Study of Iron Complex Photosensitizer with Hollow Double-Shell Nano Structure Used to Enhance Ferroptosis and Photodynamic Therapy.

Ferroptosis therapy, which uses ferroptosis inducers to produce lethal lipid peroxides and induce tumor cell death, is considered a promising cancer treatment strategy. However, challenges remain regarding how to increase the accumulation of reactive oxygen species (ROS) in the tumor microenvironment (TME) to enhance antitumor efficacy. In this study, a hyaluronic acid (HA) encapsulated hollow mesoporous manganese dioxide (H-MnO2 ) with double-shell nanostructure is designed to contain iron coordinated cyanine near-infrared dye IR783 (IR783-Fe) for synergistic ferroptosis photodynamic therapy against tumors. The nano photosensitizer IR783-Fe@MnO2 -HA, in which HA actively targets the CD44 receptor, subsequently dissociates and releases Fe3+ and IR783 in acidic TME. First, Fe3+ consumes glutathione to produce Fe2+ , which promotes the Fenton reaction in cells to produce hydroxyl free radicals (·OH) and induce ferroptosis of tumor cells. In addition, MnO2 catalyzes the production of O2 from H2 O2 and enhances the production of singlet oxygen (1 O2 ) by IR783 under laser irradiation, thus increasing the production and accumulation of ROS to provide photodynamic therapy. The highly biocompatible IR783-Fe@MnO2 -HA nano-photosensitizers have exhibited tumor-targeting ability and efficient tumor inhibition in vivo due to the synergistic effect of photodynamic and ferroptosis antitumor therapies.

Mutanofactin promotes adhesion and biofilm formation of cariogenic Streptococcus mutans.

Cariogenic Streptococcus mutans is known as a predominant etiological agent of dental caries due to its exceptional capacity to form biofilms. From strains of S. mutans isolated from dental plaque, we discovered, in the present study, a polyketide/nonribosomal peptide biosynthetic gene cluster, muf, which directly correlates with a strong biofilm-forming capability. We then identified the muf-associated bioactive product, mutanofactin-697, which contains a new molecular scaffold, along with its biosynthetic logic. Further mode-of-action studies revealed that mutanofactin-697 binds to S. mutans cells and also extracellular DNA, increases bacterial hydrophobicity, and promotes bacterial adhesion and subsequent biofilm formation. Our findings provided an example of a microbial secondary metabolite promoting biofilm formation via a physicochemical approach, highlighting the importance of secondary metabolism in mediating critical processes related to the development of dental caries.

Chemical Synthesis of a Keto Sugar Nucleotide.

Keto sugar nucleotides (KSNs) are common and versatile precursors to various deoxy sugar nucleotides, which are substrates for the corresponding glycosyltransferases involved in the biosynthesis of glycoproteins, glycolipids, and natural products. However, there has been no KSN synthesized chemically due to the inherent instability. Herein, the first chemical synthesis of the archetypal KSN TDP-4-keto-6-deoxy-d-glucose (1) is achieved by an efficient and optimized route, providing feasible access to other KSNs and analogues, thereby opening a new avenue for new applications.

Curettage combined with bone cavity opening reduces recurrence of the mandibular conventional ameloblastoma and effectively preserves the mandible: a retrospective study.

BACKGROUND: Patients with mandibular conventional ameloblastoma undergoing radical surgical treatment experience greater trauma and often find it challenging to accept, whereas conservative therapy is associated with a higher recurrence rate. In this study, we have improved traditional conservative treatment for mandibular conventional ameloblastoma by curettage combined with bone cavity opening (Cur/BCO). This retrospective study aimed to evaluate the effectiveness of the Cur/BCO treatment by comparing its recurrence rate and bone mineral density (BMD) growth rate with the traditional conservative treatment approach. METHODS: A total of 40 patients, meeting the study's inclusion and exclusion criteria from 2012 to 2020, were screened, with 20 in the modified group and 20 in the traditional group. ImageJ (RRID: SCR_003070) software was employed for measuring image indices. All data were analyzed using T-test, Chi-square test and Fisher exact test in SPSS 26.0 (p = 0.05). RESULTS: The incidence of recurrence was significantly lower in the modified group, at only 5%, compared to 35% in the traditional group (p < 0.05). Regarding bone mineral density (BMD) growth rate, the average value in the modified group was 0.0862 ± 0.2302 (/month), significantly higher than the average value of 0.0608 ± 0.2474 (/month) in the traditional group (p < 0.05). CONCLUSIONS: In this study, it was found that the recurrence rate of the modified conservative treatment (Cur/BCO) was lower than that of the traditional conservative treatment for managing mandibular conventional ameloblastoma. Furthermore, the BMD growth rate was quicker in the modified group. Thus, Cur/BCO could be considered as a viable option for the conservative treatment of mandibular conventional ameloblastoma.

Biosynthesis and bioactivities of microbial genotoxin colibactins.

Covering: up to 2021Colibactin(s), a group of secondary metabolites produced by the pks island (clb cluster) of Escherichia coli, shows genotoxicity relevant to colorectal cancer and thus significantly affects human health. Over the last 15 years, substantial efforts have been exerted to reveal the molecular structure of colibactin, but progress is slow owing to its instability, low titer, and elusive and complex biosynthesis logic. Fortunately, benefiting from the discovery of the prodrug mechanism, over 40 precursors of colibactin have been reported. Some key biosynthesis genes located on the pks island have also been characterised. Using an integrated bioinformatics, metabolomics, and chemical synthesis approach, researchers have recently characterised the structure and possible biosynthesis processes of colibactin, thereby providing new insights into the unique biosynthesis logic and the underlying mechanism of the biological activity of colibactin. Early developments in the study of colibactin have been summarised in several previous reviews covering various study periods, whereas the two most recent reviews have focused primarily on the chemical synthesis of colibactin. The present review aims to provide an update on the biosynthesis and bioactivities of colibactin.

Theranostic nanosystem with supramolecular self-assembly for enhanced reactive oxygen species-mediated apoptosis guided by dual-modality tumor imaging.

With the development of precision medicine, visual and traceable treatments are highly desirable for cancer therapy. However, researchers and clinicians remain confused regarding where the drug distributes and location of the tumor, when the drug is released and when to irradiate the tumor, and how the drug presents antitumor activity, all of which hinders assessment of the cancer patient's condition and formulation of a follow-up treatment scheme for clinicians. Here, a supramolecular self-assembly theranostic nanosystem (MWNs) was designed for enhanced reactive oxygen species (ROS)-mediated cell apoptosis guided by dual-modality tumor imaging. Specifically, merocyanine was introduced in cyanine dye to extend its conjugated π-scaffolds, which could preferentially self-assemble into nanovesicles owing to its amphipathy. Furthermore, withaferin A (WA), used as a chemotherapeutic drug, was loaded to construct MWNs. The assembled or disassembled MWNs behaved differently in photoacoustic (PA) intensity and fluorescence signal intensity. The MWNs exhibited stronger PA signals and quenched fluorescence, which monitors their distribution and images the tumor location in vivo, while the disassembled MWNs showed weak PA signals and recovered fluorescence, indicating the release of drug and instructing the appropriate time to irradiate for photodynamic therapy (PDT). Thus, ROS generation introduced by PDT and released WA led to cell apoptosis. This intelligent nanosystem for precise cancer therapy that reveals where the tumor is, when to irradiate the tumor, and how the tumor is cured might establish the basis for biomedical applications of finely controlled platform.

Marine bacterial extracts as a new rich source of drugs against Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent, progressive and irreversible, neurodegenerative disease with no disease modifying treatment yet available. The projected burden of AD on our healthcare system is immense and thus there is an immediate need for new drugs that prevent or attenuate AD symptoms. While most efforts in the field are directed at treatments that reduce amyloid or tau burden in the brain, we have taken an alternate approach - a model based on reducing AD-associated neuronal cell cycle events. Using this model, we have screened a largely unexplored source of compounds with therapeutic potential - the natural products created by diverse strains of marine bacteria. Two hundred and twenty-five bacterial extracts from different strains were tested for both toxicity and neuroprotective properties by crystal violet and In-cell Western - first in HT22 cells and then in mouse primary neuronal cultures. Based on these screens, we have identified several promising leads, and here we focus on the most promising of these. We found that we could directly assay even a crude bacterial extract in our E16 mouse cortical neuronal cultures and screen for activities that prevent cell cycle reentry and preserve synaptic structure. Preliminary tests in 1-month-old animals from a mouse model of Ataxia telangiectasia, showed that blockage of cell cycle-related neuronal death could also be successful in vivo. This adds an important extension to our in vitro studies. These findings showcase a new effective and efficient assay system and validate the use of marine natural compounds as a novel source for new drugs to fight Alzheimer's disease. Cover Image for this issue: doi: 10.1111/jnc.14733.

Natural protoberberine alkaloids, identified as potent selective LSD1 inhibitors, induce AML cell differentiation.

Natural protoberberine alkaloids were first identified and characterized as potent, selective and cellular active lysine specific demethylase 1 (LSD1) inhibitors. Due to our study, isoquinoline-based tetracyclic scaffold was identified as the key structural element for their anti-LSD1 activity, subtle changes of substituents attached to the core structure led to dramatic changes of the activity. Among these protoberberine alkaloids, epiberberine potently inhibited LSD1 (IC50 = 0.14 ± 0.01 µM) and was highly selective to LSD1 over MAO-A/B. Furthermore, epiberberine could induce the expression of CD86, CD11b and CD14 in THP-1 and HL-60 cells, confirming its cellular activity of inducing acute myeloid leukemia (AML) cells differentiation. Moreover, epiberberine prolonged the survival of THP-1 cells bearing mice and inhibited the growth of AML cells in vivo without obvious global toxicity. These findings give the potential application of epiberberine in AML treatment, and the isoquinoline-based tetracyclic scaffold could be used for further development of LSD1 inhibitors.

Apelin shorten QT interval by inhibiting Kir2.1/IK1 via a PI3K way in acute myocardial infarction.

QT interval prolongation and depolarization of resting membrane potential (RMP) were found in acute myocardial infarction (MI) which is involved in the arrhythmogenic mechanism and raising the risk to initiate torsade de pointes. However, clinical anti-arrhythmic agents that primarily act on QT interval and RMP are not currently available. Our objective was to determine whether Apelin, an endogenous peptide ligand of receptor APJ, affects QT interval and RMP and underlying mechanisms. To test this viewpoint, mice were subjected to MI by ligating the left main coronary artery and Apelin was applied through tail vein at 5 min prior coronary occlusion in tested group. Compared to MI group, pretreatment of Apelin (15 µg/kg) shortened QTc and QT interval induced by MI, significantly elevated RMP and shortened action potential duration (APD) by increased IK1 currents recorded using whole-cell patch technique from cardiomyocytes underwent MI. In cultured neonatal mouse cardiomyocytes, Apelin (1 µmol/L) restored hypoxia-induced Kir2.1 down-regulation, which was abolished by IP3K inhibitor LY-294002. Additionally, Apelin elicited a time-dependent increase in phosphorylation of Akt leading to increase in PI3-kinase activity. These results showed that Apelin enhanced IK1/Kir2.1 currents via IP3K pathway as by rescue ischemia- and hypoxia-induced RMP depolarization and prolongation of QT interval, which may prevent or cure acute ischemic-mediated arrhythmias. This study brings new information to anti-arrhythmic theories and provides a potential target for the clinical management of acute ischemia-related arrhythmias.

Discovery of novel chalcone-dithiocarbamates as ROS-mediated apoptosis inducers by inhibiting catalase.

Novel chalcone-dithiocarbamate hybrids were designed, synthesized and evaluated for antiproliferative activity against selected cancer cell lines (MGC803, MCF7, and PC3). Among these analogues, (E)-2-oxo-2-((4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)amino)ethyl-4-(2-hydroxyethyl)piperazine-1-carbodithioate (12d) showed the best inhibitory activity against PC3 cells (IC50 = 1.05 µM). Cellular mechanism studies elucidated 12d could inhibit colony formation, arrest cell cycle at G2/M phase and induce DNA damage against PC3 cells. Compound 12d also induced mitochondrial apoptosis by caspase activation, MMP decrease, ROS production and catalase (CAT) inhibition. Importantly, 12d inhibited epithelial-mesenchymal transition (EMT) process by regulating EMT-related proteins (E-cadherin, N-cadherin, Vimentin, MMP2, MMP9). These results indicated that 12d is a promising lead compound and deserves further investigation for prevention and treatment of human prostate cancer.

Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor.

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC50 of 3.98 ±â€¯0.3 µM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting.

Sanggenon O induced apoptosis of A549 cells is counterbalanced by protective autophagy.

Sanggenon O (SO) is a Diels-Alder type adduct extracted fromMorus alba, which has been used for its anti-inflammatory action in the Oriental medicine. However, whether it has regulatory effect on human cancer cell proliferation and what the underlying mechanism remains unknown. Here, we found that SO could significantly inhibit the growth and proliferation of A549 cells and induce its pro-apoptotic action through a caspase-dependent pathway. It could also impair the mitochondria which can be reflected by mitochondrial membrane permeabilization. Besides, SQSTM1 up-regulation and autophagic flux measurement demonstrated that exposure to SO led to autophagosome accumulation, which plays a protective role in SO-treated cells. In addition, knocking down of LC3B increased SO triggered apoptotic cell rates. These results indicated that SO has great potential as a promising candidate combined with autophagy inhibitor for the treatment of NSCLC. In conclusion, our results identified a novel mechanism by which SO exerts potent anticancer activity.

Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin.

Colibactin is an as-yet-uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.

Bioactivity evaluation of natural product α-mangostin as a novel xanthone-based lysine-specific demethylase 1 inhibitor to against tumor metastasis.

Lysine-specific demethylase 1 (LSD1), which has been reported to be overexpressed in several human cancers, has recently emerged as an attractive therapeutic target for treating cancer. To date, almost all the developed LSD1 inhibitors are chemo-synthesized molecules, while α-mangostin is first characterized as xanthone-based natural inhibitor in the current study with IC50 values of 2.81 ±â€¯0.44 µM. Bioactivity study and docking analysis indicated that α-mangostin could inhibit MDA-MB-231 cells migration and evasion through inhibit intracellular LSD1 activity. These findings provides new molecular skeleton for LSD1 inhibitor study and should encourage further modification of α-mangostin to produce more potent LSD1 inhibitors with potential anticancer activity.

Family-wide Structural Characterization and Genomic Comparisons Decode the Diversity-oriented Biosynthesis of Thalassospiramides by Marine Proteobacteria.

The thalassospiramide lipopeptides have great potential for therapeutic applications; however, their structural and functional diversity and biosynthesis are poorly understood. Here, by cultivating 130 Rhodospirillaceae strains sampled from oceans worldwide, we discovered 21 new thalassospiramide analogues and demonstrated their neuroprotective effects. To investigate the diversity of biosynthetic gene cluster (BGC) architectures, we sequenced the draft genomes of 28 Rhodospirillaceae strains. Our family-wide genomic analysis revealed three types of dysfunctional BGCs and four functional BGCs whose architectures correspond to four production patterns. This correlation allowed us to reassess the "diversity-oriented biosynthesis" proposed for the microbial production of thalassospiramides, which involves iteration of several key modules. Preliminary evolutionary investigation suggested that the functional BGCs could have arisen through module/domain loss, whereas the dysfunctional BGCs arose through horizontal gene transfer. Further comparative genomics indicated that thalassospiramide production is likely to be attendant on particular genes/pathways for amino acid metabolism, signaling transduction, and compound efflux. Our findings provide a systematic understanding of thalassospiramide production and new insights into the underlying mechanism.

A Drinking Water Sensor for Lead and Other Heavy Metals.

Leakage of lead and other heavy metals into drinking water is a significant health risk and one that is not easily detected. We have developed simple sensors containing only platinum electrodes for the detection of heavy metal contamination in drinking water. The two-electrode sensor can identify the existence of a variety of heavy metals in drinking water, and the four-electrode sensor can distinguish lead from other heavy metals in solution. No false-positive response is generated when the sensors are placed in simulated and actual tap water contaminated by heavy metals. Lead detection on the four-electrode sensor is not affected by the presence of common ions in tap water. Experimental results suggest the sensors can be embedded in water service lines for long-time use until lead or other heavy metals are detected. With its low cost (∼$0.10/sensor) and the possibility of long-term operation, the sensors are ideal for heavy metal detection of drinking water.

Polycyclic Polyprenylated Derivatives from Hypericum uralum: Neuroprotective Effects and Antidepressant-like Activity of Uralodin A.

The isolation of the new polycyclic polyprenylated acylphloroglucinols uraliones A-K (1-11) together with five known analogues (12-16) from a whole Hypericum uralum plant was reported. The structures of these compounds were established through spectroscopic methods, and a single-crystal X-ray diffraction analysis was used to confirm the absolute configuration of 1. The protective effects of the isolates against corticosterone-induced PC12 cell injury were assessed. Except for compound 9, all tested compounds exhibited significant protective effects against induced injury in PC12 cells. Uralodin A (14), orally administered in doses of 13 and 26 mg/kg, exhibited antidepressant-like activity in the tail suspension and forced-swimming tests in mice.

Synergetic mechanism and enantioseparation of aromatic ß-amino acids by biphasic chiral high-speed counter-current chromatography.

A biphasic chiral recognition system based on chiral ligand exchange with Cu(II)-N-n-dodecyl-L-proline and hydroxypropyl-ß-cyclodextrin as an additive was developed to enantioseparate aromatic ß-amino acids by high-speed counter-current chromatography. The biphasic chiral recognition system was established with an n-butanol/water (1:1, v/v) solvent system by adding N-n-dodecyl-L-proline and Cu(II) ions to the organic phase and hydroxypropyl-ß-cyclodextrin to the aqueous phase. Several separation parameters, such as temperature, pH value, and chiral selector concentration, were systematically investigated by enantioselective liquid-liquid extraction. Under the optimal separation conditions, 54.5 mg of (R,S)-ß-phenylalanine and 74.3 mg of (R,S)-ß-3,4-dimethoxyphenylalanine were baseline enantioseparated. More importantly, the synergistic enantiorecognition mechanism, based on the Cu(II)-N-n-dodecyl-L-proline and hydroxypropyl-ß-cyclodextrin, was discussed for the first time.

Critical Intermediates Reveal New Biosynthetic Events in the Enigmatic Colibactin Pathway.

Colibactin is a potent genotoxin that induces DNA double-strand breaks; it is produced by Escherichia coli strains harboring a pks+ island. However, the structure of this compound remains elusive. Here, using transformation-associated recombination (TAR) cloning to perform heterologous expression, we took advantage of the significantly increased yield of colibactin pathway-related compounds to determine and isolate a series of vital (pre)colibactin intermediates. The chemical structures of compounds 8, 10 and 11 were identified by NMR and MS(n) analyses. The new 1H-pyrrolo[3,4-c]pyridine-3,6(2H,5H)-dione- and thiazole-containing compound 10 provides new insights regarding the biosynthetic pathway to (pre)colibactin and establishes foundations for future investigation of the intriguing (pre)colibactin structures and its modes of action.

Involucratustones A-C: Unprecedented Sesquiterpene Dimers Containing Multiple Contiguous Quaternary Carbons from Stahlianthus involucratus.

Involucratustones A-C (1-3), three cadinane dimers containing multiple contiguous quaternary carbons, were isolated from the rhizomes of Stahlianthus involucratus. Their structures were determined by a combination of NMR spectroscopy, chemical conversion, and X-ray diffraction analysis. Compounds 1 and 2 are rearranged homodimers of cadinane sesquiterpene fused with a unique fully substituted 1-oxaspiro[4.4]nonane core observed for the first time in natural products, and 3 is a novel 3',4'-seco-cadinane-dimer. Compounds 1 and 2 exhibited potent cytotoxic activities, and 3 showed notable anti-inflammatory effect.