Structural studies of WDR5 in complex with MBD3C WIN motif reveal a unique binding mode.

The nucleosome remodeling and deacetylase (NuRD) complex plays a pivotal role in chromatin regulation and transcriptional repression. In mice, methyl-CpG binding domain 3 isoform C (MBD3C) interacts specifically with the histone H3 binding protein WD repeat-containing protein 5 (WDR5) and forms the WDR5-MBD3C/NuRD complex. Despite the functional significance of this interaction on embryonic stem cells gene regulation, the molecular mechanism underlying MBD3C recognition by WDR5 remains elusive. Here, we determined the crystal structure of WDR5 in complex with the peptide (residues 40-51) derived from the MBD3C protein at a resolution of 1.9 Å. Structural analysis revealed that MBD3C utilizes a unique binding mode to interact with WDR5, wherein MBD3C Arg43 and Phe47 are involved in recognizing the WDR5-interacting (WIN) site and Tyr191-related B site on the small surface of WDR5, respectively. Notably, the binding induces a ∼91° rotation of WDR5 Tyr191, generating the hydrophobic B site. Furthermore, mutation experiments combined with isothermal titration calorimetry (ITC) assays confirmed the importance of both Arg43 and Phe47 in mediating WDR5 binding affinity. By determining structures of various peptides bound to WDR5, we demonstrated that the WDR5 WIN site and B site can be concurrently recognized by WIN motif peptides containing ''Arg-Cys/Ser-Arg-Val-Phe'' consensus sequence. Overall, this study reveals the structural basis for the formation of the WDR5-MBD3C subcomplex and provides new insights into the recognition mode of WDR5 for the WIN motif. Moreover, these findings shed light on structural-based designs of WDR5-targeted anti-cancer small molecule inhibitors or peptide-mimic drugs.

Efficacy and safety of Ferrous iron on the prevention of Vascular cOgnitive impaiRment among patients with cerebral Infarction/TIA (FAVORITE): rationale and design of a multicentre randomised trial.

BACKGROUND: The incidence of vascular cognitive impairment (VCI) is high in patients suffering from ischaemic stroke or transient ischaemic attack (TIA) or with vascular risk factors. Effective prevention strategies for VCI remain limited. Anaemia or low haemoglobin was found as an independent risk factor for adverse outcomes after acute stroke. Anaemia or low haemoglobin was possibly associated with an increased risk of poststroke cognitive impairment. Whether supplement of ferrous iron to correct anaemia reduces the risk of VCI and improves adverse outcomes in patients with ischaemic cerebrovascular disease remains uncertain. AIM: We aim to introduce the design and rationale of the safety and efficacy of Ferrous iron on the prevention of Vascular cOgnitive impaiRment in patients with cerebral Infarction or TIA (FAVORITE) trial. DESIGN: FAVORITE is a randomised, placebo-controlled, double-blind, multicentre trial that compares supplement of ferrous iron with placebo for recent minor stroke/TIA patients complicated with mild anaemia or iron deficiency: Ferrous succinate sustained-release tablet 0.2 g (corresponding to 70 mg of elemental iron) once daily after or during breakfast for 12 weeks or placebo with much the same colour, smell and size as ferrous iron once daily during or after breakfast for 12 weeks. All paticipants will be followed within the next year. STUDY OUTCOMES: The primary effective outcome is the incidence of VCI at 3 months after randomisation and the primary safety outcome includes any gastrointestinal adverse event during 3 months. DISCUSSION: The FAVORITE trial will clarify whether supplement of ferrous iron to correct low haemoglobin reduces the risk of VCI in patients with recent ischaemic stroke or TIA complicated with mild anaemia or iron deficiency compared with placebo. TRIAL REGISTRATION NUMBER: NCT03891277.

Differential risk factor profile and neuroimaging markers of small vessel disease between lacunar ischemic stroke and deep intracerebral hemorrhage.

Background: Lacunar ischemic stroke (LIS) and deep intracerebral hemorrhage (dICH) are two stroke phenotypes of deep perforator arteriopathy. It is unclear what factors predispose individuals with deep perforator arteriopathy to either ischemic or hemorrhagic events. Objectives: We aimed to investigate risk factors and neuroimaging features of small vessel disease (SVD) associated with LIS versus dICH in a cross-sectional study. Methods: We included patients with clinically presenting, magnetic resonance imaging-confirmed LIS or dICH from two tertiary hospitals between 2010 and 2021. We recorded vascular risk factors and SVD markers, including lacunes, white matter hyperintensities (WMH), perivascular spaces (PVS), and cerebral microbleeds (CMB). Logistic regression modeling was used to determine the association between vascular risk factors, SVD markers, and stroke phenotype. We further created WMH probability maps to compare WMH distribution between LIS and dICH. Results: A total of 834 patients with LIS (mean age 61.7 ± 12.1 years) and 405 with dICH (57.7 ± 13.2 years) were included. Hypertension was equally frequent between LIS and dICH (72.3% versus 74.8%, p = 0.349). Diabetes mellitus, hyperlipidemia, smoking, and prior ischemic stroke were more associated with LIS [odds ratio (OR) (95% confidence interval (CI)), 0.35 (0.25-0.48), 0.32 (0.22-0.44), 0.31 (0.22-0.44), and 0.38 (0.18-0.75)]. Alcohol intake and prior ICH were more associated with dICH [OR (95% CI), 2.34 (1.68-3.28), 2.53 (1.31-4.92)]. Lacunes were more prevalent in LIS [OR (95% CI) 0.23 (0.11-0.43)], while moderate-to-severe basal-ganglia PVS and CMB were more prevalent in dICH [OR (95% CI) 2.63 (1.35-5.27), 4.95 (2.71-9.42)]. WMH burden and spatial distribution did not differ between groups. Conclusion: The microangiopathy underlying LIS and dICH reflects distinct risk profiles and SVD features, hence possibly SVD subtype susceptibility. Prospective studies with careful phenotyping and genetics are needed to clarify the mechanisms underlying this difference.

Microneedle Delivery Platform Integrated with Codelivery Nanoliposomes for Effective and Safe Androgenetic Alopecia Treatment.

Although topical application of minoxidil is a widely used, FDA-approved therapy for androgenetic alopecia (AGA) treatment, it suffers from low bioavailability, the requirement for frequent long-term use, and side effects. With a similar structure as minoxidil, kopexil and kopyrrol are less toxic and have been commercialized, but show an inferior hair regeneration effect compared to minoxidil. Herein, we developed a hyaluronic acid (HA)-based dissolvable microneedles (MNs) delivery platform integrated with kopexil and kopyrrol coencapsulated nanoliposomes (KK-NLPs) to effectively and safely treat AGA. Facilitated by nanoliposomes and MNs, the encapsulated KK-NLPs performed efficient skin penetration and enhanced cellular internalization into human dermal papilla cells. Furthermore, within the target cells, the codelivered kopexil and kopyrrol show synergistic effects by orchestrating an upregulation in the expression of Ki67, ß-catenin, vascular endothelial growth factor (VEGF), and CD31. These molecular responses collectively foster cell proliferation, migration, and antioxidative effects, thereby facilitating the expedited progression of hair follicles (HFs) into the anagen phase and promoting peripheral angiogenesis. Notably, the KK-NLPs-integrated MNs treatment group exhibits noteworthy enhanced hair regeneration in vivo, with identical or superior therapeutic effects at a much lower dosage than that of minoxidil. These results suggest the great potential of this kopexil and kopyrrol codelivery nanoliposomes-integrated MNs platform for AGA treatment in a safe and efficient way.

A Gas Therapy Strategy for Intestinal Flora Regulation and Colitis Treatment by Nanogel-Based Multistage NO Delivery Microcapsules.

Current approaches to treating inflammatory bowel disease focus on the suppression of overactive immune responses, the removal of reactive intestinal oxygen species, and regulation of the intestinal flora. However, owing to the complex structure of the gastrointestinal tract and the influence of mucus, current small-molecule and biologic-based drugs for treating colitis cannot effectively act at the site of colon inflammation, and as a result, they tend to exhibit low efficacies and toxic side effects. In this study, nanogel-based multistage NO delivery microcapsules are developed to achieve NO release at the inflammation site by targeting the inflammatory tissues using the nanogel. Surprisingly, oral administration of the microcapsules suppresses the growth of pathogenic bacteria and increases the abundance of probiotic bacteria. Metabolomics further show that an increased abundance of intestinal probiotics promotes the production of metabolites, including short-chain fatty acids and indole derivatives, which modulate the intestinal immunity and restore the intestinal barrier via the interleukin-17 and PI3K-Akt signaling pathways. This work reveals that the developed gas therapy strategy based on multistage NO delivery microcapsules modulates the intestinal microbial balance, thereby reducing inflammation and promoting intestinal barrier repair, ultimately providing a new therapeutic approach for the clinical management of colitis.

Novel l-Cysteine Incomplete Degradation Method for Preparation of Procyanidin B2-3'-O-Gallate and Exploration of its in Vitro Anti-inflammatory Activity and in Vivo Tissue Distribution.

In this study, an effective method for preparation of bioactive galloylated procyanidin B2-3'-O-gallate (B2-3'-G) was first developed by incomplete depolymerization of grape seed polymeric procyanidins (PPCs) using l-cysteine (Cys) in the presence of citric acid. The structure-activity relationship of B2-3'-G was further evaluated in vitro through establishing lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. The results suggested that the better protective effects of B2-3'-G against inflammation were attributed to its polymerization degree and the introduction of the galloyl group, compared to its four corresponding structural units. In vivo experiments demonstrated that the B2-3'-G prototype was distributed in plasma, small intestine, liver, lung, and brain. Remarkably, B2-3'-G was able to penetrate the blood-brain barrier and appeared to play an important role in improving brain health. Furthermore, a total of 18 metabolites were identified in tissues. Potential metabolic pathways, including reduction, methylation, hydration, desaturation, glucuronide conjugation, and sulfation, were suggested.

Deciphering m6A signatures in hepatocellular carcinoma: Single-cell insights, immune landscape, and the protective role of IGFBP3.

RNA m6 methyladenosine (m6A) modifications impact tumor biology and immune processes, particularly in hepatocellular malignant tumors. Using a consensus clustering algorithm on 371 hepatocellular carcinoma (HCC) samples, we identified three m6A-modified subtypes and correlated them with positive tumor microenvironment (TME) markers for distinct immune phenotypes. Stratifying patients based on m6A scores revealed a low presentation group with better immune penetration, lower tumor mutation load, and increased expression of immune checkpoint markers like CTLA-4 and PD-1, suggesting enhanced responsiveness to immunization therapy. A machine-learning model of 23 m6A genes was constructed. Single-cell analysis revealed a surprising enrichment of IGFBP3 in astrocytes, prompting the exploration of associated signaling pathways. Experimental verification shows that IGFBP3 is significantly enhanced in normal tissues, while immunohistochemical analysis shows that its expression is lower in tumor tissues, indicating its protective effect in HCC and a good prognosis. Importantly, high IGFBP3 expression is associated with better outcomes in patients receiving immunotherapy. Moreover, cytotoxic T lymphocyte (CTL) experiments have confirmed that high expression of IGFBP3 is associated with stronger T cell-killing ability. In summary, the comprehensive evaluation of m6A modification, immune characteristics, and single-cell analysis in this study not only revealed the TME of HCC but also made significant contributions to the progress of personalized HCC immunotherapy targeting IGFBP3. This study provides a solid theoretical foundation for clinical translation and emphasizes its potential impact on developing effective treatment strategies.

Photocatalytic Umpolung Strategy for the Synthesis of α-Amino Phosphine Oxides and Deuterated Derivatives.

Direct, economical, and green synthesis of deuterated α-amino phosphine oxides remains an elusive challenge in synthetic chemistry. Herein, we report a visible-light-driven umpolung strategy for synthesizing deuterated α-amino phosphine oxides from isocyanide using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene as the photocatalyst and D2O as the deuterium source. Moreover, the streamlined and sustainable methodology can be applied in the modification of amino acids, natural products, and drugs. The strong antiproliferative activity of the desired products indicates that the method could provide a novel privileged scaffold for antitumor drug development.

L-serine combined with carboxymethyl chitosan guides amorphous calcium phosphate to remineralize enamel.

The aim of this study is to investigate a robust and stable calcium-phosphorus system to remineralize human early enamel caries lesions with nanocomplexes of carboxymethyl chitosan/L-serine/amorphous calcium phosphate (CMC-Ser-ACP) to develop an effective method for mimicking the amelogenin (AMEL) mineralization pattern through ACP assembly. A CMC-Ser-ACP nanocomplex solution was first synthesized by a chemical precipitation method, and then 1% sodium hypochlorite (NaClO) was added to induce ACP phase formation. The morphologies of the nanocomplexes were characterized by transmission electron microscopy (TEM), and zeta potential analysis and Fourier transform infrared spectroscopy (FTIR) were performed to detect surface charge and functional group changes. The subtle changes of the demineralized enamel models induced by the remineralization effect were observed by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The CMC-Ser-ACP nanocomplex solution could be preserved without any precipitation for 45 days. After the application of NaClO and through the guidance of Ser, ACP nanoparticles transformed into relatively orderly arranged hydroxyapatite (HAP) crystals, generating an aprismatic enamel-like layer closely integrated with the demineralized enamel, which resulted in enhanced mechanical properties for the treatment of early enamel caries lesions. The CMC-Ser-ACP nanocomplex solution is a remineralization system with great solution stability, and when NaClO is added, it can rapidly regenerate an aprismatic enamel-like layer in situ on the demineralized enamel surface. This novel remineralization system has stable chemical properties and can greatly increase the therapeutic effects against early enamel caries.

APOE ε4 Gene Carriers Demonstrate Reduced Retinal Capillary Densities in Asymptomatic Older Adults.

Early identification of Apolipoprotein E (APOE)-related microvascular pathology will help to study the microangiopathic contribution to Alzheimer's disease and provide a therapeutic target for early intervention. To evaluate the differences in retinal microvasculature parameters between APOE ε4 carriers and non-carriers, asymptomatic older adults aged ≥ 55 years underwent APOE ε4 genotype analysis, neuropsychological examination, and optical coherence tomography angiography (OCTA) imaging. One hundred sixty-three older adults were included in the data analysis. Participants were also defined as cognitively impaired (CI) and non-cognitively impaired (NCI) according to their MoCA scores and educational years. APOE ε4 carriers demonstrated reduced SVC (p = 0.023) compared to APOE ε4 non-carriers. Compared to NCI, CI participants showed reduced SVC density (p = 0.006). In the NCI group, no significant differences (p > 0.05) were observed in the microvascular densities between APOE ε4 carriers and non-carriers. In the CI group, APOE ε4 carriers displayed reduced microvascular densities compared to non-carriers (SVC, p = 0.006; DVC, p = 0.048). We showed that CI and APOE ε4 affect retinal microvasculature in older adults. Quantitative measures of the retinal microvasculature could serve as surrogates for brain microcirculation, providing an opportunity to study microvascular contributions to AD.

[Characteristics of genetic variants in 134 patients with Acute myeloid leukemia].

OBJECTIVE: To analyze the characteristics of genetic variants in 134 patients diagnosed with Acute myeloid leukemia (AML). METHODS: Clinical data of the 134 patients with AML (non-acute promyelocytic leukemia) initially diagnosed at the 940th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army from June 2017 to June 2022 were retrospectively analyzed. Potential variants of AML-related genes were detected by next-generation sequencing, and the frequency of variants was analyzed by using SPSS v26.0 software, and likelihood ratio χ2 test and Fisher exact test were used for data analysis. RESULTS: The patients had included 72 males and 62 females, with a gender ratio of 1.7 : 1 and a median age of 51 years (9 ~ 86 years old). One hundred twenty patients (76.1%) had harbored at least one genetic variant, including 26 (19.4%) having a single variant, 27 (20.1%) having two variants, and 49 (36.6%) having >= 3 variants. 32 (23.9%) had no detectable variants. Genetic variants detected in over 10% of the 134 patients had included NPM1 (n = 24, 17.91%), FLT3-ITD (n = 21, 15.67%), DNMT3A (n = 20, 14.93%), CEBPA (single variant; n = 14, 10.45%), TET2 (n = 14, 10.45%), and NRAS (n = 14, 10.45%). The patients were also divided into low risk, intermediate risk and high risk groups based on their chromosomal karyotypes. The mutational rates for genes in different groups have varied, with 19 patients from the low risk group harboring variants of NRAS (n = 4, 21.05%), KRAS (n = 4, 21.05%), and KIT (n = 2, 10.53%); and 96 patients from the intermediate risk group harboring variants of NPM1 (n = 24, 25.00%), FLT3-ITD (n = 20, 20.83%), DNMT3A (n = 18, 18.75%), CEBPA (n = 12, 12.50%), and TET2 genes (n = 12, 12.50%). The mutational frequencies for the 19 patients from the high risk group were ASXL1 (n = 7, 21.05%), NRAS (n = 3, 15.97%), TP53 (n = 3, 15.79%), and EZH2 (n = 2, 10.53%). A significant difference was found in the frequencies of KIT, NPM1, FLT3-ITD, DNMT3A, and ASXL1 gene variants among the low-risk, medium-risk, and high-risk groups. CONCLUSION: AML patients have a high frequency for genetic variants, with 76.1% harboring at least one variant. The frequency of genetic variants have varied among patients with different chromosomal karyotypes, and there are apparent dominant variants. KIT, NPM1, FLT3-ITD, DNMT3A, and ASXL1 may be used as prognostic factors for evaluating their prognosis.

Factors influencing spiritual wellbeing among pancreatic ductal adenocarcinoma patients receiving chemotherapy.

BACKGROUND: Spiritual wellbeing emphasizes optimistic and positive attitudes while self-regulating negative emotions when coping with stress. However, there have only been a few small studies of spiritual wellbeing of pancreatic ductal adenocarcinoma (PDAC) patients undergoing chemotherapy. The core factors influencing spiritual wellbeing in this clinical population are still unclear. AIM: To identify factors influencing spiritual wellbeing among patients with PDAC receiving chemotherapy. METHODS: A total of 143 PDAC patients receiving chemotherapy were enrolled from January to December 2022. Patients completed general information questionnaires including: Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being 12 Item Scale (FACIT-Sp-12), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Zung's Self-rating Anxiety Scale (SAS). Independent sample t-test, one-way analysis of variance, Pearson's correlation analysis, and multiple linear regression analysis were adopted for statistical analyses. P < 0.05 (two-tailed) was considered statistically significant for all tests. RESULTS: Total spiritual wellbeing (FACIT-Sp-12) score was 32.16 ± 10.06 points, while dimension sub-scores were 10.85 ± 3.76 for faith, 10.55 ± 3.42 for meaning, and 10.76 ± 4.00 for peace. Total spiritual wellbeing score was negatively correlated with SAS score for anxiety and with the symptom domain of EORTC QLC-C30. Conversely, spiritual wellbeing score was positively correlated with global health status and EORTC QLQ-C30 role functioning domain score. Multivariate regression analysis identified educational level, health insurance category, symptom domain, functional role domain, and global health status as significant independent factors influencing spiritual wellbeing among PDAC patients undergoing chemotherapy (R2 = 0.502, P < 0.05). CONCLUSION: Individualized spiritual support is needed for PDAC patients. Health, daily functioning, emotional, cognitive, and social function status should be taken into account to promote implementation of spirituality in nursing practice.

Spiritual Well-being and Quality of Life for Patients Undergoing Chemotherapy for Pancreatic Cancer: Correlates and Influencing Factors.

Context: Pancreatic cancer (PC) is one of the most malignant digestive cancers, characterized by a poor prognosis. PC patients receiving chemotherapy can endure immense physical and psychological pain, negatively impacting spiritual well-being and QoL. Objective: The study intended to investigate PC patients' statuses regarding spiritual well-being and QoL, to identify and analyze the influencing factors, and to develop feasible spiritual-care plans, which could provide a reference for clinicians in promoting the spiritual well-being and QoL of PC chemotherapy patients. Design: The research team performed a prospective survey. Setting: The study took place at the Second Affiliated Hospital of the Army Medical University in Chongqing, China. Participants: Participants were 120 patients who underwent chemotherapy for pancreatic cancer (PC) at the hospital between November 2020 and April 2022. The research team selected participants using convenience sampling. Outcome Measures: The outcome measures included: (1) a self-designed questionnaire to identify participants' demographic and clinical characteristics and (2) the Functional Assessment of Chronic Illness Therapy-Spiritual Well-being Scales (FACIT-Sp). The research team used the FACIT-Sp's two subscales, FACT-G and the FACIT-Sp-12, to evaluate participants' quality of life (QoL) and spiritual well-being, respectively. Results: The total scores for participants' spiritual well-being and QoL were 26.2 ± 5.39 and 65.44 ± 17.1, respectively. Spiritual well-being was positively correlated with the QoL (P < .001). According to the multiple linear regression analysis, the main factors influencing spiritual well-being were age (P < .01), education level (P < .001), average monthly income per capita of the family (P < .001), recurrence (P < .001), and pain (P < .05). The main factors influencing QoL were age (P = .008), education level (P < .001), average monthly income per capita of the family (P < .001), recurrence (P < .001), and pain (P < .01). Conclusions: Patients who undergo chemotherapy for PC experience a low-to-medium level of spiritual well-being and a medium level of QoL. The detrimental factors include: (1) being middle-aged, (2) having a low education level, (3) having a low family income, (4) suffering a recurrence of the disease, and (5) experiencing moderate-to-severe pain. Medical practitioners should provide extra care and support to protect the spiritual well-being of these patients and ultimately improve their QoL.

The Time, Electric Field, and Temperature Dependence of Charging and Discharging Currents in Polypropylene Films.

The insulating properties of polypropylene (PP) film play a very important role in the operating status of direct current (DC) support capacitors. Charging and discharging currents in PP film under high DC electric fields and temperatures correspond to charge transportation and accumulation, which significantly influence the electrical insulating properties of PP. In this paper, we have comprehensively studied the dependence of charging/discharging currents in PP film on time, electric field (150-670 kV/mm), and temperature (40-120 °C). The results showed that the charging current increased by almost an order of magnitude from 150 kV/mm to 670 kV/mm and exhibits a steep increase with temperature above 80 °C. The discharging currents are about 10 times less than the corresponding charging currents. Carrier mobility varies little with the electric field and becomes slightly larger with an increase in temperature. The quantity of the accumulated charges was calculated by the integral of the charging and discharging current differentials and showed a significant increase with the electric field and temperature. The corresponding electric field distortion becomes larger above 80 °C compared to 20-60 °C. Both electric field and temperature have an important effect on PP film and capacitors based on charge transport and accumulation and their electric field distortion. This study is innovative in that it combines the operating status of DC support capacitors with traditional methods to research synthetically charged transport mechanisms of PP film. The findings are meaningful for understanding the insulation failure mechanisms of PP film and capacitors under complex stresses.

Systematic Study of Paeonol/Madecassoside Co-Delivery Nanoemulsion Transdermal Delivery System for Enhancing Barrier Repair and Anti-Inflammatory Efficacy.

Sensitive skin is defined as skin with low tolerance and high reactivity. Natural products, such as paeoniflorin and madecassoside, have unique skin care functionality. However, because they are hampered by the skin barrier, paeoniflorin and madecassoside have difficulty penetrating the stratum corneum, resulting in weakened skin barrier repair and anti-inflammatory effects. In addition, there is a lack of detailed studies on the efficacy of paeonol and madecassic in human skin, especially in 3D skin models and clinical trials. To overcome the low transdermal delivery issue, we developed nanoemulsions (PM-NEs) loaded with paeonol and madecassoside to improve their delivery efficiency and promote sensitive skin repair and anti-inflammation effects. Furthermore, systematic evaluations of the efficacy in cell line models, 3D skin models, and clinical trials were conducted. The PM-NEs effectively improved the efficacy of paeonol and madecassoside glucoside transdermal penetration and retention and enhanced cellular uptake. Cellular assays and 3D epidermal models showed that the PM-NEs significantly promoted the secretion of filamentous protein, aquaporin 3, Claudin-1, and hyaluronic acid, and considerably inhibited the secretion of interleukin 1α, interleukin 6, tumor necrosis factor-α, and prostaglandin E2 compared to free components. Notably, clinical trial data showed that the PM-NEs significantly reduced transepidermal water loss, a* values, erythropoietin, the amount of non-inflammatory acne, and the amount of inflammatory acne in the facial skin. Three levels of systematic studies suggest that co-delivery of paeoniflorin and madecassoside via nanoemulsions is a promising strategy to improve topical delivery efficiency and anti-inflammatory repair efficacy in sensitive skin.

RNA polymerase I subunit RPA43 activates rRNA expression and cell proliferation but inhibits cell migration.

The products synthesized by RNA polymerase I (Pol I) play fundamental roles in several cellular processes, including ribosomal biogenesis, protein synthesis, cell metabolism, and growth. Deregulation of Pol I products can cause various diseases such as ribosomopathies, leukaemia, and solid tumours. However, the detailed mechanism of Pol I-directed transcription remains elusive, and the roles of Pol I subunits in rRNA synthesis and cellular activities still need clarification. In this study, we found that RPA43 expression levels positively correlate with Pol I product accumulation and cell proliferation, indicating that RPA43 activates these processes. Unexpectedly, RPA43 depletion promoted HeLa cell migration, suggesting that RPA43 functions as a negative regulator in cell migration. Mechanistically, RPA43 positively modulates the recruitment of Pol I transcription machinery factors to the rDNA promoter by activating the transcription of the genes encoding Pol I transcription machinery factors. RPA43 inhibits cell migration by dampening the expression of c-JUN and Integrin. Collectively, we found that RPA43 plays opposite roles in cell proliferation and migration except for driving Pol I-dependent transcription. These findings provide novel insights into the regulatory mechanism of Pol I-mediated transcription and cell proliferation and a potential pathway to developing anti-cancer drugs using RPA43 as a target.

Mechanical digit sensory stimulation: a randomized control trial on neurological and motor recovery in acute stroke.

Background: Mechanical digit sensory stimulation (MDSS) is a novel therapy designed to accelerate the recovery of upper limb (including hand) function in patients with hemiplegia following a stroke. The primary goal of this study was to investigate the effect of MDSS on patients with acute ischemic stroke (AIS). Methods: Sixty-one inpatients with AIS were randomly divided into conventional rehabilitation group (RG) and stimulation group (SG), and the latter group received MDSS therapy. A healthy group consisting of 30 healthy adults was also included. The interleukin-17A (IL-17A), vascular endothelial growth factor A (VEGF-A), and tumor necrosis factor-alpha (TNF-α) plasma levels were measured in all subjects. The neurological and motor functions of patients were evaluated using the National Institutes of Health Stroke Scale (NIHSS), Mini-Mental State Examination (MMSE), Fugel-Meyer Assessment (FMA), and Modified Barthel Index (MBI). Results: After 12 days of intervention, the IL-17A, TNF-α, and NIHSS levels were significantly decreased, while the VEGF-A, MMSE, FMA, and MBI levels were significantly increased in both disease groups. No significant difference was observed between both disease groups after intervention. The levels of IL-17A and TNF-α were positively correlated with NIHSS but negatively correlated with MMSE, FMA, and MBI. The VEGF-A levels were negatively correlated with NIHSS but positively correlated with MMSE, FMA, and MBI. Conclusion: Both MDSS and conventional rehabilitation significantly reduce the production of IL-17A and TNF-α, increase the VEGF-A levels, and effectively improve cognition and motor function of hemiplegic patients with AIS, and the effects of MDSS and conventional rehabilitation are comparable.

Bioactive fatty acid analog-derived hybrid nanoparticles confer antibody-independent chemo-immunotherapy against carcinoma.

Typical chemo-immunotherapy against malignant carcinoma, is characterized by the combined application of chemotherapeutic agents and monoclonal antibodies for immune checkpoint blockade (ICB). Temporary ICB with antibodies would not depress tumor intrinsic PD-L1 expression and potential PD-L1 adaptive upregulation during chemotherapy, thus exerting limited immunotherapy efficacy. Herein, we developed novel polymer-lipid hybrid nanoparticles (2-BP/CPT-PLNs) for inducing PD-L1 degradation by inhibiting palmitoylation with bioactive palmitic acid analog 2-bromopalmitate (2-BP) to replace PD-L1 antibody (αPD-L1) for ICB therapy, thus achieving highly efficient antitumor immune via immunogenic cell death (ICD) induced by potentiated chemotherapy. GSH-responsive and biodegradable polymer-prodrug CPT-ss-PAEEP10 assisted as a cationic helper polymer could help to stabilize 2-BP/CPT-PLNs co-assembled with 2-BP, and facilitate the tumor site-specific delivery and intracellular release of water-insoluble camptothecin (CPT) in vivo. 2-BP/CPT-PLNs would reinforce cytotoxic CD8+ T cell-mediated antitumor immune response via promoting intratumoral lymphocytes cells infiltration and activation. 2-BP/CPT-PLNs significantly prevented melanoma progression and prolonged life survival of mice beyond the conventional combination of irinotecan hydrochloride (CPT-11) and αPD-L1. Our work first provided valuable instructions for developing bioactive lipid analogs-derived nanoparticles via lipid metabolism intervention for oncotherapy.

NaWRKY3 is a master transcriptional regulator of the defense network against brown spot disease in wild tobacco.

WRKY transcription factors are involved in plant defense against pathogens. No WRKYs have been reported to be involved in resistance to tobacco brown spot disease caused by Alternaria alternata. Here, we found that NaWRKY3 plays a critical role in Nicotiana attenuata defense against A. alternata. NaWRKY3 bound and regulated many defense genes, including: lipoxygenase 3, ACC synthase 1, and ACC oxidase 1, three jasmonate- and ethylene-biosynthetic genes; feruloyl-CoA 6'-hydroxylase 1 (NaF6'H1), the biosynthetic gene for the phytoalexins scopoletin and scopolin; and three A. alternata resistance genes, the long non-coding RNA L2, NADPH oxidase (NaRboh D), and berberine bridge-like (NaBBL28). Silencing L2 reduced jasmonate concentrations and NaF6'H1 expression. NaRboh D-silenced plants were severely impaired in reactive oxygen species production and stomatal closure responses. NaBBL28 was the first A. alternata resistance BBL identified and was involved in the hydroxylation of 17-hydroxygeranyllinalool diterpene glycosides. NaWRKY3 bound to its own promoter but repressed its expression. Thus, we demonstrated that NaWRKY3 is a fine-tuned master regulator of the defense network against A. alternata in N. attenuata by regulating several signaling pathways and defense metabolites. This is the first time such an important WRKY has been identified in Nicotiana species, providing new insights into defense against A. alternata.

All-Natural Immunomodulatory Bioadhesive Hydrogel Promotes Angiogenesis and Diabetic Wound Healing by Regulating Macrophage Heterogeneity.

Macrophages are highly heterogeneous and exhibit a diversity of functions and phenotypes. They can be divided into pro-inflammatory macrophages (M1) and anti-inflammatory macrophages (M2). Diabetic wounds are characterized by a prolonged inflammatory phase and difficulty in healing due to the accumulation of pro-inflammatory (M1) macrophages in the wound. Therefore, hydrogel dressings with macrophage heterogeneity regulation function hold great promise in promoting diabetic wound healing in clinical applications. However, the precise conversion of pro-inflammatory M1 to anti-inflammatory M2 macrophages by simple and biosafe approaches is still a great challenge. Here, an all-natural hydrogel with the ability to regulate macrophage heterogeneity is developed to promote angiogenesis and diabetic wound healing. The protocatechuic aldehyde hybridized collagen-based all-natural hydrogel exhibits good bioadhesive and antibacterial properties as well as reactive oxygen species scavenging ability. More importantly, the hydrogel is able to convert M1 macrophages into M2 macrophages without the need for any additional ingredients or external intervention. This simple and safe immunomodulatory approach shows great application potential for shortening the inflammatory phase of diabetic wound repair and accelerating wound healing.