A Less-is-More Strategy for Mitochondria-Targeted Photodynamic Therapy of Rheumatoid Arthritis.

Conventional photodynamic therapy (PDT) of rheumatoid arthritis (RA) faces a dilemma: low-power is insufficient to kill pro-inflammatory cells while high-power exacerbates inflammation. Herein, mitochondrial targeting is introduced in PDT of RA to implement a "less-is-more" strategy, where higher apoptosis in pro-inflammatory cells are achieved with lower laser power. In arthritic rats, chlorine 6-loaded and mitochondria-targeting liposomes (Ce6@M-Lip) passively accumulated in inflamed joints, entered pro-inflammatory macrophages, and actively localized to mitochondria, leading to enhanced mitochondrial dysfunction under laser irradiation. By effectively disrupting mitochondria, pro-inflammatory macrophages are more susceptible to PDT, resulting in increased apoptosis initiation. Additionally, it identifies that high-power irradiation caused cell rupture and release of endogenous danger signals that recruited and activated additional macrophages. In contrast, under low-power irradiation, mitochondria-targeting Ce6@M-Lip not only prevented inflammation but also reduced pro-inflammatory macrophage infiltration and pro-inflammatory cytokine secretion. Overall, targeting mitochondria reconciled therapeutic efficacy and inflammation, thus enabling efficacious yet inflammation-sparing PDT for RA. This highlights the promise of mitochondrial targeting to resolve the dilemma between anti-inflammatory efficacy and inflammatory exacerbation in PDT by implementing a "less-is-more" strategy.

Changing Patterns in Digestive Diseases Mortality in Urban and Rural Areas - China, 1987-2021.

What is already known about this topic?: Digestive diseases (DDs) are a global health concern with a substantial epidemiological and economic impact, given their high prevalence. What is added by this report?: This study investigated the trends in mortality related to DDs in China from 1987 to 2021, focusing on the urban-rural divide. Additionally, it aimed to determine the specific impacts of age, period, and cohort on DDs mortality. What are the implications for public health practice?: There is a need to prioritize and allocate more resources toward the future management of DDs in order to effectively address the challenges posed by urbanization and aging populations.

Choice of cooperation strategy under demand updating and altruistic behavior.

The integration of logistics service supply chains to improve the service quality of has become the choice of many logistics integrator. This paper considers two common cooperation modes, namely, enabling cooperation and merger cooperation. Meanwhile, this paper takes demand updating and integrator's altruistic behavior into account, establishes a Stackelberg game model and draws the following key conclusions. First, this paper determines the conditions of cooperation, when provider's profit distribution ratio is in the middle, the integrator and the provider cooperate successfully and adopt the merger strategy. Second, this paper finds that demand updating affects the scope of cooperation. When demand decreases (increases), the scope of cooperation between suppliers and integrator decreases (increases). Finally, when the demand reduction degree is small, the demand updating benefits the integrator's profit. In this situation, integrator has incentive to share updated demand information to provider.

Biomimetic nanoparticle synchronizing pyroptosis induction and mitophagy inhibition for anti-tumor therapy.

Inducing pyroptosis in cancer cells can result in a strong anti-tumor immune response. Our preliminary study indicates that pyroptosis can be temporarily strengthened by disrupting mitochondria, but ultimately diminished by defensive mitophagy. Here, this study reports a nano-system camouflaged with hybrid membranes consisting of homologous cell membrane and corresponding mitochondrial membrane, which is used to deliver a drug complex Ca@GOx consisting of calcium phosphate and glucose oxidase. By taking advantage of the homing effects of cell membrane and the orientated fusion mechanism of subcellular membrane, the nano-system is able to deliver Ca@GOx to mitochondria, induce mitochondrial Ca2+ overload and generate significant levels of ROS, thus leading to pyroptosis. However, it's found that this system exhibits limited anti-tumor effects in vivo due to the compensatory activation of mitophagy serving as negative feedback to pyroptosis. To address this issue, mitophagy-inhibiting chloroquine is loaded into nanoparticles to intensify pyroptosis. As a result, the combination significantly promotes tumor infiltration of CD8+T cells and improves anti-tumor effects. Together, this study establishes a rational combination of targeted mitochondria disruption and mitophagy blockage for effective pyroptosis-based therapy.

Modulation of Autophagy Direction to Enhance Antitumor Effect of Endoplasmic-Reticulum-Targeted Therapy: Left or Right?

Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER-targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER-related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER-targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial-mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER-targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca2+ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca2+ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER-targeting therapy benefits from the autophagy-enhancing strategy more than the autophagy-inhibiting strategy for antitumor and antimetastasis treatment.

Butyrate Modification Promotes Intestinal Absorption and Hepatic Cancer Cells Targeting of Ferroptosis Inducer Loaded Nanoparticle for Enhanced Hepatocellular Carcinoma Therapy.

Sorafenib is an oral-administered first-line drug for hepatocellular carcinoma (HCC) treatment. However, the therapeutic efficacy of sorafenib is relatively low. Here, an oral delivery platform that increases sorafenib uptake by HCC and induces potent ferroptosis is designed. This platform is butyrate-modified nanoparticles separately encapsulated with sorafenib and salinomycin. The multifunctional ligand butyrate interacts with monocarboxylate transporter 1 (MCT-1) to facilitate transcytosis. Specifically, MCT-1 is differentially expressed on the apical and basolateral sides of the intestine, highly expressed on the surface of HCC cells but lowly expressed on normal hepatocytes. After oral administration, this platform is revealed to boost transepithelial transport effectively and continuously in the intestine, drug accumulation in the liver, and HCC cell uptake. Following drug release in cancer cells, sorafenib depletes glutathione peroxidase 4 and glutathione, consequently initiating ferroptosis. Meanwhile, salinomycin enhances intracellular iron and lipid peroxidation, thereby accelerating ferroptosis. In vivo experiments performed on the orthotopic HCC model demonstrate that this combination strategy induces pronounced ferroptosis damage and ignites a robust systemic immune response, leading to the effective elimination of tumors and establishment of systemic immune memory. This work provides a proof-of-concept demonstration that an oral delivery strategy for ferroptosis inducers may be beneficial for HCC treatment.

Maternal emotional regulation strategy is associated with newborn feeding practices within 72 h after delivery: Cross sectional analyses of a multi-center study in China.

BACKGROUND: Early feeding practices have a great impact on the growth and development of infants, and the health of mothers. Maternal emotional regulation (ER) is closely related to infant feeding practices. Exploring the relationship between ER strategy and feeding practice can inform early exclusive breastfeeding (EBF) interventions. METHODS: Using baseline survey of a longitudinal study, 965 mothers in Chongqing municipality, Guangzhou city, and Huizhou city were enrolled. At baseline, the study used self-administrated questionnaires to investigate the socio-demographic characteristics, maternal ER strategies and feeding practice within 72 h of delivery. Chi-square test and logistic regression were used to determine the associations of the mothers' ER and feeding practices within 72 h postpartum. RESULTS: Among 965 participants, 27.8 % of mothers practiced EBF, and 69.5 % of mothers reported getting breastfeeding education from health providers. The average scores on the cognitive reappraisal and the expressive suppression of the ERQ were 29.95 ± 7.24 and 14.47 ± 5.16 respectively. Multivariable analysis showed women with expressive suppression were less likely to practice EBF (aOR = 0.96, 95%CI: 0.93-0.98, p = 0.002), while receiving breastfeeding education was positively associated with EBF (aOR = 1.52, 95%CI: 1.09-2.12, p = 0.013). LIMITATIONS: Because the study started during the COVID-19 pandemic, the lock-down measures paused recruitments for quite some time reducing the enrollment of participation. The data we used was within 72 h postpartum, hence the period of time to study feeding practices was short. CONCLUSION: Mothers' ER strategy and breastfeeding education need to be addressed as part of interventions designed to improve EBF rates during the newborn period in China.

Changing Patterns in Cancer Mortality from 1987 to 2020 in China.

BACKGROUND: China has the highest number of new cancer cases and deaths worldwide, posing huge health and economic burdens to society and affected families. This study comprehensively analyzed secular trends of national cancer mortality statistics to inform future prevention and intervention programs in China. METHODS: The annual estimate of overall cancer mortality and its major subtypes were derived from the National Health Commission (NHC). Joinpoint analysis was used to detect changes in trends, and we used age-period-cohort modeling to estimate cohort and period effects in Cancers between 1987 and 2020. Net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks were calculated. RESULTS: The age-standardized cancer mortality in urban China has shown a steady downward trend but has not decreased significantly in rural areas. Almost all cancer deaths in urban areas have shown a downward trend, except for colorectal cancer in men. Decreasing mortality from cancers in rural of the stomach, esophagus, liver, leukemia, and nasopharynx was observed, while lung, colorectal cancer female breast, and cervical cancer mortality increased. Birth cohort risks peaked in the cohorts born around 1920-1930 and tended to decline in successive cohorts for most cancers except for leukemia, lung cancer in rural, and breast and cervical cancer in females, whose relative risks were rising in the very recent cohorts. In addition, mortality rates for almost all types of cancer in older Chinese show an upward trend. CONCLUSIONS: Although the age-standardized overall cancer mortality rate has declined, and the urban-rural gap narrowed, the absolute cancer cases kept increasing due to the growing elderly population in China. The rising mortality related to lung, colorectal, female breast, and cervical cancer should receive higher priority in managing cancer burden and calls for targeted public health actions to reverse the trend.

Increasing stiffness promotes pulmonary retention of ligand-directed dexamethasone-loaded nanoparticle for enhanced acute lung inflammation therapy.

Inhaled nanoparticles (NPs) need to penetrate the bronchial mucosa to deliver drug payloads deeply in the lung for amplified local therapy. However, the bronchial mucociliary barrier eliminates NPs rapidly, which considerably limits their mucosal penetration. In this study, we find that surface ligand modification and stiffness adjustment of NPs contribute to the significantly enhanced bronchial mucosal absorption and pulmonary retention of inhaled drugs. We utilize neonatal Fc receptor ligand (FcBP) to modify the rationally designed low stiffness NPs (Soft-NP) and high stiffness NPs (Stiff-NP) to target bronchial mucosa. In an acute lung inflammation rat model, after intranasal administration with dexamethasone-loaded NPs, Stiff-NP endowed with FcBP displays superior therapeutic effects. The in vitro data demonstrate that the promotion effect of FcBP to bronchial mucosal absorption of Stiff-NP dominates over Soft-NP. This could be attributed to the higher affinity between ligand-receptor when incorporating FcBP on the Stiff-NP surface. Meanwhile, high stiffness modulates more actin filaments aggregation to mediate endocytosis, along with strengthened Ca2+ signal to enhance exocytosis. Conclusively, we highlight that FcBP-modified NPs with higher stiffness would be a potential pulmonary drug delivery system.

Cascade Delivery to Golgi Apparatus and On-Site Formation of Subcellular Drug Reservoir for Cancer Metastasis Suppression.

As the foremost cause of cancer-related death, metastasis consists of three steps: invasion, circulation, and colonization. Only targeting one single phase of the metastasis cascade may be insufficient since there are many alternative routes for tumor cells to disseminate. Here, to target the whole cascade of metastasis, hybrid erythrocyte and tumor cell membrane-coated nanoparticle (Hyb-NP) is designed with dual functions of increasing circulation time and recognizing primary, circulating, and colonized tumors. After loading with monensin, a recently reported metastasis inhibitor, the delivery system profoundly reduces spontaneous metastasis in an orthotopic breast cancer model. Underlying mechanism studies reveal that Hyb-NP can deliver monensin to its action site in the Golgi apparatus, and in return, monensin can block the exocytosis of Hyb-NP from the Golgi apparatus, forming a reservoir-like subcellular structure. Notably, the Golgi apparatus reservoir displays three vital functions for suppressing metastasis initialization, including enhanced subcellular drug retention, metastasis-related cytokine release inhibition, and directional migration inhibition. Collectively, based on metastasis cascade targeting at the tissue level, further formation of the Golgi apparatus drug reservoir at the subcellular level provides a potential therapeutic strategy for cancer metastasis suppression.

Application of short-term analysis of skin temperature variability in prediction of survival in patients with cirrhosis.

Background: Liver cirrhosis is a complex disorder, involving several different organ systems and physiological network disruption. Various physiological markers have been developed for survival modelling in patients with cirrhosis. Reduction in heart rate variability and skin temperature variability have been shown to predict mortality in cirrhosis, with the potential to aid clinical prognostication. We have recently reported that short-term skin temperature variability analysis can predict survival independently of the severity of liver failure in cirrhosis. However, in previous reports, 24-h skin temperature recordings were used, which are often not feasible in the context of routine clinical practice. The purpose of this study was to determine the shortest length of time from 24-h proximal temperature recordings that can accurately and independently predict 12-month survival post-recording in patients with cirrhosis. Methods: Forty individuals diagnosed with cirrhosis participated in this study and wireless temperature sensors (iButtons) were used to record patients' proximal skin temperature. From 24-h temperature recordings, different length of recordings (30 min, 1, 2, 3 and 6 h) were extracted sequentially for temperature variability analysis using the Extended Poincaré plot to quantify both short-term (SD1) and long-term (SD2) variability. These patients were then subsequently followed for a period of 12 months, during which data was gathered concerning any cases of mortality. Results: Cirrhosis was associated with significantly decreased proximal skin temperature fluctuations among individuals who did not survive, across all durations of daytime temperature recordings lasting 1 hour or more. Survival analysis showcased 1-h daytime proximal skin temperature time-series to be significant predictors of survival in cirrhosis, whereby SD2, was found to be independent to the Model for End-Stage Liver Disease (MELD) score and thus, the extent of disease severity. As expected, longer durations of time-series were also predictors of mortality for the majority of the temperature variability indices. Conclusion: Crucially, this study suggests that 1-h proximal skin temperature recordings are sufficient in length to accurately predict 12-month survival in patients with cirrhosis, independent from current prognostic indicators used in the clinic such as MELD.

Timing of Breastfeeding Initiation Mediates the Association between Delivery Mode, Source of Breastfeeding Education, and Postpartum Depression Symptoms.

Background: Emergency cesarean section (EMCS) and breastfeeding difficulties increase the risk of postpartum depressive (PPD) symptoms. Early initiation of breastfeeding (EIBF) may not only alleviate PPD symptoms but also facilitate subsequent breastfeeding success. EMCS is a risk factor for not practicing EIBF. Therefore, it is important to understand the relationship between EMCS, EIBF, and PPD symptoms. Methods: We conducted a prospective cohort study in three areas of China. At baseline, a total of 965 mothers completed electronic questionnaires within 72 h postpartum. Women were screened for PPD symptoms using the Edinburgh Postpartum Depression Scale (EPDS). Multivariate logistic regression was used to identify the determinants of PPD symptoms. Mediation analysis was used to determine if EIBF mediated the relationship between delivery mode or breastfeeding education source and PPD symptoms. Results: The prevalence of EIBF was 40.6%; 14% of 965 mothers experienced EMCS, and 20.4% had PPD symptoms. The risk factors for developing PPD symptoms were excessive gestational weight gain (adjusted odds ratio [aOR] = 1.55, confidence interval [95% CI]: 1.03−2.33, p = 0.037) and EMCS (aOR = 2.05, 95% CI: 1.30−3.25, p = 0.002). The protective factors for developing PPD symptoms were monthly household income over CNY 10000 (aOR = 0.68, 95% CI: 0.47−0.97, p = 0.034), EIBF (aOR = 0.49, 95% CI: 0.34−0.72, p < 0.001), and prenatal breastfeeding education from nurses (aOR = 0.46, 95% CI: 0.29−0.73, p = 0.001). EIBF indirectly affected PPD symptoms in patients who had undergone EMCS (percentage mediated [PM] = 16.69, 95% CI: 7.85−25.25, p < 0.001). The source of breastfeeding education through EIBF also affected PPD symptoms (PM = 17.29, 95% CI: 3.80−30.78, p = 0.012). Conclusion: The association between EMCS on PPD symptoms was mediated by EIBF. By providing breastfeeding education, nurses could also help alleviate PPD symptoms.

Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression.

Poor anti-metastasis effects and side-effects remain a challenge for the clinical application of camptothecin (CPT). Mitochondria can be a promising target for the treatment of metastatic tumors due to their vital roles in providing energy supply, upregulating pro-metastatic factors, and controlling cell-death signaling. Thus, selectively delivering CPT to mitochondria appears to be a feasible way of improving the anti-metastasis effect and reducing adverse effects. Here, we established a 2-(dimethylamino) ethyl methacrylate (DEA)-modified N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-CPT conjugate (P-DEA-CPT) to mediate the mitochondrial accumulation of CPT. The mitochondria-targeted P-DEA-CPT could overcome multiple barriers by quickly internalizing into 4T1 cells, then escaping from lysosome, and sufficiently accumulating in mitochondria. Subsequently, P-DEA-CPT greatly damaged mitochondrial function, leading to the reactive oxide species (ROS) elevation, energy depletion, apoptosis amplification, and tumor metastasis suppression. Consequently, P-DEA-CPT successfully inhibited both primary tumor growth and distant metastasis in vivo. Furthermore, our studies revealed that the mechanism underlying the anti-metastasis capacity of P-DEA-CPT was partially via downregulation of various pro-metastatic proteins, such as hypoxia induction factor-1α (HIF-1α), matrix metalloproteinases-2 (MMP-2), and vascular endothelial growth factor (VEGF). This study provided the proof of concept that escorting CPT to mitochondria via a mitochondrial targeting strategy could be a promising approach for anti-metastasis treatment.

Constructing Ni-VN interfaces with superior electrocatalytic activity for alkaline hydrogen evolution reaction.

The promotional effects of inert nitrides for metal catalysts in the electrolysis are rarely reported. Recently, we reported an efficient Ni-VN/NF (that NF represents Ni foam) composite by nitriding treatment of NiV-layered double hydroxides (NiV-LDH) precursor that was in-situ hydrothermal growth on nickel foam. The optimal Ni-VN/NF exhibited outstanding electrocatalytic performance for hydrogen evolution reaction (HER) with a small overpotential of 39 mV at 10 mA cm-2 and strong durability for 100 h without degradation. The optimized electronic structure and local charge density at the hetero-interface of Ni-VN, evidenced by both experiment and DFT results, were significantly modulated by the electron transfer from Ni to V-N bond at the interfaces, leading to moderate H* adsorption energy and diminished barrier for H2O dissociation, synergistically promoted basic HER. This work highlights the design principle of strong metal-nitride interactions for advanced HER catalysts.

Combination of mitochondria impairment and inflammation blockade to combat metastasis.

Targeted induction of mitochondria impairment has emerged as a promising strategy for anti-metastasis therapy. However, problems such as limited mitochondria targeting efficiency, undesired drug leakage and insufficient drug release inside mitochondria remain crucial challenges for mitochondria-targeting therapy. Here, we constructed an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer based cationic system that could target to mitochondria and facilitate on demand drug release in response to excessive mitochondrial reactive oxygen species. Whereas, this drug delivery system is still challenged by limitations of (1) in vivo application, and (2) inflammatory tumor microenvironment (TME). On one aspect, to prolong blood circulation and increase tumor targeting, we designed a nanocomposite (PDT-NCs) that assembled from the cationic HPMA polymer and anionic hyaluronic acid via electrostatic interaction. On another aspect, a celecoxib loaded liposome (Lip-Cel) was further fabricated to alleviate inflammation in TME by downregulating various metastasis-associated factors. Ultimately, PDT-NCs and Lip-Cel led to a drastic improvement in the suppression of primary tumor growth and distant lung metastasis. Our work provided a generalizable approach of mitochondria dysfunction and inflammation blockade to combat metastatic tumors.

A bimodal-pore strategy for synthesis of Pt3Co/C electrocatalyst toward oxygen reduction reaction.

A bimodal-pore strategy was developed for preparation of the Pt3Co/C catalyst with active Pt3Co nanoparticles located around the mass transfer channels rather than inside them, which leads to ca. 29% higher mass transfer efficiency and a superior single-cell performance under an ultralow Pt loading.