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Yi Zhang,1,2,* Hui Guo,1,* Brian Chi-Yan Cheng,1 Tao Su,1 Xiu-Qiong Fu,1 Ting Li,1 Pei-Li Zhu,1 Kai-Wing Tse,1 Si-Yuan Pan,3 Zhi-Ling Yu1,3,4 1Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong; 2Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, People’s Republic of China; 4Consun Chinese Medicines Research Centre for Renal Diseases, Hong Kong Baptist University, Hong Kong, People’s Republic of China *These authors contributed equally to this work Background: Dingchuan tang (asthma-relieving decoction), a formula of nine herbs, has been used for treating respiratory inflammatory diseases for >400 years in the People’s Republic of China. However, the mechanisms underlying the anti-inflammatory action of dingchuan tang is not fully understood. This study aims to investigate the effects of Dingchuan tang essential oil (DCEO) on inflammatory mediators and the underlying mechanism of action.Materials and methods: DCEO was extracted by steam distillation. Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were used as the cell model. Production of nitric oxide (NO) was determined by the Griess test. Protein secretion and mRNA levels of inflammatory mediators were measured by the enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Protein levels were examined by Western blot. Nuclear localization of nuclear factor-kappa B (NF-κB) was detected using immunofluorescence analyses.Results: DCEO significantly reduced LPS-triggered production of NO and prostaglandin E2 (PGE2) and decreased protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). LPS induced upregulation of protein and mRNA levels of cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]), and chemokines (monocyte chemoattractant protein-1 [MCP-1], chemokine [C-C motif] ligand 5 [CCL-5], and macrophage inflammatory protein [MIP]-1α) were suppressed by DCEO treatment. Phosphorylation and nuclear protein levels of transcription factors (activator protein-1 [AP-1], NF-κB, interferon regulatory factor 3 [IRF3]) were decreased by DCEO. Protein levels of phosphorylated IκB-α, IκB kinase α/β (IKKα/β), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), TGF β-activated kinase 1 (TAK1), TANK-binding kinase 1 (TBK1), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), and c-Jun N-terminal kinase (JNK) were lowered by DCEO. Moreover, degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) and IRAK4 induced by LPS was inhibited by DCEO treatment.Conclusion: Suppression of the interleukin-1 receptor-associated kinase (IRAK)/NF-κB, IRAK/AP-1 and TBK1/IRF3 pathways was associated with the inhibitory effects of DCEO on inflammatory mediators in LPS-stimulated RAW264.7 macrophages. This study provides a pharmacological justification for the use of dingchuan tang in managing inflammatory disorders. Keywords: traditional Chinese medicine, respiratory diseases, anti-inflammation, molecular pathways

Yi Zhang,1,2 Zhi-Wei Zhou,2 Hua Jin,2 Chengbin Hu,2 Zhi-Xu He,3 Zhi-Ling Yu,4 Kam-Ming Ko,5 Tianxin Yang,6 Xueji Zhang,7 Si-Yuan Pan,1 Shu-Feng Zhou2 1Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino–US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, People’s Republic of China; 4School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, People’s Republic of China; 5Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People’s Republic of China; 6Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA; 7Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People’s Republic of China Abstract: A number of drugs and herbal compounds have been documented to cause ­hepatoxicity. Schisandrin B (Sch B) is an active dibenzocyclooctadiene isolated from Schisandrae fructus, with a wide array of pharmacological activities. However, the potential hepatotoxicity of Sch B is a major safety concern, and the underlying mechanism for Sch B-induced liver toxic effects is not fully elucidated. In the present study, we aimed to investigate the liver toxic effects and the molecular mechanisms of Sch B in mouse liver and macrophage cells. The results have shown that Sch B exhibits potent grow inhibitory, proapoptotic, and proautophagic effects in AML-12 and RAW 264.7 cells. Sch B markedly arrested cells in G1 phase in both cell lines, accompanied by the down-regulation of cyclin dependent kinase 2 (CDK2) and cyclin D1 and up-regulation of p27 Kip1 and checkpoint kinase 1. Furthermore, Sch B markedly increased the apoptosis of AML-12 and RAW 264.7 cells with a decrease in the expression of B-cell lymphoma-extra-large and (Bcl-xl) B-cell lymphoma 2 (Bcl-2), but an increase in the expression of B-cell lymphoma 2-associated X protein (Bax). Sch B promoted the cleavage of caspase 3 and poly-adenosine diphosphate-ribose polymerase (PARP) in both cell lines. Additionally, Sch B significantly induced autophagy of AML-12 and RAW 264.7 cells. Sch B inhibited the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, as indicated by their altered phosphorylation, contributing to the proautophagic effect of Sch B. Taken together, our findings show that the inducing effects of Sch B on cell cycle arrest, apoptosis, and autophagy may contribute to its liver toxic effects, which might provide a clue for the investigation of the molecular toxic targets and underlying mechanisms for Sch B-induced hepatotoxicity in herbal consumers. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Sch B for clinical use.Keywords: herbal medicine, liver toxicity, mTOR, Bcl-2, AML-12 cell, RAW 264.7 cell

Pei-Li Zhu,1 Si-Yuan Pan,1 Shu-Feng Zhou,2 Yi Zhang,1 Xiao-Yan Wang,1 Nan Sun,1 Zhu-Sheng Chu,1 Zhi-Ling Yu,3 Kam-Ming Ko41Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, People’s Republic of China; 4Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People’s Republic of ChinaBackground: Currently, combined therapy using herbs and synthetic drugs has become a feasible therapeutic intervention against some diseases. The purpose of this study was to assess the effects of supplementation with fenofibrate (FF), a chemical drug used for the treatment of hyperlipidemia, and the aqueous extract of Schisandrae Fructus (SF, a Chinese herb) pulp (AqSF-P) or an SF-related synthetic analog, bicyclol (BY), on serum/hepatic lipid levels and liver status in normal and hypercholesterolemic (HCL) mice.Methods: Male mice obtained from the Institute of Cancer Research (ICR) were fed on a normal diet (ND) or high cholesterol/bile salt (0.5%/0.15%, w/w) diet (HCBD) containing FF (0.03% or 0.1%, w/w) with or without AqSF-P (0.3%-9.0%, based on crude herbal material, w/w) or BY (0.025%, w/w) for 10 days. Then serum lipid levels and alanine aminotransferase (ALT) activity, as well as hepatic triglyceride (TG), total cholesterol (TC), and glucose levels, were measured.Results: Oral supplementation with FF significantly reduced serum and hepatic TG, TC, and hepatic glucose levels (approximately 79%) in mice fed with ND or HCBD. FF supplementation combined with AqSF-P or BY increased FF-induced reduction in hepatic TC and TG contents in ND-fed mice (up to 67%) and in HCBD-fed mice (up to 54%), when compared with FF supplementation alone. Hepatic glucose-lowering effect of FF was enhanced (up to 19%) by AqSF-P cosupplementation in both normal and HCL mice. FF supplementation enhanced the excretion of fecal TC (by 75%) in mice fed with HCBD. Fecal TC contents were increased by 14%/9% in the combination therapy with FF and AqSF-P in ND-/HCBD-fed mice. Serum ALT activity was elevated by 45% in HCBD-fed mice. FF caused a significant increase in ALT activity by 198% and 120% in normal and HCL mice, respectively. BY markedly attenuated the ALT activity by 54% in mice fed with ND supplemented with 0.1% FF and by 42% in mice fed with HCBD supplemented with 0.03% FF.Conclusion: AqSF-P cosupplementation augmented the hepatic lipid-/glucose-lowering effects of FF. BY ameliorated FF-induced liver injury in normal and HCL mice.Keywords: bicyclol, hepatotoxicity, synergist, fatty liver disease, fat index, interaction

Yi Zhang,1 Si-Yuan Pan,1 Shu-Feng Zhou,2 Xiao-Yan Wang,1 Nan Sun,1 Pei-Li Zhu,1 Zhu-Sheng Chu,1 Zhi-Ling Yu,3 Kam-Ming Ko4 1Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3School of Chinese Medicine, Hong Kong Baptist University, 4Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China Background: Schisandrin B (Sch B), a dibenzocyclooctadiene compound, is isolated from schisandrae fructus (SF). This study was conducted to compare the time- and dose-response between Sch B- and SF oil (SFO)-induced changes in hepatic and serum parameters in mice. Methods: Institute of Cancer Research (ICR) mice were given a single oral dose of Sch B (0.125–2 g/kg) or SFO (0.3–5 g/kg). Serum alanine aminotransferase (ALT) activity, hepatic malondialdehyde, and triglyceride (TG) levels were measured at increasing time intervals within 6–120 hours postdosing. Results: Serum ALT activity was elevated by 60%, with maximum effect (Emax) =45.77 U/L and affinity (KD) =1.25 g/kg at 48–96 hours following Sch B, but not SFO, treatment. Sch B and SFO treatments increased hepatic malondialdehyde level by 70% (Emax =2.30 nmol/mg protein and KD =0.41 g/kg) and 22% (Emax =1.42 nmol/mg protein and KD =2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%–60% (Emax =11.01, KD =0.68 g/kg) and 8%–32% (Emax =9.88, KD =4.47 g/kg) at 12–120 hours and 24–120 hours after the administration of Sch B and SFO, respectively. Hepatic TG level was increased by 40%–158% and 35%–85%, respectively, at 12–96 hours and 6–48 hours after Sch B and SFO treatment, respectively. The values of Emax and KD for Sch B/SFO-induced increase in hepatic TG were estimated to be 22.94/15.02 µmol/g and 0.78/3.03 g/kg, respectively. Both Sch B and SFO increased serum TG (up to 427% and 123%, respectively), with the values of Emax =5.50/4.60 mmol/L and KD =0.43/2.84 g/kg, respectively. Conclusion: The findings indicated that Sch B/SFO-induced increases in serum/hepatic parameters occurred in a time-dependent manner, with the time of onset being serum TG level < hepatic TG level < hepatic index < serum ALT activity. However, the time of recovery of these parameters to normal values varied as follow: serum TG level < hepatic TG level and liver injury < hepatic index. The Emax and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO. Keywords: pharmacodynamics, hepatomegaly, alanine aminotransaminase, affinity, maximum effect

© 2017, National Academy of Sciences. All rights reserved. Human schistosomiasis, caused by Schistosoma species, is a major public health problem affecting more than 700 million people in 78 countries, with over 40 mammalian host reservoir species complicating the transmission ecosystem. The primary cause of morbidity is considered to be granulomas induced by fertilized eggs of schistosomes in the liver and intestines. Some host species, like rats (Rattus norvegicus), are naturally intolerant to Schistosoma japonicum infection, and do not produce granulomas or pose a threat to transmission, while others, like mice and hamsters, are highly susceptible. The reasons behind these differences are still a mystery. Using inducible nitric oxide synthase knockout (iNOS−/−) Sprague–Dawley rats, we found that inherent high expression levels of iNOS in wild-type (WT) rats play an important role in blocking growth, reproductive organ formation, and egg development in S. japonicum, resulting in production of nonfertilized eggs. Granuloma formation, induced by fertilized eggs in the liver, was considerably exacerbated in the iNOS−/−rats compared with the WT rats. This inhibition by nitric oxide acts by affecting mitochondrial respiration and energy production in the parasite. Our work not only elucidates the innate mechanism that blocks the development and production of fertilized eggs in S. japonicum but also offers insights into a better understanding of host–parasite interactions and drug development strategies against schistosomiasis.

Hole-transporting material (HTMs) are crucial for obtaining the stability and high efficiency of perovskite solar cells (PSCs). However, the current state-of-the-art n-i-p PSCs relied on the use of 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-OMeTAD) exhibit inferior intrinsic and ambient stability due to the p-dopant and hydrophilic Li-TFSI additive. In this study, a new spiro-type HTM with a critical quasi-planar core (Z-W-03) is developed to improve both the thermal and ambient stability of PSCs. The results suggest that the planar carbazole structure effectively passivates the trap states compared to the triphenylamine with a propeller-like conformation in spiro-OMeTAD. This passivation effect leads to the shallower trap states when the quasi-planar HTMs interact with the Pb-dimer. Consequently, the device using Z-W-03 achieves a higher V oc of 1.178 V compared to the spiro-OMeTAD's 1.155 V, resulting in an enhanced efficiency of 24.02 %. In addition, the double-column π-π stacking of Z-W-03 results in high hole mobility (~10 -4  cm 2  V -1  s -1 ) even without p-dopant. Moreover, when the surface interface is modified, the undoped Z-W-03 device can achieve an efficiency of nearly 23 %. Compared to the PSCs using spiro-OMeTAD, those with Z-W-03 exhibit enhanced stability under N 2 and ambient conditions. This superior performance is attributed to the quasi-planar core structure and the presence of multiple CH/π and π-π intermolecular stacking in Z-W-03. The multiple CH/π and π-π intermolecular contacts of HTMs can improve the hole hopping transport. Therefore, it is imperative to focus on further molecular structure design and optimization of spiro-type HTMs incorporating quasi-planar cores and carbazole moieties for the commercialization of PSCs., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Polybrominated diphenyl ethers (PBDEs) and their alternatives (e.g., dechlorane plus (DPs) and decabromodiphenyl ethane (DBDPE)) are ubiquitous in various environmental media. However, limited data is available on these chemicals in edible fish species from the wide-open South China Sea (SCS). In the present study, ten legacy PBDEs and three substitutions (DBDPE and two DPs) were analyzed in 16 wild fish species sampled from the open SCS to investigate their spatial and species-specific variations. The results showed that the total concentrations of PBDEs, DBDPE, and DPs in fish samples were in the range of 1.69-47.6, not detected (nd) to 21.0, and nd to 3.80 ng/g lipid weight (lw), respectively. BDEs 47, 209 and 100 were the dominant target PBDE congeners, representing 49.2%, 17.2% and 9.93% of the total PBDE concentrations, respectively. Higher concentrations of PBDEs, DBDPE, and DPs were found in fish species from the Wanshan Archipelago compared to those from the Mischief Reef and the Yongxing Island, suggesting the significant influence of anthropogenic activities. Species-specific differences in levels of PBDEs were observed, with the order of bathydemersal > demersal > pelagic ≈ reef-associated > benthopelagic species. The average f anti value of all fish samples was 0.68, suggesting commercial DP products as a contamination source. The levels of PBDEs, DPs, and DBDPE in fish samples were relatively low compared with those from other locations around the globe. Finally, the health risks concerning the ingestion of BDEs 47, 99, 153 and 209 via fish consumption collected from the SCS are negligible., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Upper digestive tract cancers, such as oral cavity, laryngeal, esophageal, and gastric cancers, account for 10% of cancer cases and 14.5% of cancer-related deaths worldwide. Conventional treatments often provide limited survival benefits and are frequently associated with adverse effects and drug resistance. Chinese herbal drugs (CHDs) are widely used in the Far East for managing these cancers. In this narrative review, we summarize current clinical studies (published up to June 2024) on the use of 138 CHDs in the treatment of cancers and precancerous lesions of the upper digestive tract. For cancer treatment, 126 CHDs were tested, all in combination with conventional therapies. Each CHD increased the clinical efficacy and/or reduced the adverse effects of conventional therapies. The five-year survival rate is a critical metric for evaluating the clinical benefits of cancer treatments. Four of the CHDs were reported to increase five-year survival rates of patients receiving conventional therapies. The four CHDs are Sishen Jiedu Decoction, Pingxiao Tablet, Fuzheng Guben Granule, and Buyang Huanwu Tang. For managing precancerous lesions, 12 CHDs were tested: six used alone and six in combination with conventional therapies. Zengshengping is one of the CHDs used alone and is the only one that has been proven to prevent the development of esophageal cancer with convincing evidence. This review provides information about the clinical benefits of CHDs and offers a reference for their rational application in treating upper digestive tract cancers. The reviewed studies have limitations: most trials had small sample sizes and were not multi-center; only one study investigated the mechanisms of action of the studied CHD; and the active components of CHDs were not explored. To promote international recognition of CHDs, rigorously designed studies on clinical outcomes, mechanisms of action, and active components are warranted. Moreover, the studied CHDs should be standardized., (© 2024. The Author(s).)

Objective: This study summarizes and analyzes the characteristics of deep circumflex iliac artery (DCIA) flap reconstruction for maxillary defects and proposes a generalized protocol under the guidance of computer-assisted technique to enhance surgical efficiency and success rate., Materials and Methods: We retrospectively reviewed 10 cases of maxillary defects reconstructed using DCIA flaps under the application of computer-assisted technique, collecting clinical data for statistical analysis., Results: These cases included 2 cystic lesions, 2 mucinous tumors, 2 ameloblastomas, 1 mucoepidermoid carcinoma, 1 odontogenic fibroma, 1 bone defect following squamous cell carcinoma (SCC) surgery, and 1 ossifying fibroma. According to Brown's classification system, there were 7 Type IIb defects, 1 Type IId defect, 1 Type IIIb defect, and 1 Type IIId defect. The length of the iliac bone harvested ranged from 42 mm to 100 mm, and the width from 20 mm to 51 mm. In 7 patients, chimeric iliac myofascial flaps were used; in 2 patients, deep circumflex iliac artery perforator (DCIAP) flaps were utilized; and in 1 patient, a vascularized iliac crest was employed. The recipient vessels were the facial artery and vein in all cases. Intraoral anastomoses were performed in 4 cases, and submandibular anastomoses in 6 cases. The donor site was chosen from the ipsilateral ilium in 8 patients and from the contralateral ilium in 2 patients. The mean operative time was 8.74 hours. Postoperatively, 9 patients recovered well without any complications, while 1 patient experienced necrosis of the bone flap on the first day after surgery and underwent secondary reconstruction using a vascularized fibula flap. The average postoperative hospital stay was 8.6 days., Conclusion: The combination of DCIA flaps with computer-assisted technique provides a reliable method for the reconstruction of maxillary defects and functional restoration. Establishing generalized procedures could facilitate its broader application., Competing Interests: Declaration of conflicting interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Malignancies can compromise systemic innate immunity, but the underlying mechanisms are largely unknown. Here, we find that tumor-derived small extracellular vesicles (sEVs; TEVs) deliver PD-L1 to host macrophages, thereby impeding antibacterial immunity. Mice implanted with Rab27a-knockdown tumors are more resistant to bacterial infection than wild-type controls. Injection of TEVs into mice impairs macrophage-mediated bacterial clearance, increases systemic bacterial dissemination, and enhances sepsis score in a PD-L1-dependent manner. Mechanistically, TEV-packaged PD-L1 inhibits Bruton's tyrosine kinase/PLCγ2 signaling-mediated cytoskeleton reorganization and reactive oxygen species generation, impacting bacterial phagocytosis and killing by macrophages. Neutralizing PD-L1 markedly normalizes macrophage-mediated bacterial clearance in tumor-bearing mice. Importantly, circulating sEV PD-L1 levels in patients with tumors can predict bacterial infection susceptibility, while patients with tumors treated with αPD-1 exhibit fewer postoperative infections. These findings identify a mechanism by which cancer cells dampen host innate immunity-mediated bacterial clearance and suggest targeting TEV-packaged PD-L1 to reduce bacterial infection susceptibility in tumor-bearing conditions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

A 32-year-old male presented with a painless swelling on his nasal dorsum, persisting for over 3 months. He reported a gradual increase in the size of the mass, with no identifiable triggers except occasional skin redness. He denied nosebleeds, rhinorrhea, nasal obstruction, trauma, prior surgery, or spontaneous pain. His medical history revealed gout, managed with colchicine and diclofenac. Despite dietary and pharmaceutical interventions, he continued to have bouts of hyperuricemia, with blood uric acid levels measuring 739 μmol/L. Multiple tophi were evident, especially on the left first metatarsophalangeal joint (Figure 1A). Examination revealed an irregularly shaped, immobile, hard swelling at the nasal radix, measuring 3 cm×2 cm. Computerized tomography (CT) imaging of the nose showed bilateral nasal bone destruction from the lesion. Given its impact on the patient's appearance and his history of gout, the mass was initially diagnosed as unusual gouty tophus. The patient requested surgical removal of the lesion, and the dissection revealed a mass partly encased by a capsule-like connective tissue adherent to the nasal bone. As the lesion damaged the nasal bone, removal of the lesion led to defect of nasal bone. After an extensive rinse of the surgery site, the incision was sutured., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

The removal of tumors at the root of the tongue can be challenging due to anatomic constraints (deep location of the root of the tongue, obstruction by the mandible), leading to poor surgical visibility. Clear visibility of the surgical field is crucial for complete excision to reduce recurrence, hence the need to choose an appropriate surgical approach based on the tumor's location and size. In this report, the authors describe a case where a midline mandibulotomy and temporary midline glossectomy were utilized to expose and resect a tumor at the root of the tongue. This approach allowed for the complete removal of the tumor while preserving the anterior tongue tissue and bilateral lingual arteries. The defect was then reconstructed using an anterolateral thigh flap. The patient showed good postoperative recovery with significant improvement in swallowing and speech functions. The authors emphasize that the surgical treatment of squamous cell carcinoma (SCC) at the root of the tongue should strive to ensure radical tumor removal while preserving surrounding healthy tissues and critical anatomic structures, particularly the lingual arteries, to facilitate better postoperative recovery for patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

The amelioration of cadmium (Cd 2+ ) toxicity in plants by ammonium (NH 4 + ) has been widely investigated. However, the molecular mechanisms underpinning this amelioration have remained ambiguous. Here, we found that NH 4 + significantly reduces Cd 2+ accumulation and enhances antioxidant capacity by increasing ABA accumulation, which, in turn, improves Cd 2+ tolerance in rice seedlings. A combination of qPCR, yeast-one-hybrid and dual-luciferase assays, and CUT&RUN-qPCR methods demonstrates that OsbZIP20 directly binds to the promoters of OsAPX2 and OsCATA, activating their transcription, and we show that the process requires phosphorylation modification of OsbZIP20 by OsSAPK9. Under Cd 2+ stress, Osbzip20 and Ossapk9 mutants show reduced peroxidase and catalase activities, higher H 2 O 2 accumulation, and reduced Cd 2+ tolerance. In sum, our results elucidate a novel mechanism by which NH 4 + enhances Cd 2+ resistance, through ABA-SAPK9-bZIP20-APX2/CATA, offering a new strategy for improving Cd 2+ resistance in rice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

PD-L1-positive extracellular vesicles (PD-L1 + EVs) play a pivotal role as predictive biomarkers in cancer immunotherapy. These vesicles, originating from immune cells (I-PD-L1 + EVs) and tumor cells (T-PD-L1 + EVs), hold distinct clinical predictive values, emphasizing the importance of deeply differentiating the PD-L1 + EV subtypes for effective liquid biopsy analyses. However, current methods such as ELISA lack the ability to differentiate their cellular sources. In this study, a novel step-wedge microfluidic chip that combines magnetic microsphere separation with single-layer fluorescence counting is developed. This chip integrates magnetic microspheres modified with anti-PD-L1 antibodies and fluorescent nanoparticles targeting EpCAM (tumor cell marker) or CD45 (immunocyte marker), enabling simultaneous quantification and sensitive analysis of PD-L1 + EV subpopulations in oral squamous cell carcinoma (OSCC) patients' saliva without background interference. Analysis results indicate reduced levels of I-PD-L1 + EVs in OSCC patients compared to those in healthy individuals, with varying levels of heterogeneous PD-L1 + EVs observed among different patient groups. During immunotherapy, responders exhibit decreased levels of total PD-L1 + EVs and T-PD-L1 + EVs, accompanied by reduced levels of I-PD-L1 + EVs. Conversely, nonresponders show increased levels of I-PD-L1 + EVs. Utilizing the step-wedge microfluidic chip allows for simultaneous detection of PD-L1 + EV subtypes, facilitating the precise prediction of oral cancer immunotherapy outcomes.

Background: Due to the relative rarity of malignant sublingual gland tumors, diagnosing and treating them clinically pose challenges. Hence, there's a need to explore the pathological types, characteristics, treatment methods, and prognosis of primary malignant tumors of the sublingual gland to improve our understanding and management of these rare yet highly malignant conditions., Methods: This study reviewed cases of primary malignant sublingual gland tumors, analyzing their characteristics. The treatment methods included surgical excision, with additional radiotherapy, or brachytherapy for advanced stages or positive surgical margins. The study also summarized different treatment approaches, including lymph node dissection and soft tissue reconstruction using free flaps such as the anterolateral thigh flap and forearm flap., Results: We have gathered 23 cases of sublingual gland malignancies treated at the Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, from January 2013 to May 2024. The most common pathological types were adenoid cystic carcinoma and mucoepidermoid carcinoma, with rare cases of mucosa-associated lymphoid tissue (MALT) lymphoma and nonspecific salivary gland clear cell carcinoma. Early diagnosis and surgical intervention were crucial for a favorable prognosis. Marginal mandibulectomy was necessary for cases involving the mandible. Patients with positive preoperative lymph node detection required cervical lymph node dissection. Extensive tissue defects in the floor of the mouth were effectively reconstructed with free flaps to prevent oral-mandibular fistula., Conclusion: Surgical excision remains the preferred treatment for malignant sublingual gland tumors. Early diagnosis and comprehensive surgical management are essential for improving prognosis. The study's limitations include a small sample size and short follow-up duration, necessitating further research with larger clinical samples to confirm these findings., (© 2024. The Author(s).)

Gingival squamous cell carcinoma (SCC) of the posterior mandible often requires marginal resection of the mandible in conventional surgery. However, the posterior location of the lesion can limit surgical visibility, which is critical for complete tumor removal and minimizing recurrence. Typically, marginal resection of the posterior mandible is achieved through a midline lower lip incision and mental nerve transection, providing adequate exposure but resulting in nerve damage, lip numbness, and facial scarring. In this paper, we describe a case using a submandibular incision for neck dissection, extending from the mandibular angle to the mental foramen, to fully expose the posterior mandible. The intraoral incision, extending 1 cm beyond the tumor margin, connected with the submandibular incision. Under direct vision, we performed a marginal resection of the mandible, preserving the inferior alveolar neurovascular bundle and the mental nerve, and maintaining at least 1 cm of the inferior mandibular margin. This technique achieved complete tumor removal while preserving mental nerve function and lower lip integrity, reducing surgical difficulty and patient trauma. This approach maintains nerve function and aesthetics as much as possible, with a faster postoperative recovery. In treating gingival SCC of the posterior mandible, it is essential to preserve surrounding healthy tissue and critical anatomical structures, minimizing postoperative complications while ensuring complete tumor resection., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the characteristics and treatment modalities of malignant tumors originating from the sublingual gland, as well as evaluate the therapeutic outcomes following free flap reconstruction., Methods: A retrospective statistical analysis was conducted on the clinical data of nine patients diagnosed with malignant neoplasms tumor of the sublingual gland., Results: Nine case of malignant tumors originated from the sublingual glandular tissue, encompassing eight adenoid cystic carcinoma (ACC) and a single case of bipartite differentiated carcinoma-a hybrid of epithelial-myoepithelial carcinoma and adenoid cystic carcinoma. Among the nine patients, four anterolateral thigh flaps were used (three of which were thin flaps), and five forearm flaps were also empoyed. The size of flaps varied, with the lengths ranging from 4 cm to 9 cm, and the widths ranging from 2.5 cm to 6 cm. The vessels chosen for anastomosis were the superior thyroid artery in seven cases, the facial artery in one case, and the lingual artery in one case. Among the eight patients who underwent dissection of cervical lymph nodes, metastasis were found in one case. Two patients underwent adjuvant radiotherapy. Upon postoperative follow-up, there was no recurrence in any of the nine patients ., Conclusion: The anterolateral thigh perforator flap thinning technique can be employed for postoperative reconstruction of malignant sublingual gland tumors., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Pea protein isolate (PPI) was used as a carrier matrix to load tannic acid (TA) due to its multiple cavity structures and reaction sites, after that, magnesium ion (M) was further added to form more stable carrier structures. PPI was covalently bound with TA to form TA-PPI complexes in alkaline conditions, then M induced the aggregation of TA-PPI to produce M-TA-PPI complexes. TA mainly interacted with free amino groups and sulfhydryl groups of PPI, thereby decreasing their content in complexes. TA further decreased the α-helix content and increased the β-sheet and β-turn content in TA-PPI complexes correspondingly, nevertheless the M would decline these changes in M-TA-PPI complexes. As a result of binding, TA and M jointly increased the average molecular size of complexes. The higher TA addition amount (10-20 mg/g PPI) was conducive to the stronger intramolecular interactions (more hydrophobic interactions and disulfide bonds), gel structure (higher hardness value) and storage modulus in M-TA-PPI gels. Compared with TA-PPI complexes, M-TA-PPI complexes showed higher stability in gastric digestion and higher TA releasement and antioxidant capacity of its digesta in intestinal digestion. This kind of metal-phenolics-protein complexes may have potentials to be a stable and efficient carrier for loading gastric sensitive polyphenols., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The vascularized iliac crest flap has garnered widespread acclaim within the field of mandibular reconstruction attributable to its sufficient bone mass and congruent curved morphology. However, when the precise orientation of the iliac crest is imperative during mandibular reconstruction and there exists an accompanying defect within the oral soft tissue, the indispensability of an additional flap to facilitate concurrent defect repair becomes evident. In such instances, the submental island flap emerges as an exemplary candidate., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Background: In recent years, the utilization of autogenous vascularized iliac crest flap for repairing jaw defects has seen a significant rise. However, the visual monitoring of iliac bone flaps present challenges, frequently leading to delayed detection of flap loss. Consequently, there's a urgent need to develop effective indicators for monitoring postoperative complications in iliac crest flaps., Methods: A retrospective analysis was conducted on 160 patients who underwent vascularized iliac crest flap transplantation for jawbone reconstruction from January 2020 to December 2022. We investigated the changes in D-dimer levels among patients with or without postoperative complications. Additionally, multivariable logistic regression analysis was performed to explore potential individual risk factors, including surgical duration, age, pathology type, absolute and relative D-dimer levels, and gender, culminating in the development of a nomogram., Results: On the first day following surgery, patients who experienced thrombosis exhibited a substantial increase in plasma D-dimer levels, reaching 3.75 mg/L, 13.84 times higher than the baseline. This difference was statistically significant (P < 0.05) compared to patients without postoperative complications. Furthermore, the nomogram we have developed and validated effectively predicts venous thrombosis, assigning individual risk scores to patients. This predictive tool was assessed in both training and validation cohorts, achieving areas under the curve (AUC) of 0.630 and 0.600, with the 95% confidence intervals of 0.452-0.807 and 0.243-0.957, respectively., Conclusions: Our study illustrates that postoperative plasma D-dimer levels can serve as a sensitive biomarker for monitoring thrombosis-induced flap loss. Moreover, we have developed a novel prediction model that integrates multiple factors, thereby enhancing the accuracy of early identification of patients at risk of thrombosis-associated flap loss. This advancement contributes to improving the overall management and outcomes of such procedures., (© 2024. The Author(s).)

In recent years, the cargo profiles of extracellular vesicles (EVs), which were inherited from their parent cells, have emerged as a reliable biomarker for liquid biopsy (LB) in disease diagnosis, prognosis, and treatment monitoring. EVs secreted by different cells exhibit distinct characteristics, particularly in terms of disease diagnosis and prediction. However, currently available techniques for the quantitative analysis of EV cargoes, including enzyme-linked immunosorbent assay (ELISA), cannot specifically identify the cellular origin of EVs, thus seriously affecting the accuracy of EV-based liquid biopsy. In light of this, we here developed ultrabright fluorescent nanosphere (FNs)-based test strips which have the unique capability to specifically assess the levels of PD-L1-positive EVs (PD-L1 + EVs) derived from both tumor cells and immune cells in bodily fluids. The levels of PD-L1 + EV subpopulations in human saliva were quantified using the ultrabright fluorescent nanosphere-based test strips with more convenience and higher efficiency (detection time <30 min). Results demonstrated that the fluorescence intensity of the test line exhibited a good linear relationship respectively with the PD-L1 levels of tumor cell- ( R 2 = 0.993) and immune cell-derived EVs ( R 2 = 0.982) in human saliva. By assessing the levels of PD-L1 + EV subpopulations, our test strips hold immense potential for advancing the application of PD-L1 + EV subpopulation-based predictions in tumor diagnosis and prognosis evaluation. In summary, by integrating the benefits of FNs and lateral flow chromatography, we here provide a strategy to accurately measure the cargo levels of EVs originating from diverse cell sources in bodily fluids.

Habitual daytime napping is a common behavioral and lifestyle practice in particular countries and is often considered part of a normal daily routine. However, recent evidence suggests that the health effects of habitual daytime napping are controversial. We systematically searched PubMed, Web of Science, Embase, and Cochrane Library databases from inception to March 9, 2024, to synthesize cohort studies of napping and health outcome risk. A total of 44 cohort studies with 1,864,274 subjects aged 20-86 years (mean age 56.4 years) were included. Overall, habitual napping increased the risk of several adverse health outcomes, including all-cause mortality, cardiovascular disease, metabolic disease, and cancer, and decreased the risk of cognitive impairment and sarcopenia. Individuals with a napping duration of 30 min or longer exhibited a higher risk of all-cause mortality, cardiovascular disease, and metabolic disease, whereas those with napping durations less than 30 min had no significant risks. No significant differences in napping and health risks were observed for napping frequency, percentage of nappers, sample size, sex, age, body mass index, follow-up years, or comorbidity status. These findings indicate that individuals with a long napping duration should consider shortening their daily nap duration to 30 min or less., Competing Interests: Declaration of competing interest The authors do not have any conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is a fatal neurodegenerative disease in which senile plaques and neurofibrillary tangles are crucially involved in its physiological and pathophysiological processes. Growing animal and clinical studies have suggested that AD is also comorbid with some metabolic diseases, including type 2 diabetes mellitus (T2DM), and therefore, it is often considered brain diabetes. AD and T2DM share multiple molecular and biochemical mechanisms, including impaired insulin signaling, oxidative stress, gut microbiota dysbiosis, and mitochondrial dysfunction. In this review article, we mainly introduce oxidative stress and mitochondrial dysfunction and explain their role and the underlying molecular mechanism in T2DM and AD pathogenesis; then, according to the current literature, we comprehensively evaluate the possibility of regulating oxidative homeostasis and mitochondrial function as therapeutics against AD. Furthermore, considering dietary polyphenols' antioxidative and antidiabetic properties, the strategies for applying them as potential therapeutical interventions in patients with AD symptoms are assessed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A ternary complex composed of soybean protein isolated (SPI), tannic acid (TA) and magnesium ion (M) was established to enhance the capability of protein carriers for TA delivery. SPI was firstly covalently bind with TA (TA-SPI) and then M was employed to form the ternary complex (M-TA-SPI). Their structures, gel and digestion properties were further investigated. TA was observed to covalently bind with SPI. TA-SPI and M-TA-SPI complexes showed different molecule size and spatial structures after binding with M and TA. The increasing of TA amount changed the intramolecular interactions, microstructure and texture properties of M-TA-SPI gels. Compared with TA-SPI, M retarded the gastric digestion of M-TA-SPI and caused higher TA release amount in intestinal tract. In this study, M-TA-SPI was determined to be a good carrier to protect and release TA in gastrointestinal digestion. This kind of complex may have potential applications for loading polyphenols in nutraceuticals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In Asian populations with non-small-cell lung cancer (NSCLC), EGFR mutations are highly prevalent, occurring in roughly half of these patients. Studies have revealed that individuals with EGFR mutation typically fare worse with immunotherapy. In patients who received EGFR tyrosine kinase inhibitor (TKI) treatment followed by anti-PD-1 therapy, poor results were observed. The underlying mechanism remains unclear. We used high-resolution flow cytometry and ELISA to detect the circulating level of small extracellular vesicle (sEV) PD-L1 in NSCLC individuals with EGFR mutations before and after receiving TKIs. The secretion amount of sEV PD-L1 of lung cancer cell lines with EGFR mutations under TKI treatment or not were detected using high-resolution flow cytometry and Western blotting. The results revealed that patients harboring EGFR mutations exhibit increased levels of sEV PD-L1 in circulation, which inversely correlated with the presence of CD8 + T cells in tumor tissues. Furthermore, tumor cells carrying EGFR mutations secrete a higher quantity of PD-L1-positive sEVs. TKI treatment appeared to amplify the levels of PD-L1-positive sEVs in the bloodstream. Mutation-induced and TKI-induced sEVs substantially impaired the functionality of CD8 + T cells. Importantly, our findings indicated that EGFR mutations and TKI therapies promote secretion of PD-L1-positive sEVs via distinct molecular mechanisms, namely the HRS and ALIX pathways, respectively. In conclusion, the increased secretion of PD-L1-positive sEVs, prompted by genetic alterations and TKI administration, may contribute to the limited efficacy of immunotherapy observed in EGFR -mutant patients and patients who have received TKI treatment.

Inflammatory bowel disease (IBD) is characterized by persistent damage to the intestinal barrier and excessive inflammation, leading to increased intestinal permeability. Current treatments of IBD primarily address inflammation, neglecting epithelial repair. Our previous study has reported the therapeutic potential of notoginsenoside R1 (NGR1), a characteristic saponin from the root of Panax notoginseng, in alleviating acute colitis by reducing mucosal inflammation. In this study we investigated the reparative effects of NGR1 on mucosal barrier damage after the acute injury stage of DSS exposure. DSS-induced colitis mice were orally treated with NGR1 (25, 50, 125 mg·kg -1 ·d -1 ) for 10 days. Body weight and rectal bleeding were daily monitored throughout the experiment, then mice were euthanized, and the colon was collected for analysis. We showed that NGR1 administration dose-dependently ameliorated mucosal inflammation and enhanced epithelial repair evidenced by increased tight junction proteins, mucus production and reduced permeability in colitis mice. We then performed transcriptomic analysis on rectal tissue using RNA-sequencing, and found NGR1 administration stimulated the proliferation of intestinal crypt cells and facilitated the repair of epithelial injury; NGR1 upregulated ISC marker Lgr5, the genes for differentiation of intestinal stem cells (ISCs), as well as BrdU incorporation in crypts of colitis mice. In NCM460 human intestinal epithelial cells in vitro, treatment with NGR1 (100 μM) promoted wound healing and reduced cell apoptosis. NGR1 (100 μM) also increased Lgr5 + cells and budding rates in a 3D intestinal organoid model. We demonstrated that NGR1 promoted ISC proliferation and differentiation through activation of the Wnt signaling pathway. Co-treatment with Wnt inhibitor ICG-001 partially counteracted the effects of NGR1 on crypt Lgr5 + ISCs, organoid budding rates, and overall mice colitis improvement. These results suggest that NGR1 alleviates DSS-induced colitis in mice by promoting the regeneration of Lgr5 + stem cells and intestinal reconstruction, at least partially via activation of the Wnt/β-Catenin signaling pathway. Schematic diagram of the mechanism of NGR1 in alleviating colitis. DSS caused widespread mucosal inflammation epithelial injury. This was manifested by the decreased expression of tight junction proteins, reduced mucus production in goblet cells, and increased intestinal permeability in colitis mice. Additionally, Lgr5 + ISCs were in obviously deficiency in colitis mice, with aberrant down-regulation of the Wnt/β-Catenin signaling. However, NGR1 amplified the expression of the ISC marker Lgr5, elevated the expression of genes associated with ISC differentiation, enhanced the incorporation of BrdU in the crypt and promoted epithelial restoration to alleviate DSS-induced colitis in mice, at least partially, by activating the Wnt/β-Catenin signaling pathway., (© 2024. The Author(s).)

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy. Prior research has illuminated reasons behind drug resistance, including increased drug efflux, alterations in drug targets, and abnormal activation of oncogenic pathways. However, there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment (TME). Recent studies on extracellular vesicles (EVs) have provided valuable insights. EVs are membrane-bound particles secreted by all cells, mediating cell-to-cell communication. They contain functional cargoes like DNA, RNA, lipids, proteins, and metabolites from mother cells, delivered to other cells. Notably, EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs. This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance, covering therapeutic approaches like chemotherapy, targeted therapy, immunotherapy and even radiotherapy. Detecting EV-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance. Additionally, targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance. We highlight the importance of conducting in-depth mechanistic research on EVs, their cargoes, and functional approaches specifically focusing on EV subpopulations. These efforts will significantly advance the development of strategies to overcome drug resistance in anti-tumor therapy., Competing Interests: The authors declare that there are no conflicts of interest., (© 2023 The Author(s).)

This study aimed to investigate the impact of spatiotemporal changes in land use on ecosystem carbon storage. The study analyzed the spatiotemporal changes in carbon storage in the study area based on land use data from five periods (1985, 1995, 2005, 2015, and 2020) using the InVEST model. The PLUS model was used to predict land use changes in the study area under four different scenarios (natural development, farmland protection, ecological protection, and double protection of farmland and ecology) in 2035, and the ecosystem carbon storage under different scenarios was estimated. The results of the study indicated that the farmland in the area under investigation had been decreasing consistently from 1985 to 2020, with a more rapid rate of change observed between 2015 and 2020. During this period, the overall dynamic attitude towards land use reached 34.62 %. Additionally, the carbon storage in the area showed a decreasing trend over the years, with a decrease of 1.55×10 5 t from 1985 to 2020. Between 2005 and 2015, the carbon storage showed a decrease of 1.22×10 5 t, with an average annual decrease of 1.22×10 4 t. The areas with higher carbon storage were located in the eastern part of the study area, whereas areas with lower carbon storage were found in the central and northwestern parts. Although the proportion of carbon storage in farmland decreased from 66.89 % to 57.73 %, farmland remained the most important carbon pool in the study area. The conversion of other land use types to grassland and forestland was advantageous for increasing ecosystem carbon storage. Finally, the study projected that by 2035, the carbon storage in the natural development scenario, the farmland protection scenario, the ecological protection scenario, and the dual protection scenario would be 81.77×10 5 , 82.45×10 5 , 82.82×10 5 , and 82.51×10 5 t, respectively.

Background: Five Polyporales mushrooms, namely Amauroderma rugosum, Ganoderma lucidum, G. resinaceum, G. sinense and Trametes versicolor, are commonly used in China for managing insomnia. However, their active components for this application are not fully understood, restricting their universal recognition., Purpose: In this study, we aimed to identify sedative-hypnotic compounds shared by these five Polyporales mushrooms., Study Design and Methods: A UPLC-Q-TOF-MS/MS-based untargeted metabolomics, including OPLS-DA (orthogonal projection of potential structure discriminant analysis) and OPLS (orthogonal projections to latent structures) analysis together with mouse assays, were used to identify the main sedative-hypnotic compounds shared by the five Polyporales mushrooms. A pentobarbital sodium-induced sleeping model was used to investigate the sedative-hypnotic effects of the five mushrooms and their sedative-hypnotic compounds., Results: Ninety-two shared compounds in the five mushrooms were identified. Mouse assays showed that these mushrooms exerted sedative-hypnotic effects, with different potencies. Six triterpenes [four ganoderic acids (B, C1, F and H) and two ganoderenic acids (A and D)] were found to be the main sedative-hypnotic compounds shared by the five mushrooms., Conclusion: We for the first time found that these six triterpenes contribute to the sedative-hypnotic ability of the five mushrooms. Our novel findings provide pharmacological and chemical justifications for the use of the five medicinal mushrooms in managing insomnia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Small extracellular vesicles (sEVs) residing at tumor tissues are valuable specimens for biopsy. Tumor heterogeneity is common across all cancer types, but the heterogeneity of tumor tissue-derived sEVs (Ti-sEVs) is undefined. This study aims to discover the spatial distributions of Ti-sEVs in oral squamous cell carcinoma (OSCC) tissues and explore how these vesicle distributions affect the patients' prognosis. Multi-regional sampling enabled us to uncover that Ti-sEVs' accumulation at peritumoral sites correlates with a higher disease-free survival rate, and conversely, sparse peritumoral Ti-sEVs tend to forecast a higher risk of relapse. Of those relapsed patients, Ti-sEVs strongly bind to extracellular matrix and subsequently degrade it for allowing themselves enter the bloodstream rather than staying in situ. In advanced OSCC patients, the quantity and spatial distribution of Ti-sEVs prior to anti-PD-1 treatment, as well as the temporal variance of Ti-sEVs before and after immunotherapy, strongly map the clinical response and can help to distinguish the patients with shrinking tumors from those with growing tumors. Our work elucidates the correlation of spatiotemporal features of Ti-sEVs with patients' therapeutic outcomes and exhibit the potential for using Ti-sEVs as a predictor to forecast prognosis and screen the responders to anti-PD-1 therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80 + I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity., (© 2024. The Author(s).)

Electromagnetic source imaging (ESI) requires solving a highly ill-posed inverse problem. To seek a unique solution, traditional ESI methods impose various forms of priors that may not accurately reflect the actual source properties, which may hinder their broad applications. To overcome this limitation, in this article, a novel data-synthesized spatiotemporally convolutional encoder-decoder network (DST-CedNet) method is proposed for ESI. The DST-CedNet recasts ESI as a machine learning problem, where discriminative learning and latent-space representations are integrated in a CedNet to learn a robust mapping from the measured electroencephalography/magnetoencephalography (E/MEG) signals to the brain activity. In particular, by incorporating prior knowledge regarding dynamical brain activities, a novel data synthesis strategy is devised to generate large-scale samples for effectively training CedNet. This stands in contrast to traditional ESI methods where the prior information is often enforced via constraints primarily aimed for mathematical convenience. Extensive numerical experiments as well as analysis of a real MEG and epilepsy EEG dataset demonstrate that the DST-CedNet outperforms several state-of-the-art ESI methods in robustly estimating source signals under a variety of source configurations.

The supramolecular solvent (SUPRAS) has garnered significant attention as an innovative, efficient, and environmentally friendly solvent for the effective extraction and separation of bioactive compounds from natural resources. However, research on the use of a SUPRAS for the extraction of phenolic compounds from plants, which are highly valued in food products due to their exceptional antioxidant properties, remains scarce. The present study developed a green, ultra-sound-assisted SUPRAS method for the simultaneous determination of three phenolic acids in Prunella vulgaris using high-performance liquid chromatography (HPLC). The experimental parameters were meticulously optimized. The efficiency and antioxidant properties of the phenolic compounds obtained using different extraction methods were also compared. Under optimal conditions, the extraction efficiency of the SUPRAS, prepared with octanoic acid reverse micelles dispersed in ethanol-water, significantly exceeded that of conventional organic solvents. Moreover, the SUPRAS method demonstrated greater antioxidant capacity. Confocal laser scanning microscopy (CLSM) images revealed the spherical droplet structure of the SUPRAS, characterized by a well-defined circular fluorescence position, which coincided with the position of the phenolic acids. The phenolic acids were encapsulated within the SUPRAS droplets, indicating their efficient extraction capacity. Furthermore, molecular dynamics simulations combined with CLSM supported the proposed method's mechanism and theoretically demonstrated the superior extraction performance of the SUPRAS. In contrast to conventional methods, the higher extraction efficiency of the SUPRAS can be attributed to the larger solvent contact surface area, the formation of more types of hydrogen bonds between the extractants and the supramolecular solvents, and stronger, more stable interaction forces. The results of the theoretical studies corroborate the experimental outcomes.

Background: Tumor-associated macrophages, as the major immunocytes in solid tumors, show divided loyalty and remarkable plasticity in tumorigenesis. Once the M2-to-M1 repolarization is achieved, they could be switched from the supporters for tumor development into the guardians for host immunity. Meanwhile, Lipid metabolic reprogramming is demonstrated to be one of the most important hallmarks of tumor-associated macrophages, which plays a decisive role in regulating their phenotypes and functions to promote tumorigenesis and immunotherapy resistance. Therefore, targeting the lipid metabolism of TAMs may provide a new direction for anti-tumor strategies., Conclusion: In this review, we first summarized the origins, classifications and general lipid metabolic process of TAMs. Then we discussed the currently available drugs and interventions that target lipid metabolic disorders of TAMs, including those targeting lipid uptake, efflux, lipolysis, FAO and lipid peroxidation. Besides, based on the recent research status, we summarized the present challenges for this cancer immunotherapy, including the precise drug delivery system, the lipid metabolic heterogeneity, and the intricate lipid metabolic interactions in the TME, and we also proposed corresponding possible solutions. Collectively, we hope this review will give researchers a better understanding of the lipid metabolism of TAMs and lead to the development of corresponding anti-tumor therapies in the future., (© 2023. Springer Nature Switzerland AG.)

Uridine-disphosphate glucuronosyltransferase 1A9 (UGT1A9), an important detoxification and inactivation enzyme for toxicants, regulates the exposure level of environmental pollutants in the human body and induces various toxicological consequences. However, an effective tool for high-throughput monitoring of UGT1A9 function under exposure to environmental pollutants is still lacking. In this study, 1,3-dichloro-7-hydroxy-9,9-dimethylacridin-2(9H)-one (DDAO) was found to exhibit excellent specificity and high affinity towards human UGT1A9. Remarkable changes in absorption and fluorescence signals after reacting with UGT1A9 were observed, due to the intramolecular charge transfer (ICT) mechanism. Importantly, DDAO was successfully applied to monitor the biological functions of UGT1A9 in response to environmental pollutant exposure not only in microsome samples, but also in living cells by using a high-throughput screening method. Meanwhile, the identified pollutants that disturb UGT1A9 functions were found to significantly influence the exposure level and retention time of bisphenol S/bisphenol A in living cells. Furthermore, the molecular mechanism underlying the inhibition of UGT1A9 by these pollutant-derived disruptors was elucidated by molecular docking and molecular dynamics simulations. Collectively, a fluorescent probe to characterize the responses of UGT1A9 towards environmental pollutants was developed, which was beneficial for elucidating the health hazards of environmental pollutants from a new perspective., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Scope: Gut microbiota can convert a variety of alkaloids and TMAO into TMA, which is then transported by the blood to the liver, and converted into TMAO. In recent years, TMAO has attracted wide attention as a metabolic risk factor in cardiovascular disease, diabetes, and other diseases. However, it is still unclear about the role of gut microbial metabolite TMA in the adverse health impacts of TMAO., Methods and Results: Male C57BL/6J is treated with intraperitoneal (i.p.) or oral TMAO for 8 weeks, the area under the OGTT curve of oral group is significantly increased by about 15% compared to the control and injection groups. Serum triglyceride levels in the oral group are significantly higher by 28.2% and 24.6% than those in the control and injection groups, respectively. Meanwhile, cholesterol content in serum is significantly elevated by 27.6% and 30.7%. Similarly, proinflammatory factors gene expressions are significantly increased with oral but not i.p. TMAO intervention. Furthermore, transformation in HepG2 cells shows that TMAO could not be converted into TMA by hepatocytes., Conclusion: The adverse effects of TMAO on glucose and lipid metabolism in C57BL/6J mice may act through gut microbiota metabolite TMA., (© 2024 Wiley‐VCH GmbH.)

Background: Early diagnosis of atrial fibrillation is important as it is crucial for improving patient outcomes. Fibroblast growth factor-2 (FGF2) may serve as a diagnostic biomarker for heart failure due to its ability to promote cardiac fibrosis and hypertrophy; however, the relationship between FGF2 concentration and heart failure is unclear. Therefore, this study aimed to explore whether FGF2 could aid in distinguishing patients with heart failure from healthy controls and those with dyspnea without heart failure. Additionally, to evaluate the possible correlation between serum FGF2 levels and its diagnostic parameters in patients with heart failure., Methods: Plasma FGF2 concentration was measured in 114 patients with a complaint of dyspnea (enrolled in the study between January 2022 and August 2022). Based on heart failure diagnosis, the patients were assigned to three groups, as follows: heart failure (n = 80), non-heart-failure dyspnea (n = 34), and healthy controls (n = 36), following physical examination. Possible correlations between serum FGF2 levels and other prognostic parameters in patients with heart failure were analyzed., Results: Serum FGF2 levels were higher in patients with heart failure (125.60 [88.95, 183.40] pg/mL) than in those with non-heart-failure dyspnea (65.30 [28.85, 78.95] pg/mL) and healthy controls (78.90 [60.80, 87.20] pg/mL) (p < 0.001). Receiver operating characteristic curve analysis identified FGF2 concentration as a significant predictor in heart failure diagnosis, with an area under the curve of 0.8693 (p < 0.0001). Importantly, in the heart failure group, serum FGF2 concentrations correlated with key prognostic parameters for heart failure, such as reduced left ventricular ejection fraction and elevated serum levels of N-terminal pro-B-type natriuretic peptide., Conclusions: Elevated serum FGF2 level is strongly associated with an increased risk of heart failure and could serve as a useful biomarker to complement vital diagnostic parameters for heart failure., (© 2024. The Author(s).)

A retrospective analysis of birth data hospital-based obtained from 14 monitoring areas in the Huaihe River Basin from 2009 to 2019 was conducted. Trend in the total prevalence of birth defects (BDs) and subgroups were analyzed using the Joinpoint Regression model. The incidence of BDs increased gradually from 118.87 per 10,000 in 2009 to 241.18 per 10,000 in 2019 (AAPC = 5.91, P  < 0.001). Congenital heart diseases were the most common subtype of BDs. The proportion of maternal age younger than 25 decreased but the age 25-40 years increased significantly (AAPC <20 =-5.58; AAPC 20-24 =-6.38; AAPC 25-29  = 5.15; AAPC 30-35  = 7.07; AAPC 35-40  = 8.27; All P  < 0.05). Compared with the one-child policy period, the risk of BDs was greater for groups among maternal age younger than 40 years during the partial and universal two-child policy period ( P  < 0.001). The incidence of BDs and the proportion of women with advanced maternal age in Huaihe River Basin is increasing. There was an interaction between changes in birth policy and the mother's age on the risk of BDs.

Ethnopharmacological Relevance: Inulae Herba (IH) is known as Jinfeicao recorded in Chinese Pharmacopoeia with effects of lowering qi and eliminating phlegm, and used for the treatment of pulmonary diseases. However, its protective mechanism on pulmonary diseases, especially acute lung injury (ALI), is still undefined., Aim of the Study: This study aimed to explore anti-inflammatory and anti-oxidation effects of IH and its underlying mechanism for treating ALI., Materials and Methods: We constructed a lipopolysaccharide (LPS)-ALI mouse model to reveal the therapeutical effect of IH. Western blot, real-time quantitative PCR, flow cytometry, small RNA interference, immunohistochemical staining, and the dual-luciferase experiment were performed to study the mechanism of IH for treating ALI., Results: IH attenuated LPS-mediated pathological changes (e.g. pneumonedema and pulmonary congestion) through inactivation of macrophages in an ALI mouse model. The result of flow cytometry demonstrated that IH regulated the homeostasis of M1 (CD80 + CD206 - ) and M2 (CD80 + CD206 + ) phenotype macrophages. Furthermore, IH suppressed mRNA expressions of M1 phenotype markers, such as iNOS and IL-6, whereas promoted mRNA expressions of M2 phenotype markers, such as ARG1 and RETNLA in LPS-mediated mice. Notably, IH targeted Keap1 to activate the Nrf2 receptor, exerting its anti-inflammatory and anti-oxidation effects proved by using immunohistochemical staining, dual-luciferase, and Keap1 knockdown technologies., Conclusion: These findings suggested that targeting Keap1 with IH alleviated LPS-mediated ALI, and it could serve as a herbal agent for developing anti-ALI drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)