IP3R2 regulates apoptosis by Ca2+ transfer through mitochondria-ER contacts in hypoxic photoreceptor injury.

Mitochondria-associated ER membranes (MAMs) are contact sites that enable bidirectional communication between the ER (endoplasmic reticulum) and mitochondria, including the transfer of Ca2+ signals. MAMs are essential for mitochondrial function and cellular energy metabolism. However, unrestrained Ca2+ transfer to the mitochondria can lead to mitochondria-dependent apoptosis. IP3R2 (Inositol 1,4,5-trisphosphate receptor 2) is an important intracellular Ca2+ channel. This study investigated the contribution of IP3R2-MAMs to hypoxia-induced apoptosis in photoreceptor cells. A photoreceptor hypoxia model was established by subretinal injection of hyaluronic acid (1%) in C57BL/6 mice and 1% O2 treatment in 661W cells. Transmission electron microscopy (TEM), ER-mitochondria colocalization, and the MAM reporter were utilized to evaluate MAM alterations. Cell apoptosis and mitochondrial homeostasis were evaluated using immunofluorescence (IF), flow cytometry, western blotting (WB), and ATP assays. SiRNA transfection was employed to silence IP3R2 in 661W cells. Upon hypoxia induction, MAMs were significantly increased in photoreceptors both in vivo and in vitro. This was accompanied by the activation of mitochondrial apoptosis and disruption of mitochondrial homeostasis. Elevated MAM-enriched IP3R2 protein levels induced by hypoxic injury led to mitochondrial calcium overload and subsequent photoreceptor apoptosis. Notably, IP3R2 knockdown not only improved mitochondrial morphology but also restored mitochondrial function in photoreceptors by limiting MAM formation and thereby attenuating mitochondrial calcium overload under hypoxia. Our results suggest that IP3R2-MAM-mediated mitochondrial calcium overload plays a critical role in mitochondrial dyshomeostasis, ultimately contributing to photoreceptor cell death. Targeting MAM constitutive proteins might provide an option for a therapeutic approach to mitigate photoreceptor death in retinal detachment.

Lessons learned from a multi-data source research collaboration: The mirabegron post-authorization safety study program.

BACKGROUND: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies. OBJECTIVES: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder. RESULTS: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results. CONCLUSIONS: This large PMR/PASS program was a long-term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi-data source NI-PASS.

Palliation of malignant esophageal stent esophagorespiratory fistula with rigid bronchoscope and Y silicone trachea stent: experience with seven patients.

Background: Malignant esophageal stent esophagorespiratory fistula (ERF) is an abnormal communication between esophagus and airway among advanced tumor patients with indwelling esophageal stent, which is devastating and life-threatening. This study aims to provide a new feasible treatment scheme for malignant esophageal stent ERF and report its potential advantage compared with double stenting, which was recommended by European Society of Gastrointestinal Endoscopy Guideline. Methods: We retrospectively analyzed the medical data of malignant esophageal stent ERF patients between January 2018 to May 2023 at the First Affiliated Hospital of Guangzhou Medical University and divided them into two groups. Group 1 consisted of patients treated with rigid bronchoscopy to remove the esophageal stent and implant Y silicone trachea stent, while group 2 consisted of patients treated with additional airway stenting without removing the esophageal stent. Demographic parameters, disease diagnoses and treatment, radiological findings before and after the intervention, and complications caused by the stents were obtained and analyzed with chi-squared, Mann-Whitney U, independent-samples t-tests, Kaplan-Meier methods, and log-rank test. Results: Ten patients (seven patients in group 1 and three in group 2) were included. No procedure complications occurred in both groups. The mean Karnofsky Performance Score after the procedure significantly improved compared to the pre-procedure (57.14 vs. 77.14, P=0.001) in group 1, while decreased in group 2 (50 vs. 40, P=0.026). The control of pneumonia in group 1 patients is better than that in group 2. There was significant improvement in the degree of dysphagia after the procedure (3.86 vs. 2.43, P=0.002) in group 1, while no improvement was found in group 2 (4.00 vs. 3.33, P=0.423). The mean survival of group 1 was significantly longer group 2 (381.00 vs. 80.33 days, P<0.001, log-rank test). No patient needed stent repositioning due to migration in both groups. Cause of death in the group 1 included disease progression, novel coronavirus pneumonia, massive hemoptysis, and respiratory insufficiency, while group 2 included severe pneumonia and disease progression. No death was directly attributed to the procedure in both groups. Conclusions: Removing the esophageal stent and implanting Y silicone trachea stent through a rigid bronchoscopy is a safe and feasible treatment for malignant esophageal stent ERF. This procedure can effectively seal the fistula, prevent from recurrent aspiration pneumonia, improve the quality of life, and prolong the survival time.

Jiawei guomin decoction regulates the degranulation of mast cells in atopic dermatitis mice via the HIS/PAR-2 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Guomin decoction (GMD) is a traditional Chinese medicine commonly used in clinical practice. It has traditionally been used to treat all allergic diseases. Currently, Jiawei Guomin Decoction (JWGMD) is used to treat sensitive skin after initial therapy. Although it has a significant clinical therapeutic effect, the exact role of mast cell degranulation in treating atopic dermatitis (AD) is still unclear. AIM OF THE STUDY: GMD and JWGMD can both treat allergic diseases, while JWGMD focuses on skin allergies. This study aims to explore the potential effect of JWGMD on the degranulation of mast cells in an AD mouse model induced by 2,4-dinitrofluorobenzene (DNFB) and investigate the effectiveness of JWGMD in alleviating disease progression to further provide specific therapeutic targets for treating AD. MATERIALS AND METHODS: The scratching times and skin lesions of model mice induced by DNFB were observed, and skin tissues were collected for subsequent measurement. Histopathological changes in the back skin of mice were observed by haematoxylin eosin (H&E) staining, Toluidine blue staining was used to detect the degranulation of mouse skin mast cells, and the relationship between the expression of histamine (HIS), mast cell tryptase (MCT) and mast cell degranulation was analysed by enzyme-linked immunosorbent assay (ELISA). The expression of protease-activated receptor-2 (PAR-2), histamine 1 receptor (H1R), H2R, H4R and MCT proteins in AD mice was detected by Western blot (WB). Immunofluorescence assay (IFA) further confirmed the localization of PAR-2, H1R, H2R, H4R, and MCT proteins in the skin. Quantitative real-time PCR (qPCR) was used to determine PAR-2, H1R, H2R and H4R mRNA levels in skin lesions to further clarify the mechanism by which JWGMD amplifies mast cell degranulation in AD. In addition, a reliable ultrahigh-performance liquid chromatography-quadrupole electrostatic field orbitrap mass spectrometry (UPLC-QE-MS) nontargeted metabolomics analysis was performed to analyse the differences in metabolite abundance between GMD and JWGMD, and these results were used to identify the active components in JWGMD that may have antipruritic and anti-inflammatory properties and inhibit mast cell degranulation. RESULTS: After intermittent stimulation with DNFB, the skin lesions showed extensive desquamation, dryness, scabbing, skin thickening, and slight bleeding. Both treatments alleviated this phenomenon and reduced the number of scratches, with JWGMD being the most effective. JWGMD can significantly reduce inflammatory cell infiltration, oedema, and some capillary neogenesis in mice and reduce the degranulation of mast cells. The ELISA results showed that JWGMD can increase the levels of MCT and HIS proteins. The WB and IFA results demonstrated that JWGMD reduced the expression levels of PAR-2, H1R, H4R, and MCT proteins in skin lesions, with protein localization mainly in the epidermal layer, while H2R protein levels were increased and mainly localized in the dermis. In addition, JWGMD downregulates the mRNA expression of PAR-2, H1R, H2R, and H4R. Interestingly, through UPLC-QE-MS nontargeted metabolomic analysis, we detected the anti-inflammatory and antiallergy active substances in JWGMD, such as methyl eugenol, dictamnine and sinapine. CONCLUSIONS: JWGMD may alleviate itching through methyl syringol, dictamnine, sinapine and other substances, and its mechanism may be related to inhibiting the HIS/PAR-2 pathway in AD model mice and further regulating the self-amplification of mast cell degranulation. JWGMD is a potential drug for treating AD. Therefore, it deserves continuous attention and research.

Anticholinergic exposure and its association with dementia/Alzheimer's disease and mortality in older adults.

BACKGROUND: Use of anticholinergic (ACH) medications is associated with increased risk of cognitive decline in the elderly. However, little is known about this association from a health plan perspective. METHODS: This retrospective cohort study used the Humana Research Database to identify individuals with at least one ACH medication dispensed in 2015. Patients were followed until incidence of dementia/Alzheimer's disease, death, disenrollment or end of December 2019. Multivariate Cox regression models were used to assess the association between ACH exposure and study outcomes, adjusting for demographics and clinical characteristics. RESULTS: A total of 12,209 individuals with no prior ACH use or dementia/Alzheimer's disease diagnosis were included. As ACH polypharmacy increased (i.e., from no ACH exposure, to one, two, three, and four or more ACH medications), there was a stair-step increase in the incidence rate of dementia/Alzheimer's disease (15, 30, 46, 56 and 77 per 1,000 person-years of follow-up) and in the incidence of mortality (19, 37, 80, 115 and 159 per 1,000 person-years of follow-up). After adjusting for confounders, ACH exposure to one, two, three and four or more ACH medications was associated with a 1.6 (95% CI 1.4-1.9), 2.1 (95% CI 1.7-2.8), 2.6 (95% CI 1.5-4.4), and 2.6 (95% CI 1.1-6.3) times, respectively, increased risk of a dementia/Alzheimer's disease diagnosis compared to periods of no ACH exposure. ACH exposure to one, two, three and four or more medications was associated with a 1.4 (95% CI 1.2-1.6), 2.6 (95% CI 2.1-3.3), 3.8 (95% CI 2.6-5.4), and 3.4 (95% CI 1.8-6.4) times, respectively, increased risk of mortality compared to periods of no ACH exposure. CONCLUSIONS: Reducing ACH exposure may potentially minimize long-term adverse effects in older adults. Results suggest populations which may benefit from targeted interventions to reduce ACH polypharmacy.

Health literacy interventions among patients with chronic diseases: A meta-analysis of randomized controlled trials.

OBJECTIVES: This study was conducted to determine the effectiveness and impact of health literacy interventions for patients with chronic diseases. METHODS: We searched PubMed, Web of Science, Embase, Scopus, and EBSCO CINAHL from inception through March 2022. Eligible chronic diseases include diabetes, heart disease, cancer, and chronic obstructive pulmonary disease. RCTs were included in eligible studies to assess health literacy and other relevant health outcomes. Two investigators selected studies, extracted data, and assessed the methodological quality of included studies independently. RESULTS: A total of 18 studies involving 5384 participants were included in the final analysis. The implementation of health literacy interventions exhibited a significant improvement in the health literacy level of individuals diagnosed with chronic diseases (SMD = 0.75, 95% CI = 0.40-1.10). Analysis of heterogeneity sources indicated statistically significant variations in the effects of interventions across different diseases and age groups (P < 0.05). However, no significant impact was observed on patients with chronic obstructive pulmonary disease (COPD), interventions with a follow-up duration exceeding three months, or application-based interventions on the health literacy level of individuals with chronic diseases. Remarkably, our findings revealed that health literacy interventions exerted a positive influence on health status (SMD = 0.74, 95% CI = 0.13-1.34), depression and anxiety (SMD = 0.90, 95% CI = 0.17-1.63), as well as self-efficacy (SMD = 0.28, 95% CI = 0.15-0.41) among patients diagnosed with chronic diseases. Furthermore, a specific analysis was conducted to evaluate the effects of these interventions on hypertension and diabetes control. The results demonstrated that health literacy interventions were more effective in enhancing hypertension control compared to diabetes control. CONCLUSION: Health literacy interventions have demonstrated effectiveness in improving the health of patients with chronic diseases. The importance of emphasizing the quality of these interventions cannot be overstated, as factors such as appropriate intervention tools, extended intervention duration, and reliable primary care services play crucial roles in their efficacy.

Mechanical Properties and Microstructure of Rice Husk Ash-Rubber-Fiber Concrete under Hygrothermal Environment.

In order to study the mechanical properties of rice husk ash-rubber-fiber concrete (RRFC) under hygrothermal environment, the optimal group was selected by orthogonal test. The mass loss, relative dynamic elastic modulus analysis, strength analysis, degradation degree analysis after cyclic loading and internal microstructure analysis of the optimal group of RRFC samples after dry-wet cycles under different environments and temperatures were compared and analyzed. The results show that the large specific surface area of rice husk ash optimizes the particle size distribution of RRFC specimens, reacts to form C-S-H gel, enhances the compactness of concrete, and forms a dense structure as a whole. The presence of rubber particles and PVA fibers effectively improves the mechanical properties and fatigue resistance of RRFC. The comprehensive mechanical properties of RRFC with rubber particle size of 1-3 mm, PVA fiber content of 1.2 kg·m-3 and rice husk ash content of 15% are the best. The compressive strength of the specimens after dry-wet cycles in different environments generally increased first and then decreased, reaching a peak at the seventh dry-wet cycle, and the compressive strength of the specimens under chloride salt solution decreased more than that under clear water solution. Thes provided new concrete materials for the construction of highways and tunnels in coastal areas. Under the premise of ensuring the strength and durability of concrete, it is of great practical significance to explore new roads for energy conservation and emission reduction.

Heart Failure Among Patients with Multiple Myeloma Treated with Carfilzomib-Based Versus Non-Carfilzomib-Based Regimens in the United States by Race.

BACKGROUND: Carfilzomib treatment for multiple myeloma (MM) can increase heart failure risk. Whether this risk differs by race is unknown. PATIENTS AND METHODS: We sought to estimate the incidence rates (IRs) of heart failure hospitalization among mostly 65-years-and-older US patients with MM by race treated with carfilzomib- and non-carfilzomib-based regimens in the real-world using Centers for Medicare & Medicaid Services Medicare Fee-for-Service data, Optum Clinformatics Data Mart, and Humana Research Database. The risk of heart failure hospitalization associated with a carfilzomib-based regimen was evaluated using propensity score matching among Black and White patients receiving second or later lines of therapy. RESULTS: Most patient-episodes (88%) were in persons 65 years or older for the 3 cohorts combined. The IR (95% CI) of heart failure hospitalization was higher for patient-episodes treated with a carfilzomib-based regimen than those with a non-carfilzomib-based regimen for both White (14.5 [12.2-17.0] vs. 10.7 [10.3-11.2] events per person-years) and Black patients (15.8 [10.1-23.5] vs. 12.1 [10.9-13.4] events per person-years) in the Medicare cohort. After propensity score matching, the hazard ratio (95% CI) of increased heart failure hospitalization comparing carfilzomib-based to non-carfilzomib-based regimens for White patients (1.6 [1.3-2.0]) was similar to that of Black patients (1.7 [1.0-2.9]) in the Medicare Database, and in the Humana Database (1.4 [0.8-2.6] and 1.2 [0.4-3.5], respectively). CONCLUSION: Although the IR of heart failure among patients with MM treated with a carfilzomib-based regimen was slightly higher, no evidence suggested the relative risk was different between White and Black patients with MM.

The engineering and application of extracellular matrix hydrogels: a review.

This review provides an overview of the engineering and application of extracellular matrix (ECM) hydrogels. ECM hydrogels are attractive materials for tissue engineering and regenerative medicine due to their unique ability to mimic the natural ECM of various tissues. The review discusses the different methods used for the preparation of ECM hydrogels and the factors that influence their properties. This review is the summary of three engineering approaches for ECM hydrogels, which are chemical modification of the gel scaffold (chemical modification), addition of active substances to the scaffold (physical addition), and gene editing of the ECM donor (biological modification). Additionally, it covers the various applications of ECM hydrogels in tissue restoration, organoid culturing, and 3D microenvironment reconstruction. The review concludes with a discussion of the advantages, limitations, and future directions of ECM hydrogel research and development. Overall, this review highlights the potential of ECM hydrogels as a promising biomaterial for a range of biomedical applications and provides fresh perspectives for ECM hydrogels to continue their clinical development.

Using Wool Keratin as a Structural Biomaterial and Natural Mediator to Fabricate Biocompatible and Robust Bioelectronic Platforms.

The design and fabrication of biopolymer-incorporated flexible electronics have attracted immense interest in healthcare systems, degradable implants, and electronic skin. However, the application of these soft bioelectronic devices is often hampered by their intrinsic drawbacks, such as poor stability, inferior scalability, and unsatisfactory durability. Herein, for the first time, using wool keratin (WK) as a structural biomaterial and natural mediator to fabricate soft bioelectronics is presented. Both theoretical and experimental studies reveal that the unique features of WK can endow carbon nanotubes (CNTs) with excellent water dispersibility, stability, and biocompatibility. Therefore, well-dispersed and electroconductive bio-inks can be prepared via a straightforward mixing process of WK and CNTs. The as-obtained WK/CNTs inks can be directly exploited to design versatile and high-performance bioelectronics, such as flexible circuits and electrocardiogram electrodes. More impressively, WK can also be a natural mediator to connect CNTs and polyacrylamide chains to fabricate a strain sensor with enhanced mechanical and electrical properties. With conformable and soft architectures, these WK-derived sensing units can be further assembled into an integrated glove for real-time gesture recognition and dexterous robot manipulations, suggesting the great potential of the WK/CNT composites for wearable artificial intelligence.

PROTAC Degraders of Androgen Receptor-Integrated Dissolving Microneedles for Androgenetic Alopecia and Recrudescence Treatment via Single Topical Administration.

Androgenetic alopecia (AGA) is a transracial and cross-gender disease worldwide with a youth-oriented tendency, but it lacks effective treatment. The binding of androgen receptor (AR) and androgen plays an essential role in the occurrence and progression of AGA. Herein, novel proteolysis targeting chimera degrader of AR (AR-PROTAC) is synthesized and integrated with dissolving microneedles (PROTAC-MNs) to achieve AR destruction in hair follicles for AGA treatment. The PROTAC-MNs possess adequate mechanical capabilities for precise AR-PROTAC delivery into the hair follicle-residing regions for AR degradation. After applying only once topically, the PROTAC-MNs achieve an accelerated onset of hair regeneration as compared to the daily application of the first-line topical drug minoxidil. Intriguingly, PROTAC-MNs via single administration still realize superior hair regeneration in AGA recrudescence, which is the major drawback of minoxidil in clinical practice. With the degradation of AR, the PROTAC-MNs successfully regulate the signaling cascade related to hair growth and activate hair follicle stem cells. Furthermore, the PROTAC-MNs do not cause systemic toxicity or androgen deficiency-related chaos in vivo. Collectively, these AR-degrading dissolving microneedles with long-lasting efficacy, one-step administration, and high biocompatibility provide a great therapeutic potential for AGA treatment.

Alternate-Day High Fat-Normal Chow Diet Ameliorates HFD-Induced Obesity and Restores Intestinal Immunity.

Purpose: To investigate the effect of alternating-day diet regimens on high-fat diet-induced metabolic disorders in mice. Materials and Methods: Eight-week-old C57BL/6J mice were fed with either a continuous normal chow diet (CD, n = 10), a continuous high-fat diet (HFD, n = 10), HFD alternating every 24 h with fasting (H-ADF, n = 20), or HFD alternating every 24 h with chow diet (H-ADC, n = 20) for 12 weeks. Weights were recorded weekly and oral glucose tolerance tests were performed 6 weeks after initiating the regimens. At the end of the study, blood samples were collected and serum insulin and lipids were measured; tissues were collected for histology and RNA-seq analysis. Results: HFD significantly increased body weight and fat percentage, while HFD alternating with fasting or CD did not significantly affect body weight and fat percentage. The glucose intolerance induced by HFD was also significantly ameliorated in these two diet intervention groups. HFD-induced elevation of total cholesterol, low-density lipoprotein and insulin were also reduced in H-ADF and H-ADC groups. Moreover, HFD-disturbed immunity, presented by Lysozyme C-1 (Lyz1) immunostaining and RNA-seq, was restored in both alternating-regimen groups, especially, with H-ADC. At the transcriptional level, some cell proliferation and lipid absorption pathways were down-regulated in both H-ADF and H-ADC groups compared to the continuous HFD group. Conclusion: Alternating an HFD with a normal diet every 24 h effectively controls weight and prevents metabolic disorders and may act by affecting both fat absorption and intestinal immunity.

Genipin improves lipid metabolism and sperm parametersin obese mice via regulation of miR-132 expression.

Obesity has now surpassed malnutrition and infectious diseases as the most significant contributor to health problems worldwide. In particular, obesity is associated with several metabolic disorders, including hyperlipidemia, hepatic steatosis, and subfertility. Genipin (GNP), the aglycone of geniposide, is isolated from the extract of the traditional Chinese medicine Gardenia jasminoides Ellis and has been used in traditional oriental medicine against several inflammation-driven diseases. However, the effect and molecular mechanism of GNP on obesity-associated dyslipidemia and sperm dysfunction still need to be explored. In this study, we detect the effects of GNP on hyperlipidemia, hepatic lipid accumulation and sperm function using a high-fat diet (HFD)-induced obese mouse model. We find that obese mice treated with GNP show an improvement in body weight, serum triglyceride levels, serum hormone levels, serum inflammatory cytokines, hepatic steatosis and sperm function. At the molecular level, HFD/GNP diversely regulates the expression of miR-132 in a tissue-specific manner. miR-132 further targets and regulates the expression of SREBP-1c in liver cells, as well as the expressions of SREBP-1c and StAR in Leydig cells in the testis, thus modifying lipogenesis and steroidogenesis, respectively. Collectively, our data demonstrate that GNP shows a broad effect on the improvement of HFD-induced metabolic disorder and sperm dysfunction in male mice by tissue-specific regulation of miR-132. Our findings reveal the function GNP in ameliorating hepatic lipid metabolism and sperm function and suggest that this compound is a versatile drug to treat metabolic disorders.

A latent profile analysis of residents' knowledge, attitude, and practice toward common chronic diseases among ethnic minority area in China.

Background: Health literacy plays an important role in preventing and managing chronic diseases, while low levels of health literacy among ethnic minorities are a major manifestation of health inequities. We believe that before effective health literacy intervention strategies, it is preferable to understand the features of health literacy among ethnic minorities. The present study firstly updated insights on health literacy among ethnic minorities by investigating the knowledge, attitude, and practice (KAP) profile of common chronic diseases in ethnic minority areas, and secondly discussed the KAP profiles in detail to inspire future health education interventions. Methods: A cross-sectional, health-literacy-sensitive study was conducted in China's typical ethnic minority area. Participants included 801 adult residents who lived in the ethnic minority area. The primary outcome was participant scores on the KAP questionnaire of common chronic diseases, followed by latent profile analysis to identify participants with similar KAP score patterns and determine whether membership in specific groups was associated with demographic or clinical characteristics. Results: The participants included 496 ethnic minorities (61.9%) and 305 Han Chinese (38.1%). Three-profile solution was determined after the latent profile analysis: incomplete transfer [I.T.] (n = 215), better practice [B.P.] (n = 301), and average [A.V.] (n = 285). IT group (26.84%) was characterized by the highest level of knowledge and attitude toward common chronic diseases and below average level for practice. Participants in B.P. group performed poorly in both knowledge and attitude toward common chronic diseases but had the highest level of practice. A.V. group reflected average knowledge, attitude, and practice toward common chronic diseases among three subgroups. Ethnic minorities were the dominant population in A.V. group (68.8%). Compared with other groups, the A.V. group contained the largest proportions of married participants (84.2%), participants with no formal education (46.7%), and high annual out-of-pocket medical expense (33.3%). Conclusion: A more specific and nuanced understanding of minority health literacy can enable service providers to provide more effective health education to their recipients, thereby improving health inequities.

Size-dependent melting of onion-like fullerenic carbons: a molecular dynamics and machine learning study.

The melting thermodynamic characteristics of 2- to 20-layered onion-like fullerenes (OLFn) (C60@C240to C60@···@C6000···@C24000) are comprehensively explored using first-principles-based ReaxFF atomistic simulations and random forest machine learning (RF ML). It is revealed that OLFnshows lower thermal stability than the counterparts of single-walled fullerenes (SWFn). The melting point of SWFnincreases monotonically with increasing size, whereas for OLFn, an unusual size-dependent melting point is observed; OLFnwith intermediate size shows the highest melting point. For small OLFn, the melting occurs from the inner to the outer, whereas for large OLFn, it nucleates from the inner to the outer and to intermediate fullerenes. The melting and erosion behaviors of both SWFnand OLFnare mainly characterized by the nucleation of non-hexagons, nanovoids, carbon chains and emission of C2. RF ML model is developed to predict the melting points of both SWFnand OLFn. Moreover, the analysis of the feature importance reveals that the Stone-Wales transformation is a critical pathway in the melting of SWFnand OLFn. This study provides new insights and perspectives into the thermodynamics and pyrolysis chemistry of fullerenic carbons, and also may shed some lights onto the understanding of thermally-induced erosion of carbon-based resources and spacecraft materials.

Conditioned media-integrated microneedles for hair regeneration through perifollicular angiogenesis.

Androgenetic alopecia (AGA), the most prevalent type of hair loss in clinic, is induced partly by insufficient perifollicular vascularization. Here we designed a dissolvable microneedles (MNs) patch that was loaded with conditioned media (CM) derived from hypoxia-pretreated mesenchymal stem cells, which contained elevated HIF-1α. The CM-integrated MNs patch (designated as CM-MNs) can puncture the stratum corneum and deliver the pro-angiogenic factors directly into skin in a one-step and minimally invasive manner. Meanwhile, the administration of CM-MNs induced a certain mechanical stimulation on the skin, which can also promote neovascularization. With the combined effects of the pro-angiogenic factors in CM and the mechanical stimulation induced by MNs, CM-MNs successfully boosted perifollicular vascularization, and activated hair follicle stem cells, thereby inducing notably faster hair regeneration at a lower administration frequency on AGA mouse model compared with minoxidil. Furthermore, we proved that the inhibition of perifollicular angiogenesis restrained the awakening of hair follicle stem cells, elucidating the tight correlation between perifollicular angiogenesis and the activation of hair follicle stem cells. The innovative integration of CM and MNs holds great promise for clinical AGA treatment and indicates that boosting angiogenesis around hair follicles is an effective strategy against AGA.

Modified Shenlingbaizhu Decoction represses the pluripotency of colorectal cancer stem cells by inhibiting TGF-ß mediated EMT program.

BACKGROUND: The Modified Shenlingbaizhu Decoction (MSD) utilizes various phytomedicines has been applied to treat colorectal cancer (CRC). Colorectal cancer stem cells (CSCs) have proven to be tightly associated with CRC progression and metastasis. The mechanism of MSD's inhibitory effect on CSCs has not been determined. PURPOSE: To figure out how MSD inhibits the pluripotency of CSCs and impedes the EMT program. METHODS: The ingredients of MSD extracts were characterized by high-performance liquid chromatography (HPLC). BALB/c-nu mice were transplanted into EGFP labeled SW480 CRC cells and the tumor weight and volume were recorded before and after various doses of MSD treatment. The concentration of TGF-ß1 was quantified with an Enzyme-linked immunosorbent assay. To delineate the logical relationship between EMT and CSCs regulated by MSD, TGF-ß/Smad inhibitor and activator were adopted in tumor-bearing mice and diverse CRC cell lines. Cancer stem cell markers were analyzed by flow cytometry. In vitro analysis of cell motility and viability were done using CCK-8, wound healing, and invasion assay. Immunohistochemistry (IHC) and western blotting (WB) were used for detecting protein expression. The collected results were statistically analyzed with GraphPad Prism 8.0. RESULTS: MSD treatment significantly reduced the size of colorectal cancer tumors and lowered the serum content of TGF-ß1 in mice. Importantly, MSD markedly reduced the expression of pluripotent factors and depressed CD133+ stem cells in the tumor tissues. The TGF-ß/Smad inhibitor neutralized the EMT signaling and lowered the pluripotency by dephosphorylation of SMAD2/3. Similarly, MSD attenuated the pluripotency by limiting TGF-ß/Smad signaling-induced EMT in vivo. MSD inhibited colorectal cancer cell proliferation, migration, and invasion. CONCLUSIONS: MSD inhibits the growth of colorectal cancer. It dampens the pluripotency of CSCs by repressing the TGF-ß-induced EMT program.

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment.

The PI3K-Akt-mTOR pathway is a viable target for cancer treatment and can be used to treat various malignant tumours, including follicular lymphoma and breast cancer. Both enzymes, PI3K and mTOR, are critical in this pathway. Hence, in recent years, an array of inhibitors targeting these two targets have been studied, showing dual PI3K/mTOR inhibition compared with single targeting small molecule inhibitors. Inhibitors not only inhibit cell proliferation but also promote cell apoptosis. These inhibitors show high potency and little drug resistance even at low doses, suggesting that PI3K/mTOR inhibitors are promising cancer drugs. Herein, we summarised the recent research of PI3K/mTOR dual inhibitors-for example, structure-activity relationship, pharmacokinetics, and clinical practice, and briefly commented on them. Clinical Trial Registration: https://clinicaltrials.gov.

Recent progress on FAK inhibitors with dual targeting capabilities for cancer treatment.

Focal adhesion kinase (FAK, also known as PTK2) is a tyrosine kinase that regulates integrin and growth factor signaling pathways and is involved in the migration, proliferation and survival of cancer cells. FAK is a promising target for cancer treatment. Many small molecule FAK inhibitors have been identified and proven in both preclinical and clinical studies to be effective inhibitors of tumor growth and metastasis. There are many signaling pathways, such as those involving FAK, Src, AKT, MAPK, PI3K, and EGFR/HER-2, that provide survival signals in cancer cells. Dual inhibitors that simultaneously block FAK and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, the antitumor mechanisms and research status of dual inhibitors of FAK and other targets, such as Pyk2, IGF-IR, ALK, VEGFR-3, JAK2, EGFR, S6K1, and HDAC2, are summarized, providing new ideas for the development of effective FAK dual-target preparations.