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Zhen Zhang,1 Hanqing Qian,2 Mi Yang,2 Rutian Li,2 Jing Hu,1 Li Li,1 Lixia Yu,2 Baorui Liu,1,2 Xiaoping Qian1,2 1Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine, 2Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute, Nanjing University, Nanjing, China Abstract: Gambogic acid (GA) is expected to be a potential new antitumor drug, but its poor aqueous solubility and inevitable side effects limit its clinical application. Despite these inhe­rent defects, various nanocarriers can be used to promote the solubility and tumor targeting of GA, improving antitumor efficiency. In addition, a cell membrane-coated nanoparticle platform that was reported recently, unites the customizability and flexibility of a synthetic copolymer, as well as the functionality and complexity of natural membrane, and is a new synthetic biomimetic nanocarrier with improved stability and biocompatibility. Here, we combined poly(lactic-co-glycolic acid) (PLGA) with red blood-cell membrane (RBCm), and evaluated whether GA-loaded RBCm nanoparticles can retain and improve the antitumor efficacy of GA with relatively lower toxicity in colorectal cancer treatment compared with free GA. We also confirmed the stability, biocompatibility, passive targeting, and few side effects of RBCm-GA/PLGA nanoparticles. We expect to provide a new drug carrier in the treatment of colorectal cancer, which has strong clinical application prospects. In addition, the potential antitumor drug GA and other similar drugs could achieve broader clinical applications via this biomimetic nanocarrier. Keywords: gambogic acid, nanocarriers, RBCm-GA/PLGA nanoparticles, colorectal cancer

Fang-bo Cui,1,* Qin Liu,1,* Ru-Tian Li,1 Jie Shen,1 Pu-yuan Wu,1 Li-Xia Yu,1 Wen-jing Hu,1 Feng-lei Wu,2 Chun-Ping Jiang,1 Guo-feng Yue,2 Xiao-Ping Qian,1 Xi-Qun Jiang,3 Bao-Rui Liu11The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, 2Nanjing Medical University, 3Laboratory of Mesoscopic Chemistry and Department of Polymer Science and Engineering, College of Chemistry and Chemical Engineering, Nanjing University, Nanjing, People's Republic of China*These authors contributed equally to this workAbstract: Radiotherapy is the main locoregional control modality for many types of unresectable tumors, including gastric cancer. However, many patients fail radiotherapy due to intrinsic radioresistance of cancer cells, which has been found to be strongly associated with cancer stem cell (CSC)-like properties. In this study, we developed a nanoparticle formulation to deliver miR-200c, which is reported to inhibit CSC-like properties, and then evaluated its potential activity as a radiosensitizer. miR-200c nanoparticles significantly augmented radiosensitivity in three gastric cancer cell lines (sensitization enhancement ratio 1.13–1.25), but only slightly in GES-1 cells (1.06). In addition to radioenhancement, miR-200c nanoparticles reduced the expression of CD44, a putative CSC marker, and the percentage of CD44+ BGC823 cells. Meanwhile, other CSC-like properties, including invasiveness and resistance to apoptosis, could be suppressed by miR-200c nanoparticles. CSC-associated radioresistance mechanisms, involving reactive oxygen species levels and DNA repair capacity, were also attenuated. We have demonstrated that miR-200c nanoparticles are an effective radiosensitizer in gastric cancer cells and induce little radiosensitization in normal cells, which suggests that they are as a promising candidate for further preclinical and clinical evaluation.Keywords: radiosensitizer, miR-200c, gelatinase-stimuli nanoparticles, cancer stem cell-like properties, gastric cancer

Qin Liu1*, Ru-Tian Li1*, Han-Qing Qian2, Mi Yang1, Zhen-Shu Zhu2, Wei Wu2, Xiao-Ping Qian1, Li-Xia Yu1, Xi-Qun Jiang2, Bao-Rui Liu11The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China; 2Laboratory of Mesoscopic Chemistry and Department of Polymer Science and Engineering College of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China*These authors contributed equally to this workAbstract: Nanoscale drug carriers have been extensively developed to improve drug therapeutic efficiency. However, delivery of chemotherapeutic agents to tumor tissues and cells has not been favorably managed. In this study, we developed a novel “intelligent” nanoparticle, consisting of a gelatinase-cleavage peptide with poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL)-based structure for tumor-targeted docetaxel delivery (DOC-TNPs). The docetaxel-loaded PEG-PCL nanoparticles (DOC-NPs) that did not display gelatinase-stimuli behaviors were used as a control. We found clear evidence that the DOC-TNPs were transformed by gelatinases, allowing drug release and enhancing the cellular uptake of DOC (P < 0.01). In vivo biodistribution study demonstrated that targeted DOC-TNPs could accumulate and remain in the tumor regions, whereas non-targeted DOC-NPs rapidly eliminated from the tumor tissues. DOC-TNPs exhibited higher tumor growth suppression than commercialized Taxotere® (docetaxel; Jiangsu Hengrui Medicine Company, Jiangsu, China) and DOC-NPs on hepatic H22 tumor model via intravenous administration (P < 0.01). Both in vitro and in vivo experiments suggest that the gelatinase-mediated nanoscale delivery system is promising for improvement of antitumor efficacy in various overexpressed gelatinase cancers.Keywords: drug delivery, stimuli-responsive, gelatinase, antitumor, docetaxel

The genus Valeriana is used in traditional Chinese medicine to treat nervous disorders, sleep disorders, epilepsy and skin diseases. A large number of sesquiterpenoids from this genus have been found to exhibit anti-inflammatory, antiproliferative, anti-influenza virus and neuroprotective activities. In order to discover more sesquiterpenoids with structural diversity and bioactivity from Valeriana plants, fifteen sesquiterpenoids, including ten undescribed ones, valernaenes A-J (1, 5-7, 9-11 and 13-15), were isolated from the roots and rhizomes of Valeriana officinalis var. latifolia. Their structures were elucidated by extensive spectroscopic techniques (1D, 2D NMR and HRESIMS) and electronic circular dichroism (ECD) calculation. Structurally, valernaenes C (6) and D (7) were two caryophyllane-type norsesquiterpenoids. In addition, valernaenes A (1) and F (10) exhibited anti-influenza virus activity with EC 50 values of 38.76 ± 1.44 and 23.01 ± 4.89 μM, respectively. Furthermore, caryophyllenol A (2) showed promoting effect on nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells with differentiation rate of 12.26% at a concentration of 10 μM. This study not only enriched the structural diversity of sesquiterpenoids in the genus Valeriana, but also provided theoretical basis for the discovery of anti-influenza virus and neuroprotective agents from this genus., Competing Interests: Declaration of competing interest We 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.)

The recent worldwide outbreaks of mpox prioritize the development of a safe and effective mRNA vaccine. The contemporary mpox virus (MPXV) exhibits changing virological and epidemiological features, notably affecting populations already vulnerable to human immunodeficiency virus (HIV). Herein, we profile the immunogenicity of AR-MPXV5, a penta-component mRNA vaccine targeting five specific proteins (M1R, E8L, A29L, A35R, and B6R) from the representative contemporary MPXV clade II strain, in both naive and simian immunodeficiency virus (SIV)-infected nonhuman primates. Immunization with two doses of AR-MPXV5 to cynomolgus macaques effectively elicits antibody responses and cellular responses. Importantly, based on the challenge model with a contemporary MPXV clade II strain, AR-MPXV5 demonstrates effective efficacy in preventing skin lesions, eliminating viremia and reducing viral loads in multiple tissues after challenge in naive male animals. More importantly, AR-MPXV5 is well-tolerated in stable chronic SIV-infected rhesus monkeys, while eliciting comparable MPXV-specific humoral and cellular responses in both naive and SIV-infected monkeys. Together, these results support further clinical development of the AR-MPXV5 vaccine., Competing Interests: Competing interests: C.F.Q., Q.Y., R.R.Z., and Z.J.W. have filed a patent related to the vaccine reported in the study. The remaining authors declare no competing interests., (© 2024. The Author(s).)

An undescribed coumarin-limonene hybrid (morusalin A, 1), an unreported steppogenin-limonene hybrid (morusalin B, 2), and three undescribed isoprenylated flavonoids (morusalins C-E, 3-5), along with forty-one known ones (6-46), were isolated from the dried roots bark of Morus alba. Their structures with absolute configurations were elucidated by detailed interpretation of NMR spectroscopy, mass spectrometry, single-crystal X-ray diffraction, and ECD calculations. In addition, all these isolated compounds were assayed for their inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine macro-phage RAW 264.7 cells and for their cytotoxic activities against human colon cancer (HCT 8) and hepatoma (HepG 2) cells. Moreover, a biosynthetic pathway for the formation of compounds 1-6 is also proposed., 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.)

Sulfadiazine (SDZ) is frequently detected in environmental samples, arousing much concern due to its toxicity and hard degradation. This study investigated the electricity generation capabilities, SDZ removal and microbial communities of a highly efficient mixed-culture system using repeated transfer enrichments in a bio-electrochemical system. The mixed-culture biofilm (S160-T2) produced a remarkable current density of 954.12 ± 15.08 μA cm -2 with 160 mg/L SDZ, which was 32.9 and 1.8 times higher than that of Geobacter sulfurreducens PCA with 40 mg/L SDZ and without additional SDZ, respectively. Especially, the impressive SDZ removal rate of 98.76 ± 0.79% was achieved within 96 h using the further acclimatized mixed-culture. The removal efficiency of this mixed-culture for SDZ through the bio-electrochemical system was 1.1 times higher than that using simple anaerobic biodegradation. Furthermore, the current density and removal efficiency in this system gradually decreased with increasing SDZ concentrations from 0 to 800 mg/L. In addition, community diversity data demonstrated that the dominant genera, Geobacter and Escherichia-Shigella, were enriched in mixed-culture biofilm, which might be responsible for the current production and SDZ removal. This work confirmed the important roles of acclimatized microbial consortia and co-substrates in the simultaneous removal of SDZ and electricity generation in an electrochemical system., 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.)

The design and synthesis of a series of metal complexes formed by non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen (IBP) and iridium(III), with the molecular formula [Ir(C^N) 2 bpy(4-CH 2 OIBP-4'-CH 2 OIBP)](PF 6 ) (Ir-IBP-1, Ir-IBP-2) (C^N = 2-phenylpyridine (ppy, Ir-IBP-1), 2-(2-thienyl)pyridine (thpy, Ir-IBP-2)) was introduced in this article. Firstly, it was found that the anti-proliferative activity of these complexes was more effective than that of cisplatin. Further research showed that Ir-IBP-1 and Ir-IBP-2 can accumulate in intracellular mitochondria, thereby disrupting mitochondrial membrane potential (MMP), increasing intracellular reactive oxygen species (ROS), blocking the G2/M phase of the cell cycle, and inducing cell apoptosis. In terms of protein expression, the expression of COX-2, MMP-9, NLRP3 and Caspase-1 proteins can be downregulated, indicating their ability to anti-inflammatory and overcome immune evasion. Furthermore, Ir-IBP-1 and Ir-IBP-2 can induce immunogenic cell death (ICD) by triggering the release of cell surface calreticulin (CRT), high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). Overall, iridium(III)-IBP conjugates exhibit various anti-tumor mechanisms, including mitochondrial damage, cell cycle arrest, inflammatory suppression, and induction of ICD., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Enterovirus genomic replication initiates at a predicted RNA cloverleaf (5'CL) at the 5' end of the RNA genome. The 5'CL contains one stem (SA) and three stem-loops (SLB, SLC, SLD). Here, we present an analysis of 5'CL conservation and divergence for 209 human health-related serotypes from the enterovirus genus, including enterovirus and rhinovirus species. Phylogenetic analysis indicates six distinct 5'CL serotypes that only partially correlate with the species definition. Additional findings include that 5'CL sequence conservation is higher between the EV species than between the RV species, the 5'CL of EVA and EVB are nearly identical, and RVC has the lowest 5'CL conservation. Regions of high conservation throughout all species include SA and the loop and nearby bases of SLB, which is consistent with known protein interactions at these sites. In addition to the known protein binding site for the Poly-C binding protein in the loop of SLB, other conserved consecutive cytosines in the stems of SLB and SLC provide additional potential interaction sites that have not yet been explored. Other sites of conservation, including the predicted bulge of SLD and other conserved stem, loop, and junction regions, are more difficult to explain and suggest additional interactions or structural requirements that are not yet fully understood. This more intricate understanding of sequence and structure conservation and variability in the 5'CL may assist in the development of broad-spectrum antivirals against a wide range of enteroviruses , while better defining the range of virus isotypes expected to be affected by a particular antiviral.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurological emergency with high mortality, and even patients receiving optimal medical care may develop long-term disability, which seriously affects their quality of life and increases the heavy medical burden on society and families. To provide comprehensive clinical management advice, the Society of Neurosurgery of the Chinese Medical Association, the Society of the Chinese Stroke Association of the National Medical Center for Neurological Diseases, and the National Clinical Research Center for Neurological Diseases jointly formulate "Chinese Guidelines for the Clinical Management of Patients With Ruptured Intracranial Aneurysms in 2024". The evidence sources are divided into the Chinese population and other populations, using a modular format to provide recommendations, summaries of relevant opinions, and future research directions on epidemiology, clinical imaging diagnosis, prognosis evaluation, treatment strategies and choices, anesthesia management, perioperative care, and recommendations for the management of aSAH in special populations. It provides practical clinical guidance and recommendations for doctors and related professionals.

With the abuse of antibiotics and azoles, drug-resistant Candida albicans infections have increased sharply and are spreading rapidly, thereby significantly reducing the antifungal efficacy of existing therapeutics. Several patients die of fungal infections every year. Therefore, there is an urgent requirement to develop new drugs. Accordingly, we synthesized a series of polypyridyl ruthenium (II) complexes having the formula [Ru (NN) 2 (bpm)] (PF 6 ) 2 (N-N = 2,2'-bipyridine) (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3) (bpm = 2,2'-bipyrimidine) and studied their antifungal activities. Ru3 alone had no effect on the drug-resistant strains, but Ru3 combined with fluconazole (FLC) exhibited significant antifungal activity on drug-resistant strains. A high-dose combination of Ru3 and FLC exhibited direct fungicidal activity by promoting the accumulation of reactive oxygen species and damaging the cellular structure of C. albicans. Additionally, the combination of Ru3 and FLC demonstrated potent antifungal efficacy in vivo in a mouse model of invasive candidiasis. Moreover, the combination significantly improved the survival state of mice, restored their immune systems, and reduced renal injury. These findings could provide ideas for the development of ruthenium (II) complexes as novel antifungal agents for drug-resistant microbial stains., 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 Inc. All rights reserved.)

Four undescribed prenylated flavonoids, sophoratones A-D (1-4), and 17 known flavonoids, were obtained from the aerial parts of Sophora tonkinensis. Their structures with absolute configurations were elucidated by detailed interpretation of NMR spectroscopy, mass spectrometry, and ECD calculations. Meanwhile, the ability of these compounds to inhibit the release of nitric oxide (NO) by a lipopolysaccharide induced mouse in RAW 264.7 cells was assayed. The results indicated that some compounds exhibited clear inhibitory effects, with IC 50 ranging from 19.91±1.08 to 35.72±2.92 μM. These results suggest that prenylated flavonoids from the aerial parts of S. tonkinensis could potentially be used as a latent source of anti-inflammatory agents., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

A series of Ir(III)-naproxen (NPX) conjugates with the molecular formula [Ir(C^N) 2 bpy(4-CH 2 ONPX-4'-CH 2 ONPX)](PF 6 ) (Ir-NPX-1-3) were designed and synthesized, including C^N = 2-phenylpyridine (ppy, Ir-NPX-1), 2-(2-thienyl)pyridine (thpy, Ir-NPX-2) and 2-(2,4-difluorophenyl)pyridine (dfppy, Ir-NPX-3). Cytotoxicity tests showed that Ir-NPX-1-3 exhibited excellent antitumor activity, especially in A549R cells. The cellular uptake experiment showed that the complexes were mainly localized in mitochondria, and induced apoptosis in A549R cells by damaging the structure and function of mitochondria. The main manifestations are a decrease in the mitochondrial membrane potential (MMP), an increase in reactive oxygen species (ROS) levels, and cell cycle arrest. Furthermore, Ir-NPX-1-3 could inhibit the migration and colony formation of cancer cells, demonstrating potential anti-metastatic ability. Finally, the anti-inflammatory and immunological applications of Ir-NPX-1-3 were verified. The downregulation of cyclooxygenase-2 (COX-2) and programmed death-ligand 1 (PD-L1) expression levels and the release of immunogenic cell death (ICD) related signaling molecules such as damage-associated molecular patterns (DAMPs) (cell surface calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP)) indicate that these Ir(III) -NPX conjugates are novel ICD inducers with synergistic effects in multiple anti-tumor pathways.

Background: Transseptal puncture (TSP) performed with the Brockenbrough (BRK) needle is technically demanding and carries potential risks. The back end of the percutaneous transluminal coronary angioplasty (PTCA) guidewire is blunt and flexible, with good support, it can puncture the right ventricle-free wall, which is thicker than the atrial-septum. The guidewire is thin and easy to manipulate. This study evaluated the performance of TSP with a PTCA guidewire and microcatheter without a needle., Methods: The back end of a PTCA guidewire was advanced into the Tiger (TIG) catheter, within the SL1 sheath, to puncture the fossa ovalis (FO) under fluoroscopy. Subsequently, the microcatheter was inserted into the left atrium (LA) above the guidewire, and the front end of the guidewire was exchanged in the LA. After the puncture site was confirmed by contrast, the TIG catheter and a 0.032 inch wire were advanced into the LA. Finally, the sheath, with the dilator, was advanced over the wire into the LA. The safety margin of this method was tested in a pig model., Results: The puncture was successful in all seven pigs tested with a puncture-to-sheath entry time of < 20 minutes and no procedure-related complications. The method was successfully used to perform a difficult TSP in a patient with an extremely tortuous inferior vena cava, in whom puncture with a BRK needle had repeatedly failed., Conclusions: Cardiologists may use the PTCA guidewire and microcatheter as an alternative to the needle while performing TSP in special conditions, such as an extremely tortuous inferior vena cava., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

A PPh 3 Au[B(C 6 F 5 ) 4 ]-catalyzed reaction of enynals and alkenes for the construction of binaphthyl derivatives was described. This transformation was achieved through o -Quinodimethane ( o -QDM) intermediate's extended conjugated addition process. The reaction has the advantages of wide substrate scopes, mild reaction conditions, high efficiency, and good scalability.

Seven undescribed compounds, including three flavones (1-3), one phenylpropanoid (19), three monoaromatic hydrocarbons (27-29), were isolated from the twigs of Mosla chinensis Maxim together with twenty-eight known compounds. The structures were characterized by HRESIMS, 1D and 2D NMR, and ECD spectroscopic techniques. Compound 20 displayed the most significant activity against A/WSN/33/2009 (H1N1) virus (IC 50  = 20.47 μM) compared to the positive control oseltamivir (IC 50  = 6.85 µM). Further research on the anti-influenza mechanism showed that compound 20 could bind to H1N1 virus surface antigen HA1 and inhibit the early attachment stage of the virus. Furthermore, compounds 9, 22, 23, and 25 displayed moderate inhibitory effects on the NO expression in LPS inducing Raw 264.7 cells with IC 50 values of 22.78, 20.47, 27.66, and 30.14 µM, respectively., (© 2024. The Author(s).)

This study aimed to assess the effects of Anti-fatigue Decoction (AFD) against central fatigue by observing the behaviors and serological indicators of rats modeled by the modified multiple platform method (MMPM) after drug intervention. Grip strength measurements were used to evaluate the muscle strength of rats. The open field test was utilized to assess anxiety-like behavior, while the Morris water maze test was conducted to evaluate the memory function of the rats. Following the behavioral assessments, rat serum samples were collected to measure the concentrations of corticosterone (CORT) and lactic acid (LAC). The concentration of LAC was determined using the colorimetric method, while the concentration of CORT was measured using the enzyme-linked immunosorbent assay (ELISA) method. Compared to the blank control group, following MMPM modeling, rats exhibited significant reductions in grip strength and impaired ability to memory. The serum analysis revealed increased levels of LAC and CORT in the model group rats. AFD can noticeably reverse these adverse changes to a certain extent. These findings highlight the positive effects of AFD and coenzymeQ10 on physical and cognitive abilities and alterations in serum biomarker levels of central fatigue rats.

Seasonal influenza still greatly threatens public health worldwide, leading to significant morbidity and mortality. Antiviral medications for influenza treatment are limited and accompanied by increased drug resistance. In severe influenza virus infection, hyperinflammation and hypoxia may be the significant threats associated with mortality, so the development of effective therapeutic methods to alleviate excessive inflammation while reducing viral damage is highly pursued. Here, a multifunctional MOF-based nanohybrid of Cu─TCPP@Mn 3 O 4 as a novel drug against influenza A virus infection (MOF = metal-organic framework; TCPP = tetrakis (4-carboxyphenyl) porphyrin) is designed. Cu─TCPP@Mn 3 O 4 exhibits potent inhibitory capability against influenza A virus infection in vitro and in vivo. The mechanism study reveals that Cu─TCPP@Mn 3 O 4 inhibits the virus entry by binding to the HA2 subunit of influenza A virus hemagglutinin. In addition, the nanoparticles of Mn 3 O 4 in Cu─TCPP@Mn 3 O 4 can scavenge intracellular ROS with O 2 generation to downregulate inflammatory factors and effectively inhibit cytokines production. By reconstructing the antioxidant microenvironment, Cu─TCPP@Mn 3 O 4 features as a promising nanomedicine with anti-inflammatory and anti-viral synergistic effects., (© 2023 Wiley-VCH GmbH.)

Developing simple, rapid and specific mRNA imaging strategy plays an important role in the early diagnosis of cancer and the new drugs development. Herein, we have established a novel binary system based DNA tetrahedron and fluorogenic RNA aptamers for highly specific and label-free mRNA imaging in living cells. This developed system consisted of tetrahedron probe A (TPA) and tetrahedron probe B (TPB). TK1 mRNA was chosen as the study model. After TPA and TPB enter into the live cells, the TK1 mRNA induces TPA and TPB to approach and activate the fluorescent aptamer, resulting in enhanced fluorescent signal in the presence of small molecules of DFHBI-1T. By this design, the high specificity label-free detection of nucleic acids was achieved with a detection limit of 1.34 nM. Confocal fluorescence imaging experiments had proved that this strategy could effectively distinguish the TK1 mRNA expression level between normal cell and cancer cell. The developed method is expected to provide a new tool for early diagnosis of diseases and new drug development., 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.)

Vitiligo, a psychologically distressing pigmentary disorder characterized by white depigmented patches due to melanocyte loss, necessitates non-invasive tools for early detection and treatment response monitoring. High-cellular-resolution full-field optical coherence tomography (CRFF-OCT) is emerging in pigmentary disorder assessment, but its applicability in vitiligo repigmentation after tissue grafting remains unexplored. To investigate the feasibility of CRFF-OCT for evaluating vitiligo lesions following tissue grafting, our investigation involved ten vitiligo patients who underwent suction blister epidermal grafting and laser ablation at a tertiary center between 2021 and 2022. Over a six-month period, clinical features, dermoscopy, and photography data were recorded. Utilizing CRFF-OCT along with artificial intelligence (AI) applications, repigmentation features were captured and analyzed. The CRFF-OCT analysis revealed a distinct dark band in vitiligo lesion skin, indicating melanin loss. Grafted areas exhibited melanocytes with dendrites around the epidermal-dermal junction and hair follicles. CRFF-OCT demonstrated its efficacy in the early detection of melanocyte recovery and accurate melanin quantification. This study introduces CRFF-OCT as a real-time, non-invasive, and in vivo evaluation tool for assessing vitiligo repigmentation, offering valuable insights into pigmentary disorders and treatment responses.

Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 μg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 μg/mL versus 4.83 μg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Five new iridoids, valeralides A-E (1-5), two new acyclic monoterpenoids, valeralides F (6) and G (7), together with two known iridoids (8 and 9), were isolated from the roots and rhizomes of Valeriana officinalis var. latifolia. Their structures were elucidated based on 1D and 2D NMR, as well as HR-ESI-MS spectroscopic data. The absolute configuration of compounds 1-4 were elucidated based on electronic circular dichroism (ECD) calculation. In addition, all the isolates were evaluated for their inhibition on nitric oxide production, cytotoxicity and anti-influenza A virus activity., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Currently available therapies for neuropathic pain show limited efficacy. This study aimed to investigate the anti-nociceptive effect of the spirocyclopiperazinium salt compound LXM-15 in spinal nerve ligation (SNL) rats and to explore the potential mechanisms., Methods: Mechanical allodynia and thermal hyperalgesia tests were used to evaluate the effects of LXM-15 in SNL rats. The expression of CaMKIIα, CREB, JAK2, STAT3, c-fos and TNF-α was detected by western blotting, ELISA or qRT-PCR analysis. Receptor blocking test was performed to explore possible target., Results: Administration of LXM-15 (1, 0.5, 0.25 mg/kg, i.g.) dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in rats subjected to SNL (p < 0.01, p < 0.05), and the effects were completely blocked by peripheral α7 nicotinic or M4 muscarinic receptor antagonist (p > 0.05). LXM-15 significantly decreased the overexpression of phosphorylated CaMKIIα, CREB, JAK2 and STAT3 proteins and the mRNA levels of TNF-α and c-fos (p < 0.01, p < 05). All of the effects could be blocked by α7 or M4 receptor antagonist. Furthermore, LXM-15 reduced the protein expression of TNF-α and c-fos (p < 0.01, p < 0.05). No significant acute toxicity or abnormal hepatorenal function was observed., Conclusions: This is the first study to report that LXM-15 exerts significant anti-nociceptive effect on SNL rats. This effect may occur by activating peripheral α7 nicotinic and M4 muscarinic receptors, further inhibiting the CaMKIIα/CREB and JAK2/STAT3 signalling pathways, and finally inhibiting the expression of TNF-α and c-fos., Significance: Existing treatments for neuropathic pain show limited efficacy with severe adverse reactions. This paper is the first to report that LXM-15, a new spirocyclopiperazinium salt compound, exerts a significant anti-nociception in SNL rats without obvious toxicity. The underlying mechanisms include activating peripheral α7 nicotinic and M4 muscarinic receptors, then inhibiting the signalling pathways of CaMKIIα/CREB and JAK2/STAT3 and the expressions of TNF-α and c-fos. This study sheds new light on the development of novel analgesic drugs with fewer side effects., (© 2023 European Pain Federation - EFIC ®.)

Fifty-nine compounds, including nineteen previously undescribed iridoids (valeriananols A-S) and an undescribed alkaloid (5'-isovaleryl uridine), were isolated from the leaves and stems of Valeriana officinalis var. latifolia. Their structures were elucidated based on Mass spectrometry and NMR spectroscopy. The absolute configuration of valeriananols A-C, E-N, P, Q and S was determined by experimental and calculated electronic circular dichroism. Structurally, valeriananols A and B were two 1,3-seco-iridoids with a 3,6-epoxy moiety, valeriananols K and L were a pair of C-4 epimers, while valeriananol S was a 4'-deoxy iridoid glycoside. In addition, valeriananol P, stenopterin A and patriscabioin C exhibited significant inhibition on nitric oxide production with IC 50 values of 10.31, 3.93 and 8.69 μM, respectively. Furthermore, stenopterin A and patriscabioin C showed anti-proliferation activity on the MCF-7 cell line with IC 50 values of 17.28 and 13.89 μM, respectively., 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 Ltd. All rights reserved.)

(1) Background: The objective of this study was to investigate the prevalence of genetic diversity and drug resistance mutations among people living with HIV (PLWH) attending clinics in Beijing. (2) Methods: A retrospective analysis was conducted on PLWH admitted to the Fifth Medical Center of People's Liberation Army (PLA) General Hospital between 1 March 2013 and 31 July 2020. The participants were analyzed for pretreatment drug resistance (PDR) and acquired drug resistance (ADR). Nested polymerase chain reaction (PCR) was utilized to amplify the pol gene from plasma RNA samples obtained from the participants. Genotypic and HIV drug resistance were determined using the Stanford University HIV Drug Resistance Database. Univariate and multifactorial logistic analyses were used to assess the risk factors for PDR. (3) Results: The overall prevalence rates of PDR and ADR were 12.9% and 27.8%, respectively. Individuals treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) exhibited the highest prevalence of mutations. Specific mutation sites, such as V179D for NNRTIs and M184V and K65R for nucleoside reverse transcriptase inhibitors (NRTIs), were identified as prevalent mutations. Individuals treated with efavirenz (EFV) and nevirapine (NVP) were found to be susceptible to developing resistance. The multifactorial regression analyses indicated that the factors of circulating recombination form (CRF) genotype CRF07-BC and a high viral load were associated with an increased risk of PDR. CRF01-AE and CRF07-BC were the most prevalent HIV genotypes in our study. (4) Conclusions: The distribution of HIV genotypes in Beijing is complex. There is a need for baseline screening for HIV drug resistance among ART-naive individuals, as well as timely testing for drug resistance among ART-experienced individuals.

Background: Type 2 diabetes mellitus (T2DM), one of the most common public diseases threatening human health, is always accompanied by infection. Though there are still a variety of flaws in the treatment of some infectious diseases, metabolomics provides a fresh perspective to explore the relationship between T2DM and infection. Our research aimed to investigate the association between plasma free amino acids (PFAAs) and T2DM complicated with infection in Chinese patients., Methods: A cross-sectional study was conducted from May 2015 to August 2016. We retrieved the medical records of 1032 inpatients with T2DM from Liaoning Medical University First Affiliated Hospital and we used mass spectrometry to quantify 23 PFAAs. Infections contained 15 individual categories that could be retrieved from the database. Principal component analysis was used to extract factors of PFAAs. Multi-variable binary logistic regression was used to obtain odds ratios (OR) and their 95% confidence intervals (CI)., Results: Among 1032 inpatients,109 (10.6%) had infectious diseases. Six factors, accounting for 68.6% of the total variance, were extracted. Factor 4 consisted of Glu, Asp and Orn. Factor 5 consisted of Hcy and Pip. After adjusting for potential confounders, factor 4 was positively correlated with T2DM complicated with infection in Chinese T2DM patients (OR: 1.27, 95%CI: 1.06-1.52). Individual Hcy in factor 5 was positively associated with T2DM complicated with infection (OR: 1.33, 95%CI: 1.08-1.64). Furthermore, factor 4 (OR: 1.44, 95%CI: 1.11-1.87), Orn (OR: 1.01, 95%CI: 1.00-1.02) and Hcy (OR: 1.56, 95%CI: 1.14-3.14) were positively associated with bacterial infection in Chinese T2DM patients, while factor 5 (OR: 0.71, 95%CI: 0.50-1.00) was negatively associated with bacterial infection., Conclusions: Urea cycle-related metabolites (Orn, Asp, Glu) and Hcy were positively associated with T2DM complicated with infection in China. Orn and Hcy were positively associated with bacterial infection in T2DM patients in China., (© 2024. The Author(s).)

Extremity soft tissue sarcoma (ESTS) is a rare malignant nonepithelial disease, calling for combined modality treatments with surgery to further improve local control rates and long-term survival, especially in patients with multiple local recurrences with or without risk of amputation. In this double-arm, open-label, Phase II clinical trial, we will enroll 30 patients with pathologically confirmed ESTS without nodal involvement or distant metastases. Patients are randomly assigned to the combination treatment group or the radiation monotherapy group. Additionally, tumor and biological samples will be obtained directly before and after neoadjuvant therapy, allowing for studies of immune response and primary drug resistance mechanisms. Clinical Trial Registration: ChiCTR2200060659 (http://www.chictr.org.cn) (ClinicalTrials.gov).

Objective: The activation state of microglia is known to occupy a central position in the pathophysiological process of cerebral inflammation. Autophagy is a catabolic process responsible for maintaining cellular homeostasis. In recent years, autophagy has been demonstrated to play an important role in neuroinflammation. Resolvin D1 (RvD1) is a promising therapeutic mediator that has been shown to exert substantial anti-inflammatory and proresolving activities. However, whether RvD1-mediated resolution of inflammation in microglia is related to autophagy regulation needs further investigation. The present study aimed to explore the effect of RvD1 on microglial autophagy and its corresponding pathways., Methods: Mouse microglial cells (BV-2) were cultured, treated with RvD1, and examined by Western blotting, confocal immunofluorescence microscopy, transmission electron microscopy, and flow cytometry., Results: RvD1 promoted autophagy in both BV-2 cells and mouse primary microglia by favoring the maturation of autophagosomes and their fusion with lysosomes. Importantly, RvD1 had no significant effect on the activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, RvD1-induced mTOR-independent autophagy was confirmed by observing reduced cytoplasmic calcium levels and suppressed calcium/calmodulin-dependent protein kinase II (CaMK II) activation. Moreover, by downregulating ATG5, the increased phagocytic activity induced by RvD1 was demonstrated to be tightly controlled by ATG5-dependent autophagy., Conclusion: The present work identified a previously unreported mechanism responsible for the role of RvD1 in microglial autophagy, highlighting its therapeutic potential against neuroinflammation., (© 2023. Huazhong University of Science and Technology.)

Introduction: Pulmonary fibrosis is a major cause of the poor prognosis of acute respiratory distress syndrome (ARDS). While mechanical ventilation (MV) is an indispensable life-saving intervention for ARDS, it may cause the remodeling process in lung epithelial cells to become disorganized and exacerbate ARDS-associated pulmonary fibrosis. Piezo1 is a mechanosensitive ion channel that is known to play a role in regulating diverse physiological processes, but whether Piezo1 is necessary for MV-exacerbated ARDS-associated pulmonary fibrosis remains unknown., Objectives: This study aimed to explore the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis., Methods: Human lung epithelial cells were stimulated with hydrochloric acid (HCl) followed by mechanical stretch for 48 h. A two-hitmodel of MV afteracidaspiration-inducedlunginjuryin mice was used. Mice were sacrificed after 14 days of MV. Pharmacological inhibition and knockout of Piezo1 were used to delineate the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. In some experiments, ATP or the ATP-hydrolyzing enzyme apyrase was administered., Results: The stimulation of human lung epithelial cells to HCl resulted in phenotypes of epithelial-mesenchymal transition (EMT), which were enhanced by mechanical stretching. MV exacerbated pulmonary fibrosis in mice exposed to HCl. Pharmacologicalinhibitionorknockout of Piezo1 attenuated the MV-exacerbated EMT process and lung fibrosis in vivo and in vitro. Mechanistically, the observed effects were mediated by Piezo1-dependent Ca 2+ influx and ATP release in lung epithelial cells., Conclusions: Our findings identify a key role for Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis that is mediated by increased ATP release in lung epithelial cells. Inhibiting Piezo1 may constitute a novelstrategyfor the treatment of MV-exacerbated ARDS-associated pulmonary fibrosis., 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. Production and hosting by Elsevier B.V.)

Increasing evidence shows the African lineage Zika virus (ZIKV) displays a more severe neurovirulence compared to the Asian ZIKV. However, viral determinants and the underlying mechanisms of enhanced virulence phenotype remain largely unknown. Herein, we identify a panel of amino acid substitutions that are unique to the African lineage of ZIKVs compared to the Asian lineage by phylogenetic analysis and sequence alignment. We then utilize reverse genetic technology to generate recombinant ZIKVs incorporating these lineage-specific substitutions based on an infectious cDNA clone of Asian ZIKV. Through in vitro characterization, we discover a mutant virus with a lysine to arginine substitution at position 101 of capsid (C) protein (termed K101R) displays a larger plaque phenotype, and replicates more efficiently in various cell lines. Moreover, K101R replicates more efficiently in mouse brains and induces stronger inflammatory responses than the wild type (WT) virus in neonatal mice. Finally, a combined analysis reveals the K101R substitution promotes the production of mature C protein without affecting its binding to viral RNA. Our study identifies the role of K101R substitution in the C protein in contributing to the enhanced virulent phenotype of the African lineage ZIKV, which expands our understanding of the complexity of ZIKV proteins., (© 2023. The Author(s).)

The impact of microplastic particles of micro- and nanometer sizes on microbial horizontal gene transfer (HGT) remains a controversial topic. Existing studies rely on traditional approaches, which analyze population behavior, leading to conflicting conclusions and a limited understanding. The present study addressed these limitations by employing a novel microfluidic chamber system for in situ visualization and precise quantification of the effects of different concentrations of polystyrene (PS) microbeads on microbial HGT at the single-cell level. The statistical analysis indicated no significant difference in the division times of both the donor and recipient bacteria across different PS microbead concentrations. However, as the concentration of PS microbeads increased from 0 to 2000 mg L -1 , the average conjugation frequency of Escherichia coli decreased from 0.028 ± 0.015 to 0.004 ± 0.003. Our observations from the microfluidic experiments revealed that 500 nm PS microbeads created a barrier effect on bacterial conjugative transfer. The presence of microbeads resulted in reduced contact and interaction between the donor and recipient strains, thereby causing a decrease in the conjugation transfer frequency. These findings were validated by an individual-based modeling framework parameterized by the data from the individual-level microfluidic experiments. Overall, this study offers a fresh perspective and strategy for investigating the risks associated with the dissemination of antibiotic resistance genes related to microplastics.

A pharmacophore-hybridized strategy based on previously reported HSP90 C-terminal inhibitors was utilized to prepare 32 aryl/penta-1,4-dien-3-one/amine hybrids. Among them, a silicon-containing compound 1z exhibited remarkable broad-spectrum antiproliferative effects on various human breast cancer cell lines. Through fluorescence polarization and AlphaScreen-based assays, we demonstrated that 1z specifically inhibited the HSP90 C-terminus without affecting HSP90 N-terminus. Furthermore, 1z effectively inhibited the HSP90 C-terminus without inducing heat-shock response (HSR), leading to the degradation of its client proteins HER2, pAKT, AKT, and CDK4, causing G 1 arrest of MCF-7 and SKBr3 cells, and ultimately contributing to apoptosis of these cells through caspase-3, caspase-8, and caspase-9 activation. Additionally, the penta-1,4-dien-3-one linker in the hybrid, a large bulky lipophilic substitution in the aryl fragment at the 3'-site, and the presence of N -methylpiperazine as the amine fragment were identified as crucial factors that significantly contributed to the observed antiproliferative activity through structure-activity relationship (SAR) analysis. Lastly, we found that 1z exhibited superior thermostability compared to vibsanin B derivatives and good in vitro metabolic stability in simulated intestinal fluid, representing one of the few reported silicon-containing HSP90 C-terminal inhibitors., Competing Interests: The authors declare that they have no known conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Fifteen previously undescribed sesquiterpenoids (pogocablenes A-O), three first discovered natural patchoulol-type ones, coupled with fourteen known ones, were isolated from the aerial parts of Pogostemon cablin. Among them, pogocablenes A and B, a pair of C 2 epimers, possessed an unusual carbon skeleton with bicyclo[4.3.1]decane core. Pogocablene C, originated from eudesmane-type sesquiterpenoid, had an unprecedented bicyclo[5.4.0]undecane scaffold with a peroxy hemiactetal moiety. Pogocablene D possessed a rare tricyclo[5.2.2.0 1,5 ]undecane carbon skeleton derived from guaiane-type sesquiterpenoid. Pogocablene E was a 4,5-seco-guaiane derivative owning a peroxy hemiactetal unit and a spirocyclic skeleton. Pogocablene M was a nor-patchoulol-type sesquiterpenoid with α,β-unsaturated ketone moiety. Their structures with absolute configuration were determined by extensive spectroscopic analysis, in combination with quantum chemical calculation. In addition, the plausible biogenetic pathways of pogocablenes A-E were proposed. Furthermore, all isolates were evaluated for anti-influenza virus and anti-inflammatory effects., Competing Interests: Declaration of competing interest We have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Verbena officinalis is used as a Chinese folk medicine for the treatment of rheumatism and bronchitis. Herein, four undescribed triterpenes, officinalisoids A-D (1-4), together with thirty-three known compounds (5-37) were isolated from the aerial parts of V. officinalis. The chemical structures of the new compounds were determined by spectrometric data interpretation using NMR, HRESIMS, IR and UV spectroscopy. Biological evaluation results revealed that compound 30 exhibited potential anti-inflammatory activity with IC 50 value of 6.07 μM (CC 50  > 50 μM) and compound 12 showed moderate anti-dengue virus activity with the IC 50 value of 24.55 μM (CC 50  > 50 μM)., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the feasibility and preliminary clinical results of transcatheter pulmonary valve replacement (TPVR) with the domestically-produced balloon-expandable Prizvalve system. Methods: This is a prospective single-center observational study. Patients with postoperative right ventricular outflow tract (RVOT) dysfunction, who were admitted to West China Hospital of Sichuan University from September 2021 to March 2023 and deemed anatomically suitable for TPVR with balloon-expandable valve, were included. Clinical, imaging, procedural and follow-up data were analyzed. The immediate procedural results were evaluated by clinical implant success rate, which is defined as successful valve implantation with echocardiography-assessed pulmonary regurgitation

6-methoxydihydrosanguinarine (6-MS), a natural benzophenanthridine alkaloid extracted from Macleaya cordata (Willd.) R. Br, has shown to trigger apoptotic cell death in cancer cells. However, the exact mechanisms involved have not yet been clarified. The current study reveals the underlying mechanisms of 6-MS-induced cytotoxicity in hepatocellular carcinoma (HCC) cells and investigates whether 6-MS sensitizes TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. 6-MS was shown to suppress cell proliferation and trigger cell cycle arrest, DNA damage, and apoptosis in HCC cells. Mechanisms analysis indicated that 6-MS promoted reactive oxygen species (ROS) generation, JNK activation, and inhibits EGFR/Akt signaling pathway. DNA damage and apoptosis induced by 6-MS were reversed following N-acetyl-l-cysteine (NAC) treatment. The enhancement of PARP cleavage caused by 6-MS was abrogated by pretreatment with JNK inhibitor SP600125. Furthermore, 6-MS enhanced TRAIL-mediated HCC cells apoptosis by upregulating the cell surface receptor DR5 expression. Pretreatment with NAC attenuated 6-MS-upregulated DR5 protein expression and alleviated cotreatment-induced viability reduction, cleavage of caspase-8, caspase-9, and PARP. Overall, our results suggest that 6-MS exerts cytotoxicity by modulating ROS generation, EGFR/Akt signaling, and JNK activation in HCC cells. 6-MS potentiates TRAIL-induced apoptosis through upregulation of DR5 via ROS generation. The combination of 6-MS with TRAIL may be a promising strategy and warrants further investigation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cap-dependent endonuclease (CEN) in the polymerase acidic protein (PA) of influenza A virus (IAV) represents a promising drug target due to its critical role in viral gene transcription. The CEN inhibitor, baloxavir marboxil (BXM), was approved in Japan and the US in 2018 and several other countries subsequently. Along with the clinical use of BXM, the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern. Herein, we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A, an analogue of BXM. The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes, including pH1N1, H3N2, H7N9 and H9N2, in MDCK cells, and the 50% effective concentration (EC 50 ) was calculated to nanomole level and comparable to that of baloxavir acid (BXA), the active form of BXM. Furthermore, in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice, with reduced viral RNA loads and alleviated pulmonary damage. Importantly, serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage. Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA. Taken together, our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance, which provides critical clues for future drug development and drug resistance surveillance., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

Candida albicans ( C. albicans ) is a ubiquitous clinical fungal pathogen. In recent years, combination therapy, a potential treatment method to overcome C. albicans resistance, has gained traction. In this study, we synthesized a series of cyclometalated iridium(III) complexes with the formula [Ir(C-N) 2 (tpphz)](PF 6 ) (C-N = 2-phenylpyridine (ppy, in Ir1 ), 2-(2-thienyl)pyridine (thpy, in Ir2 ), 2-(2,4-difluorophenyl) pyridine (dfppy, in Ir3 ), tpphz = tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine) and polypyridyl ruthenium(II) complexes with the formula [Ru(N-N) 2 (tpphz)](PF 6 ) 2 (N-N = 2,2'-bipyridine (bpy, in Ru1 ), 1,10-phenanthroline (phen, in Ru2 ), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3 )), and investigated their antifungal activities against drug-resistant C. albicans and their combination with fluconazole (FLC). Of which, the combination of the lead iridium(III) complex Ir2 and FLC showed strong antifungal activity against drug-resistant C. albicans. Mechanism studies have shown that they can inhibit the formation of hyphae and biofilm, damage mitochondrial function and accumulate intracellular ROS. Therefore, iridium(III) complexes combined with FLC can be used as a promising treatment to exert anti-drug-resistant C. albicans activity, in order to improve the treatment efficiency of fungal infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lu, Xu, Zhu, Zhu, Ma, Wang, Li and Ye.)

Iron(Fe) is a trace metal element necessary for plant growth, but excess iron is harmful to plants. Natural resistance-associated macrophage proteins (NRAMPs) are important for divalent metal transport in plants. In this study, we isolated the MsNRAMP2 (MN&#95;547960) gene from alfalfa, the perennial legume forage. The expression of MsNRAMP2 is specifically induced by iron excess. Overexpression of MsNRAMP2 conferred transgenic tobacco tolerance to iron excess, while it conferred yeast sensitivity to excess iron. Together with the MsNRAMP2 gene, MsMYB (MN&#95;547959) expression is induced by excess iron. Y1H indicated that the MsMYB protein could bind to the "CTGTTG" cis element of the MsNRAMP2 promoter. The results indicated that MsNRAMP2 has a function in iron transport and its expression might be regulated by MsMYB . The excess iron tolerance ability enhancement of MsNRAMP2 may be involved in iron transport, sequestration, or redistribution.

The low X-ray attenuation coefficient of tumor soft tissue and the hypoxic tumor microenvironment (TME) during radiation therapy (RT) of breast cancer result in RT resistance and thus reduced therapeutic efficacy. In addition, immunosuppression induced by the TME severely limits the antitumor immunity of radiation therapy. In this paper, we propose a PCN-224@IrNCs/D-Arg nanoplatform for the synergistic radiosensitization, photodynamic, and NO therapy of breast cancer that also boosts antitumor immunity (PCN = porous coordination network, IrNCs = iridium nanocrystals, D-Arg = D-arginine). The local tumors can be selectively ablated via reprogramming the tumor microenvironment (TME), photodynamic therapy (PDT) and NO therapy, and the presence of the high-Z element Ir that sensitizes radiotherapy. The synergistic execution of these treatment modalities also resulted in adapted antitumor immune response. The intrinsic immunomodulatory effects of the nanoplatform also repolarize macrophages toward the M1 phenotype and induce dendritic cell maturation, activating antitumor T cells to induce immunogenic cell death as demonstrated in vitro and in vivo . The nanocomposite design reported herein represents a new regimen for the treatment of breast cancer through TME reprogramming to exert a synergistic effect for effective cancer therapy and antitumor immunity.

Objectives: This study aimed to assess the association between plasma glutamate (Glu) and the risk of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) and whether this association differs by gender., Material and Methods: We retrieved clinical information on 1032 consecutive patients with T2DM from a same tertiary care center from May 2015 to August 2016. Glu was quantified by liquid chromatography-tandem mass spectrometry analysis. Glu was converted into a categorical variable based on the median concentration in the whole population, while logistic regression was used to obtain the odds ratio (OR) and 95% confidence interval (CI), and the correlation between Glu and various biochemical indices was analyzed., Results: We found that Glu was positively associated with the risk of CVD in patients with T2DM. This correlation was more significant in women. In T2DM patients, the higher the age, body mass index (BMI), weight and systolic blood pressure (SBP), the lower the glycosylated hemoglobin (HbA1C) concentration and the higher the Glu. In female patients, the correlation between age, weight, BMI, SBP, and plasma Triglycerides (TG), and Glu was also statistically significant., Conclusion: In conclusion, female T2DM patients with high levels of Glu have a higher risk of developing CVD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Li, Wang, Gao, Zhang, Li, Zhang and Fang.)

Objective: To forecast mortality, age-standardized mortality, and probability of premature mortality from diabetes, and to simulate the impact of controlling risk factors by 2030 in China. Methods: We simulated the burden of disease from diabetes in six scenarios according to the development goals of risk factors control by the WHO and Chinese government. Based on the theory of comparative risk assessment and the estimates of the burden of disease for China from the Global Burden of Disease Study 2015, we used the proportional change model to project the number of deaths, age-standardized mortality, and probability of premature mortality from diabetes under different scenarios of risk factors control in 2030. Results: If the trends in exposures to risk factors from 1990 to 2015 continued. Mortality, age-standardized mortality, and probability of premature mortality from diabetes would increase to 32.57/100 000, 17.32/100 000, and 0.84% by 2030, respectively. During that time, mortality, age-standardized mortality and probability of premature mortality for males would all be higher than for females. If the goals of controlling risk factors were all achieved, the number of deaths from diabetes in 2030 would decrease by 62.10% compared to the predicted numbers based on the historical trends in exposure to risk factors, and the probability of premature mortality would drop to 0.29%. If only the exposure to a single risk factor were achieved by 2030, high fasting plasma glucose control would have the greatest impact on diabetes, resulting in a 56.00% reduction in deaths compared to the predicted numbers based on the historical trends, followed by high BMI (4.92%), smoking (0.65%), and low physical activity (0.53%). Conclusions: Risk factors control plays an important role in reducing the number of deaths, age-standardized mortality rate, and probability of premature mortality from diabetes. We suggest taking comprehensive measures to control relevant risk factors for certain populations and regions, to achieve the goal of reducing the burden of disease from diabetes as expected.

Aims: To investigate the capability, properties, and molecular mechanism of inulin fermentation by lactic acid bacteria (LAB) from Sichuan pickle., Methods and Results: A total of 79 LAB strains were purified from 30 aged Sichuan pickle brine samples, and only 21 Lactiplantibacillus plantarum strains (26.58%, 21/79) derived from 15 samples grew well through utilizing inulin as a carbon source. The fermentation tests through using long-chain inulin (lc-inulin) as a carbon source showed that only 6 L. plantarum strains grew well, while other 15 strains could only utilize short-chain oligofructose (FOS), and thin-layer chromatography analysis evidenced a strain specificity of inulin consumption patterns. Lactiplantibacillus plantarum YT041 is a vigorous inulin fermenter, and whole genome sequencing data revealed that sacPTS1 and fosRABCDXE operons might be associated with the fermentation of FOS and lc-inulin, respectively., Conclusions: The phenotype of inulin consumption is commonly present in LAB from Sichuan pickle, which is strain-specific and largely depends on their specific ecological niche and degree of polymerization., (© The Author(s) 2023. Published by Oxford University Press on behalf of Applied Microbiology International.)

The Zika virus (ZIKV) represents an important global health threat due to its unusual association with congenital Zika syndrome. ZIKV strains are phylogenetically grouped into the African and Asian lineages. However, the viral determinants underlying the phenotypic differences between the lineages remain unknown. Here, multiple sequence alignment revealed a highly conserved residue at position 21 of the premembrane (prM) protein, which is glutamic acid and lysine in the Asian and African lineages, respectively. Using reverse genetics, we generated a recombinant virus carrying an E21K mutation based on the genomic backbone of the Asian lineage strain FSS13025 (termed E21K). The E21K mutation significantly increased viral replication in multiple neural cell lines with a higher ratio of M to prM production. Animal studies showed E21K exhibited increased neurovirulence in suckling mice, leading to more severe defects in mouse brains by causing more neural cell death and destruction of hippocampus integrity. Moreover, the E21K substitution enhanced neuroinvasiveness in interferon alpha/beta (IFN-α/β) receptor knockout mice, as indicated by the increased mortality, and enhanced replication in mouse brains. The global transcriptional analysis showed E21K infection profoundly altered neuron development networks and induced stronger antiviral immune response than wild type (WT) in both neural cells and mouse brains. More importantly, the reverse K21E mutation based on the genomic backbone of the African strain MR766 caused less mouse neurovirulence. Overall, our findings support the 21st residue of prM functions as a determinant for neurovirulence and neuroinvasiveness of the African lineage of ZIKV. IMPORTANCE The suspected link of Zika virus (ZIKV) to birth defects led the World Health Organization to declare ZIKV a Public Health Emergency of International Concern. ZIKV has been identified to have two dominant phylogenetic lineages, African and Asian. Significant differences exist between the two lineages in terms of neurovirulence and neuroinvasiveness in mice. However, the viral determinants underlying the phenotypic differences are still unknown. Here, combining reverse genetics, animal studies, and global transcriptional analysis, we provide evidence that a single E21K mutation of prM confers to the Asian lineage strain FSS130125 significantly enhanced replication in neural cell lines and more neurovirulent and neuroinvasiveness phenotypes in mice. Our findings support that the highly conserved residue at position 21 of prM functions as a determinant of neurovirulence and neuroinvasiveness of the African lineage of ZIKV in mice.

Herein, three heterometallic Ru(II)-Re(I) complexes, [Ru(NN) 2 (tpphz)Re(CO) 3 Cl](PF 6 ) 2 (N-N = 2,2'-bipyridine (bpy, in RuRe1), 1,10-phenanthroline (phen, in RuRe2), 4,7-diphenyl-1,10-phenanthroline (DIP, in RuRe3), tpphz = tetrapyrido[3,2-a:2',3'-c:3″,2″-h:2″',3″'-j]phenazine), using tpphz as a bridging ligand to connect Ru(II) polypyridyl moiety and Re(I) tricarbonyl moiety were designed and synthesized. Cytotoxicity tests revealed that RuRe1-3 exhibited high phototoxicities against several cancer cell lines tested, with IC 50 values ranging from 0.8 to 6.8 μM. Notably, RuRe2 exhibited the most significant increase in cytotoxicity against human prostate cancer (PC3) cells under light (450 nm) irradiation, with phototoxicity index (PI) value increasing by >112.3-fold. Further mechanistic studies of RuRe2 revealed that RuRe2-mediated PDT could induce tumor cell apoptosis through the mitochondrial pathway. Moreover, RuRe2-mediated PDT could inhibit PC3 cell scratch healing and reduce the expression levels of matrix metalloproteinases 2 (MMP-2), matrix metalloproteinases 9 (MMP-9) and vascular endothelial growth factor receptor VEGFR2. Finally, angiogenic activity assays performed in human umbilical vein endothelial cells (HUVECs) showed that RuRe2 exerted an anti-angiogenesis effect. Our study demonstrated that RuRe1-3 were promising PDT antitumor agents with potential anti-metastatic and anti-angiogenic activities., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022. Published by Elsevier Inc.)

Background: Zika virus (ZIKV) is an emerging arbovirus of the genus flavivirus that is associated with congenital Zika syndrome (CZS) in newborns. A wide range of clinical symptoms including intellectual disability, speech delay, coordination or movement problems, and hearing and vision loss, have been well documented in children with CZS. However, whether ZIKV can invade the olfactory system and lead to post-viral olfactory dysfunction (PVOD) remains unknown., Methods: We investigated the susceptibility and biological responses of the olfactory system to ZIKV infection using mouse models and human olfactory organoids derived from patient olfactory mucosa., Findings: We demonstrate that neonatal mice infected with ZIKV suffer from transient olfactory dysfunction when they reach to puberty. Moreover, ZIKV mainly targets olfactory ensheathing cells (OECs) and exhibits broad cellular tropism colocalizing with small populations of mature/immature olfactory sensory neurons (mOSNs/iOSNs), sustentacular cells and horizontal basal cells in the olfactory mucosa (OM) of immunodeficient AG6 mice. ZIKV infection induces strong antiviral immune responses in both the olfactory mucosa and olfactory bulb tissues, resulting in the upregulation of proinflammatory cytokines/chemokines and genes related to the antiviral response. Histopathology and transcriptomic analysis showed typical tissue damage in the olfactory system. Finally, by using an air-liquid culture system, we showed that ZIKV mainly targets sustentacular cells and OECs and support robust ZIKV replication., Interpretation: Our results demonstrate that olfactory system represents as significant target for ZIKV infection, and that PVOD may be neglected in CZS patients., Funding: Stated in the acknowledgment., Competing Interests: Declaration of interests The authors declare that they have no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Human RNA binding protein Musashi-1 (MSI1) plays a critical role in neural progenitor cells (NPCs) by binding to various host RNA transcripts. The canonical MSI1 binding site (MBS), A/GU (1-3) AG single-strand motif, is present in many RNA virus genomes, but only Zika virus (ZIKV) genome has been demonstrated to bind MSI1. Herein, we identified the AUAG motif and the AGAA tetraloop in the Xrn1-resistant RNA 2 (xrRNA2) as the canonical and non-canonical MBS, respectively, and both are crucial for ZIKV neurotropism. More importantly, the unique AGNN-type tetraloop is evolutionally conserved, and distinguishes ZIKV from other known viruses with putative MBSs. Integrated structural analysis showed that MSI1 binds to the AUAG motif and AGAA tetraloop of ZIKV in a bipartite fashion. Thus, our results not only identified an unusual viral RNA structure responsible for MSI recognition, but also revealed a role for the highly structured xrRNA in controlling viral neurotropism., (© 2023. The Author(s).)