2D Differential Metallic Immunopotentiators Drive High Diversity and Capability of Antigen-specific Immunity Against Tumor.

The therapeutic efficacy of vaccines for treating cancers in clinics remains limited. Here, a rationally designed cancer vaccine by placing immunogenically differential and clinically approved aluminum (Al) or manganese (Mn) in a 2D nanosheet (NS) architecture together with antigens is reported. Structurally optimal NS with a high molar ratio of Mn to Al (MANS-H) features distinctive immune modulation, markedly promoting the influx of heterogeneous innate immune cells at the injection site. Stimulation of multiple subsets of dendritic cells (DCs) significantly increases the levels, subtypes, and functionalities of antigen-specific T cells. MANS-H demonstrates even greater effectiveness in the production of antigen-specific antibodies than the commercial adjuvant (Alhydrogel) by priming T helper (Th)2 cells rather than T follicular helper (Tfh) cells. Beyond humoral immunity, MANS-H evokes high frequencies of antigen-specific Th1 and CD8+ cell immunity, which are comparable with Quil-A that is widely used in veterinary vaccines. Immunized mice with MANS-H adjuvanted vaccines exert strong potency in tumor regression by promoting effector T cells infiltrating at tumor and overcoming tumor resistance in multiple highly aggressive tumor models. The engineered immunogen with an intriguing NS architecture and safe immunopotentiators offers the next clinical advance in cancer immunotherapy.

Attention-Guided Learning with Feature Reconstruction for Skin Lesion Diagnosis using Clinical and Ultrasound Images.

Skin lesion is one of the most common diseases, and most categories are highly similar in morphology and appearance. Deep learning models effectively reduce the variability between classes and within classes, and improve diagnostic accuracy. However, the existing multi-modal methods are only limited to the surface information of lesions in skin clinical and dermatoscopic modalities, which hinders the further improvement of skin lesion diagnostic accuracy. This requires us to further study the depth information of lesions in skin ultrasound. In this paper, we propose a novel skin lesion diagnosis network, which combines clinical and ultrasound modalities to fuse the surface and depth information of the lesion to improve diagnostic accuracy. Specifically, we propose an attention-guided learning (AL) module that fuses clinical and ultrasound modalities from both local and global perspectives to enhance feature representation. The AL module consists of two parts, attention-guided local learning (ALL) computes the intra-modality and inter-modality correlations to fuse multi-scale information, which makes the network focus on the local information of each modality, and attention-guided global learning (AGL) fuses global information to further enhance the feature representation. In addition, we propose a feature reconstruction learning (FRL) strategy which encourages the network to extract more discriminative features and corrects the focus of the network to enhance the model's robustness and certainty. We conduct extensive experiments and the results confirm the superiority of our proposed method. Our code is available at: https://github.com/XCL-hub/AGFnet.

Mulberry and Hippophae-based solid beverage attenuate hyperlipidemia and hepatic steatosis via adipose tissue-liver axis.

Dyslipidemia and hepatic steatosis are the characteristics of the initial stage of nonalcohol fatty liver disease (NAFLD), which can be reversed by lifestyle intervention, including dietary supplementation. However, such commercial dietary supplements with solid scientific evidence and in particular clear mechanistic elucidation are scarce. Here, the health benefits of MHP, a commercial mulberry and Hippophae-based solid beverage, were evaluated in NAFLD rat model and the underlying molecular mechanisms were investigated. Histopathologic examination of liver and white adipose tissue found that MHP supplementation reduced hepatic lipid accumulation and adipocyte hypertrophy. Serum biochemical results confirmed that MHP effectively ameliorated dyslipidemia and decreased circulation-free fatty acid level. RNA-Seq-based transcriptomic analysis showed that MHP-regulated genes are involved in the inhibition of lipolysis of adipose tissue and thus may contribute to the reduction of hepatic ectopic lipid deposition. Furthermore, MHP upregulated ACSL1-CPT1a-CPT2 pathway, a canonical pathway that regulated mitochondrial fatty acid metabolism, and promoted liver and adipose tissue fatty acid ß-oxidation. These results suggest that adipose tissue-liver crosstalk may play a key role in maintaining glucose and lipid metabolic hemostasis. In addition, MHP can also ameliorate chronic inflammation through regulating the secretion of adipokines. Our study demonstrates that MHP is able to improve dyslipidemia and hepatic steatosis through crosstalk between adipose tissue and liver and also presents transcriptomic evidence to support the underlying mechanisms of action, providing solid evidence for its health claims.

Role of high-frequency ultrasound in differentiating benign and malignant skin lesions: potential and limitations.

PURPOSE: This study examined the diagnostic value of high-frequency ultrasound (HFUS) features in differentiating between benign and malignant skin lesions. METHODS: A total of 1,392 patients with 1,422 skin lesions who underwent HFUS examinations were included in an initial dataset (cohort 1) to identify features indicative of malignancy. Qualitative clinical and HFUS characteristics were recorded for all lesions. To determine which HFUS and clinical features were suggestive of malignancy, univariable and multivariable logistic regression analyses were employed. The diagnostic performance of HFUS features combined with clinical information was evaluated. This assessment was validated using internal data (cohort 2) and multicenter external data (cohort 3). RESULTS: Features significantly associated with malignancy included age above 60 years; lesion location in the head, face, and neck or genital regions; changes in macroscopic appearance; crawling or irregular growth pattern; convex or irregular base; punctate hyperechogenicity; blood flow signals; and feeding arteries. The area under the receiver operating characteristic curve, sensitivity, and specificity of HFUS features combined with clinical information were 0.946, 92.5%, and 86.9% in cohort 1; 0.870, 93.1%, and 80.8% in cohort 2 (610 lesions); and 0.864, 86.2%, and 86.6% in cohort 3 (170 lesions), respectively. However, HFUS is not suitable for evaluating lesions less than 0.1 mm in thickness or lesions exhibiting surface hyperkeratosis. CONCLUSION: In a clinical setting, the integration of HFUS with clinical information exhibited good diagnostic performance in differentiating malignant and benign skin lesions. However, its utility was limited in evaluating extremely thin lesions and those exhibiting hyperkeratosis.

Metal-Organic-Framework-Derived Nitrogen-Doped Carbon-Matrix-Encapsulating Co0.5Ni0.5 Alloy as a Bifunctional Oxygen Electrocatalyst for Zinc-Air Batteries.

The development of low-cost, high-performance oxygen electrocatalysts is of great significance for energy conversion and storage. As a potential substitute for precious metal electrocatalysts, the construction of efficient and cost-effective oxygen electrocatalysts is conducive to promoting the widespread application of zinc-air batteries. Herein, CoxNiyMOF nanoparticles encapsulated within a carbon matrix were synthesized and employed as cathode catalysts in zinc-air batteries. Co0.5Ni0.5MOF exhibits superior oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) performance and durability. The zinc-air battery assembled with Co0.5Ni0.5MOF as the air cathode exhibits a maximum power density of 138.6 mW·cm-2. These improvements are mainly attributed to the optimized metal composition of the cobalt-nickel alloy, which increases the specific surface area of the material and optimizes its pore structure. Significantly, the optimization of the electronic structure and active sites within the material has led to amplified ORR/OER activity and better zinc-air battery performance. This study underscores the immense promise of Co0.5Ni0.5MOF catalysts as feasible substitutes for commercial Pt/C catalysts in zinc-air batteries.

Accelerated drug-resistant variant discovery with an enhanced, scalable mutagenic base editor platform.

Personalized cancer therapeutics bring directed treatment options to patients based on their tumor's genetic signature. Unfortunately, tumor genomes are remarkably adaptable, and acquired resistance through gene mutation frequently occurs. Identifying mutations that promote resistance within drug-treated patient populations can be cost, resource, and time intensive. Accordingly, base editing, enabled by Cas9-deaminase domain fusions, has emerged as a promising approach for rapid, large-scale gene variant screening in situ. Here, we adapt and optimize a conditional activation-induced cytidine deaminase (AID)-dead Cas9 (dCas9) system, which demonstrates greater heterogeneity of edits with an expanded footprint compared to the most commonly utilized cytosine base editor, BE4. In combination with a custom single guide RNA (sgRNA) library, we identify individual and compound variants in epidermal growth factor receptor (EGFR) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) that confer resistance to established EGFR inhibitors. This system and analytical pipeline provide a simple, highly scalable platform for cis or trans drug-modifying variant discovery and for uncovering valuable insights into protein structure-function relationships.

Detection of Intrinsically Disordered Peptides by Biological Nanopore.

Intrinsically disordered protein regions (IDPRs) are pivotal in regulation of transcription and facilitation of signal transduction. Because of their multiple conformational states of structure, characterizing the highly flexible structures of IDPRs becomes challenging. Herein, we employed the wild-type (WT) aerolysin nanopore as a real-time biosensor for identification and monitoring of long peptides containing IDPRs. This sensor successfully identified three intrinsically disordered peptides, with the lengths up to 43 amino acids, by distinguishing the unique signatures of blockade current and duration time. The analysis of the binding constant revealed that interactions between the nanopore and peptides are critical for peptide translocation, which suggests that mechanisms beyond mere volume exclusion. Furthermore, we were able to compare the conformational stabilities of various IDPRs by examining the detailed current traces of blockade events. Our approach can detect the conformational changes of IDPR in a confined nanopore space. These insights broaden the understanding of peptide structural changes. The nanopore biosensor showed the potential to study the conformations change of IDPRs, IDPRs transmembrane interactions, and protein drug discovery.

Sodium Octahydridotriborate as a Solid Electrolyte with Excellent Stability Against Sodium-Metal Anode.

Solid-state sodium metal batteries have been extensively investigated because of their potential to improve safety, cost-effectiveness, and energy density. The development of such batteries urgently required a solid-state electrolyte with fast Na-ion conduction and favorable interfacial compatibility. Herein, the progress on developing the NaB3H8 solid-state electrolytes is reported, which show a liquid-like ionic conductivity of 0.05 S cm-1 at 56 °C with an activation energy of 0.35 eV after an order-disorder phase transformation, matching or surpassing the best single-anion hydridoborate conductors investigated up to now. The steady polarization voltage and significantly decreased resistance are achieved in the symmetric Na/NaB3H8/Na cell, indicating the great electrochemical stability and favorable interfacial contact with the Na metal of NaB3H8. Furthermore, a Na/NaB3H8/TiS2 battery, the first high-rate (up to 1 C) solid-state sodium metal battery using the single-anion hydridoborate electrolyte, is demonstrated, which exhibits superior rate capability (168.2 mAh g-1 at 0.1 C and 141.2 mAh g-1 at 1 C) and long-term cycling stability (70.9% capacity retention at 1 C after 300 cycles) at 30 °C. This work may present a new possibility to solve the interfacial limitations and find a new group of solid-state electrolytes for high-performance sodium metal batteries.

Mulberry and Hippophae-based solid beverage promotes weight loss in rats by antagonizing white adipose tissue PPARγ and FGFR1 signaling.

Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Hippophae protein peptides, was evaluated in a high-fat high-fructose (HFF) diet-induced rat model of obesity. Body component analysis and histopathologic examination confirmed that MHP was effective to facilitate weight loss and adiposity decrease. Pathway enrichment analysis with differential metabolites generated by serum metabolomic profiling suggests that PPAR signal pathway was significantly altered when the rats were challenged by HFF diet but it was rectified after MHP intervention. RNA-Seq based transcriptome data also indicates that MHP intervention rectified the alterations of white adipose tissue mRNA expressions in HFF-induced obese rats. Integrated omics reveals that the efficacy of MHP against obesogenic adipogenesis was potentially associated with its regulation of PPARγ and FGFR1 signaling pathway. Collectively, our findings suggest that MHP could improve obesity, providing an insight into the use of MHP in body weight management.

Ambulatory blood pressure levels in individuals with uncontrolled clinic hypertension across Bangladesh, Pakistan, and Sri Lanka.

Hypertension is a leading risk factor for cardiovascular disease in South Asia. The authors aimed to assess the cross-country differences in 24-h ambulatory, daytime, and nighttime systolic blood pressure (SBP) among rural population with uncontrolled clinic hypertension in Bangladesh, Pakistan, and Sri Lanka. The authors studied patients with uncontrolled clinic hypertension (clinic BP ≥ 140/90 mmHg) who underwent ambulatory blood pressure monitoring (ABPM) during the baseline assessment as part of a community-based trial. The authors compared the distribution of ABPM profiles of patients across the three countries, specifically evaluating ambulatory SBP levels with multivariable models that adjusted for patient characteristics. Among the 382 patients (mean age, 58.3 years; 64.7% women), 56.5% exhibited ambulatory hypertension (24-h ambulatory BP ≥ 130/80 mmHg), with wide variation across countries: 72.6% (Bangladesh), 50.0% (Pakistan), and 51.0% (Sri Lanka; P < .05). Compared to Sri Lanka, adjusted mean 24-h ambulatory, daytime, and nighttime SBP were higher by 12.24 mmHg (95% CI 4.28-20.20), 11.96 mmHg (3.87-20.06), and 12.76 mmHg (4.51-21.01) in Bangladesh, separately. However, no significant differences were observed between Pakistan and Sri Lanka (P > .05). Additionally, clinic SBP was significantly associated with 24-h ambulatory (mean 0.38, 95% CI 0.28-0.47), daytime (0.37, 0.27-0.47), and nighttime SBP (0.40, 0.29-0.50) per 1 mmHg increase. The authors observed substantial cross-country differences in the distribution of ABPM profiles among patients with uncontrolled clinic hypertension in rural South Asia. The authors findings indicated the need to incorporate 24-h BP monitoring to mitigate cardiovascular risk, particularly in Bangladesh.

Transcriptomic insights into the lipotoxicity of high-fat high-fructose diet in rat and mouse.

Along with the increasing prevalence of obesity worldwide, the deleterious effects of high-calorie diet are gradually recognized through more and more epidemiological studies. However, the concealed and chronic causality whitewashes its unhealthy character. Given an ingenious mechanism orchestrates the metabolic adaptation to high-fat high-fructose (HFF) diet and connive its lipotoxicity, in this study, an experimental rat/mouse model of obesity was induced and a comparative transcriptomic analysis was performed to probe the mystery. Our results demonstrated that HFF diet consumption altered the transcriptomic pattern as well as different high-calorie diet fed rat/mouse manifested distinct hepatic transcriptome. Validation with RT-qPCR and Western blotting confirmed that SREBP1-FASN involved in de novo lipogenesis partly mediated metabolic self-adaption. Moreover, hepatic ACSL1-CPT1A-CPT2 pathway involved in fatty acids ß-oxidation, played a key role in the metabolic adaption to HFF. Collectively, our findings enrich the knowledge of the chronic adaptation mechanisms and also shed light on future investigations. Meanwhile, our results also suggest that efforts to restore the fatty acids metabolic fate could be a promising avenue to fight against obesity and associated steatosis and insulin resistance challenged by HFF diet.

Mediating and moderating effects of authoritative parenting styles on adolescent behavioral problems.

Introduction: This study aimed to analyze how authoritative parenting affects behavioral problems among primary, junior high, and secondary high school students. Today, parental educational anxiety and parent-child relationship conflicts are common in China and are resulting in a high incidence of child behavioral problems. High-quality family education is becoming increasingly important in China. This study sought to provide a reference for developing responsive family education services. Methods: A total of 10,441 parents in Hubei Province, including urban and rural areas, were evaluated using the Parents' Education Anxiety Questionnaire, Parental Authority Parenting Questionnaire, Parent-Child Relationship Scale, and Self-Made Behavior Problem Scale to determine the internal mechanisms of child behavioral problems in the family system. To make the sample more representative, this study collected data from primary and secondary schools representative of the southeast, northwest, and center of Hubei Province; further, the number of parents involved in each school was controlled at approximately 300 to ensure that the final sample had analytical value. Results: Educational anxiety directly affected children's behavioral problems and indirectly affected them through the conflicts between parent and child. This conflict partially mediated educational anxiety and child behavioral problems, and authoritative parenting played a significant regulatory role in this relationship. Discussion: Higher levels of educational anxiety among parents increased the likelihood of a depressed family environment. This can lead to deteriorating parent-child relationships, which can result in children's problem behaviors. Parents can address these problems by changing their approach to education and adjusting their emotions accordingly.

A Novel Ultrafiltrate Extract of Propolis Exerts Anti-inflammatory Activity through Metabolic Rewiring.

Thousands of years ago, humans started to use propolis because of its medicinal properties, and modern science has successfully identified several bioactive molecules within this resinous bee product. However, a natural propolis extract which has been removed the adhesive glue and preserved propolis bioactive compounds is urgently needed to maximise the therapeutic opportunities. In this study, a novel ultrafiltrate fraction from Brazilian green propolis, termed P30K, was demonstrated with anti-inflammatory properties, both in vitro and in vivo. Total flavonoids and total phenolic acids content in P30K were 244.6 mg/g and 275.8 mg/g respectively, while the IC50 value of inhibition of cyclooxygenase-2 (COX-2) was 8.30 µg/mL. The anti-inflammatory activity of P30K was furtherly corroborated in experimental models of lipopolysaccharides (LPS)-induced acute liver and lung injury. Mechanistically, integrated GC-MS and LC-MS based serum metabolomics analysis revealed that P30K modulated citrate cycle (TCA), pyruvate, glyoxylate and dicarboxylate metabolism pathways to inhibit secretion of pro-inflammatory cytokines. Results of network pharmacology and molecular docking suggested that P30K targeted catechol-O-methyltransferases (COMT), 11ß-hydroxysteroid dehydrogenases (HSD11B1), and monoamine oxidases (MAOA and MAOB) to promote cellular metabolomic rewiring. Collectively, our work reveals P30K as an efficient therapeutic agent against inflammatory conditions and its efficacy is related to metabolic rewiring.

A deep learning fusion network trained with clinical and high-frequency ultrasound images in the multi-classification of skin diseases in comparison with dermatologists: a prospective and multicenter study.

Background: Clinical appearance and high-frequency ultrasound (HFUS) are indispensable for diagnosing skin diseases by providing internal and external information. However, their complex combination brings challenges for primary care physicians and dermatologists. Thus, we developed a deep multimodal fusion network (DMFN) model combining analysis of clinical close-up and HFUS images for binary and multiclass classification in skin diseases. Methods: Between Jan 10, 2017, and Dec 31, 2020, the DMFN model was trained and validated using 1269 close-ups and 11,852 HFUS images from 1351 skin lesions. The monomodal convolutional neural network (CNN) model was trained and validated with the same close-up images for comparison. Subsequently, we did a prospective and multicenter study in China. Both CNN models were tested prospectively on 422 cases from 4 hospitals and compared with the results from human raters (general practitioners, general dermatologists, and dermatologists specialized in HFUS). The performance of binary classification (benign vs. malignant) and multiclass classification (the specific diagnoses of 17 types of skin diseases) measured by the area under the receiver operating characteristic curve (AUC) were evaluated. This study is registered with www.chictr.org.cn (ChiCTR2300074765). Findings: The performance of the DMFN model (AUC, 0.876) was superior to that of the monomodal CNN model (AUC, 0.697) in the binary classification (P = 0.0063), which was also better than that of the general practitioner (AUC, 0.651, P = 0.0025) and general dermatologists (AUC, 0.838; P = 0.0038). By integrating close-up and HFUS images, the DMFN model attained an almost identical performance in comparison to dermatologists (AUC, 0.876 vs. AUC, 0.891; P = 0.0080). For the multiclass classification, the DMFN model (AUC, 0.707) exhibited superior prediction performance compared with general dermatologists (AUC, 0.514; P = 0.0043) and dermatologists specialized in HFUS (AUC, 0.640; P = 0.0083), respectively. Compared to dermatologists specialized in HFUS, the DMFN model showed better or comparable performance in diagnosing 9 of the 17 skin diseases. Interpretation: The DMFN model combining analysis of clinical close-up and HFUS images exhibited satisfactory performance in the binary and multiclass classification compared with the dermatologists. It may be a valuable tool for general dermatologists and primary care providers. Funding: This work was supported in part by the National Natural Science Foundation of China and the Clinical research project of Shanghai Skin Disease Hospital.

Assessment of the Diagnostic Performance of Clinical Examinations and High-Frequency Ultrasound in Patients With Pigmented Skin Tumors.

OBJECTIVES: To investigate whether the integration of high-frequency ultrasound (HFUS) to routine clinical examinations could improve diagnostic performance and management decision for pigmented skin tumors. METHODS: Three general practitioners trained previously and a dermatologist independently assessed pigmented skin tumors and rendered management decision based on clinical examinations alone or clinical examinations integrating HFUS. RESULTS: After integrating HFUS, the diagnostic area under the curve (AUC) (0.658-0.693 versus 0.848, all P < .05) and specificity (46.6-58.6% versus 89.7%, all P < .05) for pigmented skin malignancies were improved for general practitioners, meanwhile unnecessary biopsy rate reduced (42.9-53.6% versus 10.7%, P < .001). To the dermatologist, the diagnostic AUC (0.822 versus 0.949, P < .001), sensitivity (81.7% versus 96.7%, P = .012) and specificity (0.828 versus 0.931, P = .031) improved significantly, meanwhile both missed biopsy rate (14.5% versus 4.8%, P = .031) and unnecessary biopsy rate (19.6% versus 7.1%, P = .016) decreased. Additionally, the diagnostic performance of the general practitioner with integrating HFUS could be comparable with the dermatologist based on clinical examinations alone (all P > .05). CONCLUSIONS: As a complementary tool of clinical examinations, HFUS could help physicians differentiate pigmented skin malignancies and manage decision.

Accurate Detection of Multiple Tumor Mutations in Formalin-Fixed Paraffin-Embedded Tissues by Coupling Sequence Artifacts Elimination and Mutation Enrichment With MeltArray.

Formalin-fixed paraffin-embedded (FFPE) tissues are the primary source of DNA for companion diagnostics (CDx) of cancers. Degradation of FFPE tissue DNA and inherent tumor heterogeneity constitute serious challenges in current CDx assays. To address these limitations, we introduced sequence artifact elimination and mutation enrichment to MeltArray, a highly multiplexed PCR approach, to establish an integrated protocol that provides accuracy, ease of use, and rapidness. Using PIK3CA mutations as a model, we established a MeltArray protocol that could eliminate sequence artifacts completely and enrich mutations from 23.5- to 59.4-fold via a single-reaction pretreatment step comprising uracil-DNA-glycosylase excision and PCR clamping. The entire protocol could identify 13 PIK3CA hotspot mutations of 0.05% to 0.5% mutant allele fractions within 5 hours. Evaluation of 106 breast cancer and 40 matched normal FFPE tissue samples showed that all 47 PIK3CA mutant samples were from the cancer tissue, and no false-positive results were detected in the normal samples. Further evaluation of 105 colorectal and 40 matched normal FFPE tissue samples revealed that 11 PIK3CA mutants were solely from the cancer sample. The detection results of our protocol were consistent with those of the droplet digital PCR assays that underwent sequence artifact elimination. Of the 60 colorectal samples with next-generation sequencing results, the MeltArray protocol detected 2 additional mutant samples with low mutant allele fractions. We conclude that the new protocol provides an improved alternative to current CDx assays for detecting tumor mutations in FFPE tissue DNA.

Social Determinants of Health and Disparities in Hypertension and Cardiovascular Diseases.

High blood pressure causes over 10 million preventable deaths annually globally. Populations in low- and middle-income countries suffer the most, experiencing increased uncontrolled blood pressure and cardiovascular disease (CVD) deaths. Despite improvements in high-income countries, disparities persist, notably in the United States, where Black individuals face up to 4× higher CVD mortality than White individuals. Social determinants of health encompass complex, multidimensional factors linked to an individual's birthplace, upbringing, activities, residence, workplaces, socioeconomic and environmental structures, and significantly affect health outcomes, including hypertension and CVD. This review explored how social determinants of health drive disparities in hypertension and related CVD morbidity from a socioecological and life course perspective. We present evidence-based strategies, emphasizing interventions tailored to specific community needs and cross-sector collaboration to address health inequalities rooted in social factors, which are key elements toward achieving the United Nations' Sustainable Development Goal 3.4 for reducing premature CVD mortality by 30% by 2030.

Ethanol Extract of Rosa rugosa Ameliorates Acetaminophen-Induced Liver Injury via Upregulating Sirt1 and Subsequent Potentiation of LKB1/AMPK/Nrf2 Cascade in Hepatocytes.

Acetaminophen (APAP)-induced liver injury is a common hepatic disease resulting from drug abuse. Few targeted treatments are available clinically nowadays. The flower bud of Rosa rugosa has a wide range of biological activities. However, it is unclear whether it alleviates liver injury caused by APAP. Here, we prepared an ethanol extract of Rosa rugosa (ERS) and analyzed its chemical profile. Furthermore, we revealed that ERS significantly ameliorated APAP-induced apoptosis and ferroptosis in AML-12 hepatocytes and dampened APAP-mediated cytotoxicity. In AML-12 cells, ERS elevated Sirt1 expression, boosted the LKB1/AMPK/Nrf2 axis, and thereby crippled APAP-induced intracellular oxidative stress. Both EX527 and NAM, which are chemically unrelated inhibitors of Sirt1, blocked ERS-induced activation of LKB1/AMPK/Nrf2 signaling. The protection of ERS against APAP-triggered toxicity in AML-12 cells was subsequently abolished. As expression of LKB1 was knocked down, ERS still upregulated Sirt1 but failed to activate AMPK/Nrf2 cascade or suppress cytotoxicity provoked by APAP. Results of in vivo experiments showed that ERS attenuated APAP-caused hepatocyte apoptosis and ferroptosis and improved liver injury and inflammation. Consistently, ERS boosted Sirt1 expression, increased phosphorylations of LKB1 and AMPK, and promoted Nrf2 nuclear translocation in the livers of APAP-intoxicated mice. Hepatic transcriptions of HO-1 and GCLC, which are downstream antioxidant genes of Nrf2, were also significantly increased in response to ERS. Our results collectively indicated that ERS effectively attenuates APAP-induced liver injury by activating LKB1/AMPK/Nrf2 cascade. Upregulated expression of Sirt1 plays a crucial role in ERS-mediated activation of LKB1.

Theaflavine inhibits hepatic stellate cell activation by modulating the PKA/LKB1/AMPK/GSK3ß cascade and subsequently enhancing Nrf2 signaling.

Activation of hepatic stellate cells (HSCs) constitutes a crucial etiological factor leading to liver fibrosis. Theaflavine (TF) is a characteristic bioactive compound in fermented tea. Here, we found that TF attenuated the activation of LX-2 HSCs induced by transforming growth factor-ß1 (TGF-ß1). TF potentiated nuclear factor erythroid 2-related Factor 2 (Nrf2) signaling. Knockdown of Nrf2 abrogated TF-mediated resistance to TGF-ß1. Liver kinase B1 (LKB1), AMP-activated kinase (AMPK), and glycogen synthase kinase-3ß (GSK3ß) are upstream regulators of Nrf2. TF modulated the LKB1/AMPK/GSK3ß axis. Inhibition of AMPK or knockdown of LKB1 crippled TF-mediated potentiation of Nrf2. Protein kinase A (PKA) catalyzes LKB1 phosphorylation. In LX-2 cells, TF increased the LKB1/PKA interaction without affecting their contents. Inhibition of PKA abolished TF-mediated potentiation of LKB1/Nrf2 and abrogated the inhibitory effects of TF on their activation. TF also enhanced direct binding between purified catalytic subunit α of PKA (PKA-Cα) and LKB1 proteins in vitro. Molecular docking indicated that TF showed binding activity with both LKB1 and PKA-Cα proteins. In mouse primary HSCs, TF elevated LKB1/PKA-Cα binding, boosted LKB1 phosphorylation, potentiated Nrf2 and suppressed their spontaneous activation. PKA inhibition or LKB1 knockdown eliminated TF-mediated induction of Nrf2 and suppression of HSC activation. Furthermore, TF considerably alleviated CCl4-induced mouse liver fibrosis. In mouse livers, TF increased the LKB1/PKA-Cα interaction, upregulated LKB1 phosphorylation and modulated its downstream AMPK/GSK3ß/Nrf2 cascade. Our findings collectively indicated that TF suppresses HSC activation. Mechanistically, TF elevated the LKB1/PKA interaction in HSCs, which increased LKB1 phosphorylation and subsequently modulated the downstream AMPK/GSK3ß/Nrf2 axis.

The Value of Ultra-High-Frequency Ultrasound for the Differentiation between Superficial Basal Cell Carcinoma and Bowen's Disease.

BACKGROUND: The similar visual appearance of superficial basal cell carcinoma (sBCC) and Bowen's disease (BD) may cause confusion for diagnosis. OBJECTIVE: The aim of the study was to investigate the value of ultra-high-frequency ultrasound (uHFUS) in differentiating sBCC from BD. MATERIALS AND METHODS: This prospective study included a pilot cohort of 110 patients (73 BDs and 37 sBCCs) from November 2016 to October 2020 and a validation cohort of 42 patients (30 BDs and 12 sBCCs) from July 2021 to December 2021. Clinical and uHFUS features of pathologically confirmed sBCC and BD were assessed. A predictive model was developed based on the uHFUS features of the pilot cohort. Subsequently, the model was validated and compared with clinical diagnosis in the validation cohort. RESULTS: uHFUS features with significant differences between sBCC and BD included lesion surface, skin layer involvement, hyperkeratosis, and hyperechoic spots (all p < 0.05). A prediction model based on the above features was established to identify sBCC and BD in the pilot and validation cohorts with areas under the curve (AUC) of 0.908 and 0.923, sensitivity of 82.3% and 83.3%, specificity of 91.9% and 91.7%, and accuracy of 85.5% and 85.7%, respectively, which were significantly higher than those obtained by clinical diagnosis based on photographic pictures of lesions, with the AUC of 0.692, sensitivity of 63.3%, specificity of 75.3%, and accuracy of 66.7% (all p < 0.05). CONCLUSION: uHFUS provides detailed internal features of sBCC and BD, which facilitates the differentiation between sBCC and BD, and its diagnostic performance is superior to clinical diagnosis.