indicated that each might contribute to potency differences. This work shows that combining desirable elements from VEE and SIN into a replicon particle chimera may be a valuable approach toward the goal of developing vaccine vectors with optimal in vivo potency, ease of production, and safety.