A dual responsive nitric oxide / ß-lapachone co-delivery platform for redox imbalance-enhanced tumor therapy.

Nitric oxide (NO) / ß-Lapachone (Lap) combined therapy by causing oxidative stress is an effective tumor therapy strategy. Herein, a dual-responsive lipid nanoparticles (LNPs) LSNO for NO / Lap co-delivery were constructed from the zinc-coordinated lipid (DSNO(Zn)) and the hydrophobic drug Lap in the presence of helper lipids (DOPE and DSPE-PEG2000). The zinc-coordinated structure in LSNO might elevate the Zn2+ content in tumor cells, contributing to antioxidant imbalance. The fluorescent assays proved the light-triggered NO release and fluorescent self-reporting abilities of LSNO. In addition, the LNPs had good drug release behavior under high concentration of GSH, indicating the NO / drug co-delivery capacity. In vitro antitumor assays showed that the NO / Lap combination treatment group could induce more significant tumor cell growth inhibition and cell apoptosis than individual NO or Lap treatment. The following mechanism studies revealed that NO / Lap combination treatment led to distinct oxidative stress by producing reactive oxygen species (ROS) and peroxynitrite anion (ONOO-). On the other hand, the intracellular redox balance could be further disrupted by Lap-induced NADPH consumption and Zn2+ / NO-induced reductase activities downregulation, thus promoting the degree of cell damage. Besides, it was also found that NO and Lap could directly damage nuclear DNA and induce mitochondrial dysfunction, thereby leading to caspase-3 activation and tumor cell death. These results proved that LSNO could serve as a promising multifunctional tumor therapy platform.

Advancing skeletal health and disease research with single-cell RNA sequencing.

Orthopedic conditions have emerged as global health concerns, impacting approximately 1.7 billion individuals worldwide. However, the limited understanding of the underlying pathological processes at the cellular and molecular level has hindered the development of comprehensive treatment options for these disorders. The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized biomedical research by enabling detailed examination of cellular and molecular diversity. Nevertheless, investigating mechanisms at the single-cell level in highly mineralized skeletal tissue poses technical challenges. In this comprehensive review, we present a streamlined approach to obtaining high-quality single cells from skeletal tissue and provide an overview of existing scRNA-seq technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. By utilizing these methodologies, crucial insights into the developmental dynamics, maintenance of homeostasis, and pathological processes involved in spine, joint, bone, muscle, and tendon disorders have been uncovered. Specifically focusing on the joint diseases of degenerative disc disease, osteoarthritis, and rheumatoid arthritis using scRNA-seq has provided novel insights and a more nuanced comprehension. These findings have paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders.

Regioselective Substitution of BINOL.

1,1'-Bi-2-naphthol (BINOL) has been extensively used as the chirality source in the fields of molecular recognition, asymmetric synthesis, and materials science. The direct electrophilic substitution at the aromatic rings of the optically active BINOL has been developed as one of the most convenient strategies to structurally modify BINOL for diverse applications. High regioselectivity has been achieved for the reaction of BINOL with electrophiles. Depending upon the reaction conditions and substitution patterns, various functional groups can be introduced to the specific positions, such as the 6-, 5-, 4-, and 3-positions, of BINOL. Ortho-lithiation at the 3-position directed by the functional groups at the 2-position of BINOL have been extensively used to prepare the 3- and 3,3'-substituted BINOLs. The use of transition metal-catalyzed C-H activation has also been explored to functionalize BINOL at the 3-, 4-, 5-, 6-, and 7-positions. These regioselective substitutions of BINOL have allowed the construction of tremendous amount of BINOL derivatives with fascinating structures and properties as reviewed in this article. Examples for the applications of the optically active BINOLs with varying substitutions in asymmetric catalysis, molecular recognition, chiral sensing and materials are also provided.

Three chemosensory proteins enriched in antennae and tarsi of Rhaphuma horsfieldi differentially contribute to the binding of insecticides.

Antennae and legs (primarily the tarsal segments) of insects are the foremost sensory organs that contact a diverse range of toxic chemicals including insecticides. Binding proteins expressed in the two tissues are potential molecular candidates serving as the binding and sequestering of insecticides, like chemosensory proteins (CSPs). Insect CSPs endowed with multiple roles have been suggested to participate in insecticide resistance, focusing mainly on moths, aphids and mosquitos. Yet, the molecular underpinnings underlying the interactions of cerambycid CSPs and insecticides remain unexplored. Here, we present binding properties of three antenna- and tarsus-enriched RhorCSPs (RhorCSP1, CSP2 and CSP3) in Rhaphuma horsfieldi to eight insecticide classes totaling 15 chemicals. From the transcriptome of this beetle, totally 16 CSP-coding genes were found, with seven full-length sequences. In phylogeny, these RhorCSPs were distributed dispersedly in different clades. Expression profiles revealed the abundant expression of RhorCSP1, CSP2 and CSP3 in antennae and tarsi, thus as representatives for studying the protein-insecticide interactions. Binding assays showed that the three RhorCSPs were tuned differentially to insecticides but exhibited the highest affinities with hexaflumuron, chlorpyrifos and rotenone (dissociation constants <13 µM). In particular, RhorCSP3 could interact strongly with 10 of tested insecticides, of which four residues (Tyr25, Phe42, Val65 and Phe68) contributed significantly to the binding of six, four, three and four ligands, respectively. Of these, the binding of four mutated RhorCSP3s to a botanical insecticide rotenone was significantly weakened compared to the wildtype protein. Furthermore, we also evidenced that RhorCSP3 was a broadly-tuned carrier protein in response to a wide variety of plant odorants outside insecticides. Altogether, our findings shed light on different binding mechanisms and odorant-tuning profiles of three RhorCSPs in R. horsfieldi and identify key residues of the RhorCSP3-insecticide interactions.

Investigation of polysaccharide from Radix Aconiti Lateralis Preparata (Fuzi) cardio protective effect on doxorubicin-induced chronic cardiotoxicity.

OBJECTIVES: Doxorubicin (DOX) is a chemotherapy drug for treating malignant tumours. However, its cardiotoxicity has limited its clinical application. The Radix Aconiti Lateralis Preparata, also known as Fuzi, has been used for treating heart failure. Nevertheless, there is still a deficiency of claeity as to whether the Fuzi polysaccharide (FPS) may prevent the side effects of DOX. METHODS: Mice were intraperitoneally administered DOX (15 mg/kg) to establish a mouse model of DOX-induced chronic cardiotoxicity (DICC). The mice were then administered different doses of FPS or enalapril intragastrically. KEY FINDINGS: In the DOX group, the activity of CK-MB and LDH and the content of NT-proBNP in serum of mice were increased. Myocardial infiltration of inflammatory cells and cytoplasmic vacuolation occurred. Levels of NLRP3, ASC, Caspase-1, IL-1ß, IL-18, IL-6, and Bax increased, whereas levels of Bcl-2, STAT3, and p-STAT3 decreased. After administering FPS (100 mg/kg and 200 mg/kg), there were reductions in CK-MB activity and NT-proBNP levels. Cytoplasmic vacuolation, interstitial infiltration of blood, and infiltration of inflammatory cells were alleviated. The changes in protein expression mentioned above were reversed. CONCLUSIONS: FPS can protect heart function and structure in DICC mice by inhibiting NLRP3 inflammasome-mediated pyroptosis and IL-6/STAT3 pathway-induced apoptosis.

Total flavonoids extracted from Penthorum chinense Pursh mitigates CCl4-induced hepatic fibrosis in rats via inactivation of TLR4-MyD88-mediated NF-κB pathways and regulation of liver metabolism.

Background: Penthorum chinense Pursh (PCP) is widely utilized in China to treat a variety of liver diseases. It has been shown that flavonoids inhibit inflammation and have the potential to attenuate tissue damage and fibrosis. However, the mechanisms underlying how total flavonoids isolated from PCP (TFPCP) exert their anti-fibrotic effects remain unclear. Methods: The chemical composition of TFPCP was determined using UHPLC-Q-Orbitrap HRMS. Subsequently, rats were randomly assigned to a control group (Control), a carbon tetrachloride (CCl4)-induced hepatic fibrosis model group (Model), a positive control group [0.2 mg/(kg∙day)] of Colchicine), and three TFPCP treatment groups [50, 100, and 150 mg/(kg∙day)]. All substances were administered by gavage and treatments lasted for 9 weeks. Simultaneously, rats were intraperitoneally injected with 10%-20% CCl4 for 9 weeks to induce liver fibrosis. At the end of the experiment, the liver ultrasound, liver histomorphological, biochemical indicators, and inflammatory cytokine levels were tested respectively. The underlying mechanisms were assessed using Western blot, immunohistochemistry, immunofluorescence, RT-qPCR, and metabolomics. Results: Fourteen flavonoids were identified in TFPCP. Compared with control animals, CCl4-treated rats demonstrated obvious liver injury and fibrosis, manifested as increases in gray values, distal diameter of portal vein (DDPV) and a decrease in blood flow velocity (VPV) in the ultrasound analysis; increased biochemical index values (serum levels of ALT, AST, TBIL, and ALP); marked increases in the contents of fibrotic markers (PC III, COL4, LN, HA) and inflammatory factors (serum TNF-α, IL-6, and IL-1ß); and significant pathological changes. However, compared with the Model group, the ultrasound parameters were significantly improved and the serum levels of inflammatory cytokines were reduced in the TFPCP group. In contrast, the expression of TGF-ß1, TLR4, and MyD88, as well as the p-P65/P65 and p-IκBα/IκBα ratios, were considerably reduced following TFPCP treatment. In addition, we identified 32 metabolites exhibiting differential abundance in the Model group. Interestingly, TFPCP treatment resulted in the restoration of the levels of 20 of these metabolites. Conclusion: Our findings indicated that TFPCP can ameliorate hepatic fibrosis by improving liver function and morphology via the inactivation of the TLR4/MyD88-mediated NF-κB pathway and the regulation of liver metabolism.

Regio- and Enantioselective Macrocyclization from Dynamic Imine Formation: Chemo- and Enantioselective Fluorescent Recognition of Lysine.

The dynamic covalent chemistry of imines is utilized to conduct a regioselective as well as enantioselective synthesis of an unsymmetric (C1) chiral macrocycle from the reaction of an unsymmetric (C1) chiral dialdehyde, (S)-4, that contains a salicylaldehyde unit and a benzaldehyde unit, with lysine, an unsymmetric (C1) chiral diamine. The enantioselectivity is further enhanced in the presence of Zn2+. Compound (S)-4 in combination with Zn2+ is found to be a highly chemoselective as well as enantioselective fluorescent probe for lysine. It can be used to detect specific enantiomers of this amino acid.

Galangin: A food-derived flavonoid with therapeutic potential against a wide spectrum of diseases.

Galangin is an important flavonoid with natural activity, that is abundant in galangal and propolis. Currently, various biological activities of galangin have been disclosed, including anti-inflammation, antibacterial effect, anti-oxidative stress and aging, anti-fibrosis, and antihypertensive effect. Based on the above bioactivities, more and more attention has been paid to the role of galangin in neurodegenerative diseases, rheumatoid arthritis, osteoarthritis, osteoporosis, skin diseases, and cancer. In this paper, the natural sources, pharmacokinetics, bioactivities, and therapeutic potential of galangin against various diseases were systematically reviewed by collecting and summarizing relevant literature. In addition, the molecular mechanism and new preparation of galangin in the treatment of related diseases are also discussed, to broaden the application prospect and provide reference for its clinical application. Furthermore, it should be noted that current toxicity and clinical studies of galangin are insufficient, and more evidence is needed to support its possibility as a functional food.

Erysiphe elevata causing powdery mildew on Eucalyptus urophylla × E. camaldulensis in China.

Eucalyptus urophylla × E. camaldulensis, named Chiwei eucalypt, is a hybrid species widely used in China. Many of its clones are cultivated for afforestation due to cold tolerance, high yield, high strength and disease resistance. Clone LH1 is planted extensively for its high stability and machinability in South China. In December 2021, severe powdery mildew signs were observed on clone LH1 in Zhanjiang, Guangdong (N28°8'29"; E110°17'5"). Whitish powder principally appeared on both abaxial and adaxial leaf surfaces. All plants were infected within about a week and above 90% leaves were diseased, which resulted in abnormal growth and shrinkage of leaves. Hyphae with single, lobed appressoria were hyaline, septate, branched, 3.3-6.8 µm (ave. 4.9 µm, n>50) wide. Conidiophores with a straight to flexuous foot-cell (14.7-46.1×5.4-9.7 µm, ave. 25.8×7.9 µm, n>30) were erect, hyaline, 2-septate, unbranched, 35.4-81.8 × 5.7-10.7 (ave. 56.7×8.7 µm, n>50). Conidia were solitary, hyaline, cylindrical to elliptical, 27.7-46.6 ×11.2-19.0 (ave. 35.7×16.6 µm, n>50). Chamothecia were not found on infected trees. The further identification was confirmed by partial sequences of internal transcribed spacer (ITS), large submit rRNA gene (LSU), Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glutamine synthetase (GS), and RNA polymerase II second largest subunit (RPB2) gene. A very small amount of mycelia and spores from voucher specimens CCAS-ASBF-1 and CCAS-ASBF-2 were deposited in the herbarium of Guangdong Ocean University. Specimens were PCR amplified and sequenced with primer pairs ITS1/ITS4 (White et al 1990), LROR/LR7 (Moncalvo et al 1995), PMGAPDH1/PMGAPDH3R, GSPM2/GSPM3R and PmRpb2_4/ PMRpb2_6R (Bradshaw, et al. 2022), respectively. BLASTn results showed that ITS (OP270019 and OQ380937), LSU (OP270018 and OQ380938), GAPDH, GS and RPB2 (OQ414445- OQ414450) were above 99% identical with those of E. elevata on Catalpa bignonioides (ITS: AY587013) (Cook et al 2004), Plumeria rubra (ITS: MH985631) (Yeh et al 2019), Cerbera manghas (ITS: MZ379159; LSU: MZ379160) (Mukhtar et al 2022), and Eucalyptus camaldulensis (LSU: LC177375-6) (Meebon et al. 2017), and above 99% identical with those of Erysiphe vaccinii FH00941201 on Vaccinium corymbosum (ITS: ON073869; RPB2: ON119159; GS: ON075687) and FH00112205 on V. vacillans (ITS: ON073870; GAPDH: ON075646) (Bradshaw et al 2022). This is the first sequence data for non rDNA of E. elevata. In an ITS tree phylogenetic analysis with Maximum likelihood (ML) method showed the fungus clustered in a highly supported clade with E. elevata and E. vaccinii. In a multi-locus tree, E. elevata grouped in a sister position to E. vaccinii FH00941201. Thus, the pathogen was identified as E. elevata based on morphology, DNA BLASTn and phylogenetic analysis (Braun and Cook 2012). Pathogenicity tests were conducted on healthy leaves of 1-year-old potted plants. Ten leaves were cleaned with sterile water, inoculated by gently dusting conidia from single lesion on the naturally infected leaves, and then covered with plastic bags containing wet absorbent cotton. Non-inoculated leaves served as controls. Symptoms developed on all inoculated leaves 3 to 5 days after inoculation, and the fungus was identical to the original fungus on the infected leaves, whereas control plants remained symptomless. This is the first report of powdery mildew caused by E. elevata on Eucalyptus sp. from China. This finding is helpful for land managers to diagnose and control the disease.

Near-IR Fluorescent Recognition of Arginine: High Chemoselectivity and Enantioselectivity Promoted by La3.

The first near IR fluorescent probe for the chemoselective and enantioselective recognition of arginine in aqueous solution is reported in this work. This probe, made of a 1,1'-binaphthyl-based chiral aldehyde unit and a rhodamine-based near IR chromophore, in combination with La3+ exhibits highly chemoselective as well as enantioselective fluorescent enhancement with arginine at λ=764 nm upon excitation at λ=690 nm. Little or no fluorescent response is observed toward the chirality miss-matched arginine enantiomer or other common amino acids and their enantiomers. This probe also allows visual discrimination of the arginine enantiomers because of its fast and distinct color change upon interaction with the substrate.

Bioactive compounds and mechanism of Xianglian pill in the treatment of gastric cancer: Network pharmacology analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastric cancer (GC) affects people's quality of life because of its high incidence rate and mortality. The Xianglian Pill (XLP) is a traditional Chinese medicine (TCM) prescription used to treat gastrointestinal (GI） diseases. Its anti-tumor effect has been found in recent years, but it's bioactive compounds and mechanism of action in treating GC are remain unknown. AIM OF THE STUDY: This study reveals the bioactive compounds and mechanisms of XLP in the treatment of GC through network pharmacology analysis and experimental verification. MATERIALS AND METHODS: The main compounds in XLP were searched and the active compounds with anti-GC activity were selected. Compounds targets and GC- related targets were predicted, and common targets were obtained. Subsequently, a protein-protein interaction (PPI) network of common targets is constructed, while GO and KEGG enrichment analyses were performed on common targets. Finally, the anti-GC effects of active compounds in XLP were verified in GC cell lines MGC-803 and HGC-27 by wound healing assay, cell cycle assay, cell apoptosis assay and western blotting (WB) assay. RESULTS: A total of 33 active compounds of XLP were obtained. MTT assay showed that dehydrocostus lactone (DHL) and berberrubine (BRB) had lower IC50 value in GC cells HGC-27 and MGC-803, and has a less inhibitory effect on normal gastric epithelial cells. Further, 73 common targets were obtained after the total target of DHL and BRB intersected with GC. Among them, CASP3, AKT1, SRC, STAT3,and CASP9 were the most associated genes in the PPI network. GO and KEGG enrichment analyses indicated that apoptosis played a major role in the biological processes and signaling pathways involved. Moreover, the in vitro experiment revealed that DHL and BRB inhibited GC cell viability via inducing cell cycle arrest at G2/M phase, and promoting cell apoptosis by up-regulating the caspase3 expression and down-regulating the expression of Bcl2/Bax. CONCLUSIONS: DHL and BRB are the two main anti-GC active compounds in XLP, and their mechanism is mainly to inhibit cell cycle and promote cell apoptosis.

Epidemiological characteristics and spatiotemporal analysis of mumps at township level in Wuhan, China, 2005-2019.

The resurgence and outbreaks of mumps occur frequently in many countries worldwide in recent years, even in countries with high vaccination coverage. In this study, a descriptive and spatiotemporal clustering analysis at the township level was conducted to explore the dynamic spatiotemporal aggregation and epidemiological characteristics of mumps in Wuhan. During 2005 and 2019, there were 40 685 cases reported in Wuhan, with an average annual morbidity of 28.11 per 100 000 populations. The morbidity showed a fluctuating tendency, and peaked in 2010 and 2018. Bimodal seasonality was found, with a large peak between May and July, and a mild peak from November to January in the following year. Male students aged 5-9-year-old were the main risk group of mumps infection. Significant global spatial auto-correlation was detected except in 2007, 2009 and 2015. The spatial and temporal scan statistics indicated that the hot-spots mainly located at the western and southern areas of Wuhan with variations almost every year. Our findings could assist the public health authorities to develop and improve targeted health strategies, and allocate health resources rationally.

One Molecular Probe with Opposite Enantioselective Fluorescence Enhancement at Two Distinct Emissions.

It is discovered that one enantiomer of a chiral substrate can greatly enhance the fluorescence of one molecular probe at one emitting signal (λ1 = 517 nm), while the opposite enantiomer of the substrate greatly enhances the fluorescence of the same probe at a distinctively different emission (λ2 = 575 nm). This probe is made of a 1,1'-binaphthyl-based chiral dialdehyde that in combination with Zn2+ under slightly acidic conditions shows a chemoselective and enantioselective fluorescent response to histidine. The opposite enantioselective fluorescent responses of the probe at two emissions allow it to be used to determine both the concentration and the enantiomeric composition of the substrate using a single probe. The mechanistic study has revealed two very different reaction pathways when the two enantiomers of the substrate are treated with the probe. These reaction pathways generate two different products, one dimeric and another polymeric, with very different emissions.

High-Flow Nasal Cannula Oxygen Therapy versus Non-Invasive Ventilation in AIDS Patients with Acute Respiratory Failure: A Randomized Controlled Trial.

BACKGROUND: Acute respiratory failure (ARF) remains the most common diagnosis for intensive care unit (ICU) admission in acquired immunodeficiency syndrome (AIDS) patients. METHODS: We conducted a single-center, prospective, open-labeled, randomized controlled trial at the ICU, Beijing Ditan Hospital, China. AIDS patients with ARF were enrolled and randomly assigned in a 1:1 ratio to receive either high-flow nasal cannula (HFNC) oxygen therapy or non-invasive ventilation (NIV) immediately after randomization. The primary outcome was the need for endotracheal intubation on day 28. RESULTS: 120 AIDS patients were enrolled and 56 patients in the HFNC group and 57 patients in the NIV group after secondary exclusion. Pneumocystis pneumonia (PCP) was the main etiology for ARF (94.7%). The intubation rates on day 28 were similar to HFNC and NIV (28.6% vs. 35.1%, p = 0.457). Kaplan-Meier curves showed no statistical difference in cumulative intubation rates between the two groups (log-rank test 0.401, p = 0.527). The number of airway care interventions in the HFNC group was fewer than in the NIV group (6 (5-7) vs. 8 (6-9), p < 0.001). The rate of intolerance in the HFNC group was lower than in the NIV group (1.8% vs. 14.0%, p = 0.032). The VAS scores of device discomfort in the HFNC group were lower than that in the NIV group at 2 h (4 (4-5) vs. 5 (4-7), p = 0.042) and at 24 h (4 (3-4) vs. 4 (3-6), p = 0.036). The respiratory rate in the HFNC group was lower than that in the NIV group at 24 h (25 ± 4/min vs. 27 ± 5/min, p = 0.041). CONCLUSIONS: Among AIDS patients with ARF, there was no statistical significance of the intubation rate between HFNC and NIV. HFNC had better tolerance and device comfort, fewer airway care interventions, and a lower respiratory rate than NIV. CLINICAL TRIAL NUMBER: Chictr.org (ChiCTR1900022241).

Pulmonary Infections and Outcomes in AIDS Patients with Respiratory Failure: A 10-Year Retrospective Review.

Background: Respiratory failure in acquired immunodeficiency syndrome (AIDS) patients was the leading cause of intensive care unit (ICU) admission in our center. We aimed to describe the pulmonary infections and outcomes for respiratory failure in AIDS patients. Methods: A retrospective study was conducted on AIDS adult patients with respiratory failure who were admitted to the ICU in Beijing Ditan hospital, China, from January 2012 to December 2021. We investigated pulmonary infections complicated by respiratory failure in AIDS patients. The primary outcome was ICU mortality, and a comparison between survivors and nonsurvivors was performed. Multiple logistic regression analysis was used to identify predictors of ICU mortality. The Kaplan-Meier curve and Log rank test were used for survival analysis. Results: A total of 231 AIDS patients were admitted to ICU with respiratory failure over a 10-year period with a male predominance (95.7%). Pneumocystis jirovecii pneumonia was the main etiology of pulmonary infections (80.1%). The ICU mortality was 32.9%. In multivariate analysis, ICU mortality was independently associated with invasive mechanical ventilation (IMV) [odds ratio (OR), 27.910; 95% confidence interval (CI, 8.392-92.818; p = 0.000) and the time before ICU admission (OR, 0.959; 95% CI, 0.920-0.999; p = 0.046). In the survival analysis, patients with IMV and later admission to ICU had a higher probability of mortality. Conclusion: Pneumocystis jirovecii pneumonia was the primary etiology for respiratory failure in AIDS patients admitted to the ICU. Respiratory failure remains a severe illness with high mortality, and ICU mortality was negatively associated with IMV and later admission to ICU.

Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization.

Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development. IMPORTANCE KSHV is a virus that can lead to cancer after infection. A vaccine that prevents KSHV infection or transmission would be helpful in preventing the development of these cancers. We investigated KSHV VLV as an immunogen for vaccination. We determined that antibodies targeting the viral protein ORF4 induced by VLV immunization could engage the complement system and neutralize viral infection. However, ORF4-specific antibodies were seldom detected in the sera of KSHV-infected humans. Moreover, these human sera did not potently trigger complement-mediated neutralization, indicating an improvement that immunization can confer. Our study suggests a new antibody-mediated mechanism to control KSHV infection and underscores the benefit of activating the complement system in a future KSHV vaccine.

Synthesis of a BINOL-Based C3 Symmetric Schiff Base and Its Fluorescence Response to Zn2.

A novel C3 symmetric 1,1'-bi-2-naphthol-based Schiff base (R,R,R)-6 has been synthesized which shows highly selective fluorescence enhancement with Zn2+ among 21 metal cations examined. Its sensitivity and selectivity are found to be greater than other related C2 (1) and C1 [(R)-9] symmetric compounds in the fluorescent recognition of Zn2+ . The mechanistic study reveals that the selective fluorescence enhancement of the probe can be attributed to the formation of a unimolecular multidentate 6-coordinated Zn2+ complex.

Fluorescent Self-Reporting Lipid Nanoparticles for Nitric Oxide/Gene Co-Delivery and Combination Therapy.

The combination cancer therapy of nitric oxide (NO) with gene therapy is a promising method for tumor treatment. However, efficient co-delivery of gas and therapeutic genes to tumor cells remains a challenge. Herein, we designed a nano-sized ultraviolet (UV) light-responsive cationic lipid vector DPNO(Zn). Fluorescence spectroscopy and confocal imaging experiments revealed that DPNO(Zn) lipid nanoparticles (LNPs) could rapidly release NO under low-power UV light irradiation. Moreover, the fluorescence turn-on might take place along with the release of NO, indicating the self-reporting ability. Gene delivery experiments showed that DPNO(Zn) LNPs had good gene transfection ability, making such materials a good candidate for gas/gene combination therapy. In vitro antitumor assay demonstrated that the co-delivery system was more effective in inhibiting tumor cell proliferation than individual NO or pTrail treatment. Studies on the mechanism of tumor cell apoptosis induced by NO/pTrail co-delivery showed that NO could not only effectively increase the accumulation of p53 protein in tumor cells, thereby promoting the activation of caspase-3, but also induce mitochondrial damage. On the other hand, the Trail protein expressed by pTrail gene could enhance the degree of NO-induced caspase-3 activation, indicating the synergistic effect. These results proved that DPNO(Zn) LNP may serve as a multifunctional nanocarrier for potential tumor therapy.

Chemoselective and Enantioselective Fluorescent Recognition of Prolinol.

A highly chemoselective and enantioselective fluorescent probe has been discovered for the recognition of prolinol among various primary and secondary amine-based amino alcohols. The mechanistic studies including 1D and 2D 1H/13C NMR and mass spectroscopic analyses and DFT calculations have shown that the aldehyde group of the probe can react with prolinol to generate a bicyclic oxazolidine unit which, through a possible intramolecular hydrogen bond interaction, will lead to highly selective fluorescence enhancement.

The antibacterial activity of berberine against Cutibacterium acnes: its therapeutic potential in inflammatory acne.

Cutibacterium acnes (C. acnes) is a major pathogen implicated in the evolution of acne inflammation. Inhibition of C. acnes-induced inflammation is a prospective acne therapy strategy. Berberine (BBR), a safe and effective natural ingredient, has been proven to exhibit powerful antimicrobial and anti-inflammatory properties. However, the antimicrobial effect of BBR against C. acnes and its role in C. acnes-mediated inflammatory acne have not been explored. The objective of this investigation was to assess the antibacterial activity of BBR against C. acnes and its inhibitory effect on the inflammatory response. The results of in vitro experiments showed that BBR exhibited significant inhibition zones against four C. acnes strains, with the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in the range of 6.25-12.5 µg/mL and 12.5-25 µg/mL, respectively. On the bacterial growth curve, the BBR-treated C. acnes exhibited obvious growth inhibition. Transmission electron microscopy (TEM) images indicated that BBR treatment resulted in significant morphological changes in C. acnes. High-content imaging analysis further confirmed that BBR could effectively inhibit the proliferation of C. acnes. The disruption of cell wall and cell membrane structure by BBR treatment was preliminary confirmed according to the leakage of cellular contents such as potassium (K+), magnesium (Mg2+), and alkaline phosphatase (AKP). Furthermore, we found that BBR could reduce the transcript levels of genes associated with peptidoglycan synthesis (murC, murD, mraY, and murG). Meanwhile, we investigated the modulatory ability of BBR on C. acnes-induced skin inflammation in mice. The results showed that BBR effectively reduced the number of C. acnes colonized in mice's ears, thereby alleviating ear swelling and erythema and significantly decreasing ear thickness and weight. In addition, BBR significantly decreased the levels of pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α in auricular tissues. These results suggest that BBR has the potential to treat inflammatory acne induced by C. acnes.