Recent advances in discovery and biosynthesis of natural products from myxobacteria: an overview from 2017 to 2023.

Covering: 2017.01 to 2023.11Natural products biosynthesized by myxobacteria are appealing due to their sophisticated chemical skeletons, remarkable biological activities, and intriguing biosynthetic enzymology. This review aims to systematically summarize the advances in the discovery methods, new structures, and bioactivities of myxobacterial NPs reported in the period of 2017-2023. In addition, the peculiar biosynthetic pathways of several structural families are also highlighted.

Constructing a Myxobacterial Natural Product Database to Facilitate NMR-Based Metabolomics Bioprospecting of Myxobacteria.

Myxobacteria are fascinating prokaryotes featuring a potent capacity for producing a wealth of bioactive molecules with intricate chemical topology as well as intriguing enzymology, and thus it is critical to developing an efficient pipeline for bioprospecting. Herein, we construct the database MyxoDB, the first public compendium solely dedicated to myxobacteria, which enabled us to provide an overview of the structural diversity and taxonomic distribution of known myxobacterial natural products. Moreover, we demonstrated that the cutting-edge NMR-based metabolomics was effective to differentiate the biosynthetic priority of myxobacteria, whereby MyxoDB could greatly streamline the dereplication of multifarious known compounds and accordingly speed up the discovery of new compounds. This led to the rapid identification of a class of linear di-lipopeptides (archangimins) and a rare rearranged sterol (corasterol) that were endowed with unique chemical architectures and/or biosynthetic enzymology. We also showcased that NMR-based metabolomics, MyxoDB, and genomics can also work concertedly to accelerate the targeted discovery of a polyketidic compound pyxipyrrolone C. All in all, this study sets the stage for the discovery of many more novel natural products from underexplored myxobacterial resources.

Alternatone A, an Unusual Perylenequinone-Related Compound from a Soft-Coral-Derived Strain of the Fungus Alternaria alternata.

A novel perylenequinone-related compound, alternatone A (1), with an unprecedented tricyclo[6.3.1.02,7] dodecane skeleton, together with three known perylenequinones, altertoxin I (2), stemphyperylenol (3), and alterperylenol (4), was isolated from the soft-coral-derived fungus Alternaria alternata L3111'. Their structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic analysis, electronic circular dichroism calculations, and X-ray diffraction data. Compound 4 showed cytotoxicity against A-549, HCT-116, and HeLa cell lines with IC50 values of 2.6, 2.4, and 3.1 µM, respectively. A possible biosynthetic pathway of 1 was proposed.

Phytochemical Composition, Hepatoprotective, and Antioxidant Activities of Phyllodium pulchellum (L.) Desv.

Phyllodiumpulchellum has been traditionally used as a medicinal herb because of its health-promoting effects, such as its hepatoprotective and antioxidant activities. In the present study, the petroleum ether fraction, ethyl acetate fraction, n-butanol fraction, and aqueous fraction were successively obtained from the ethanol extract of P. pulchellum. Two fractions, ethyl acetate fraction and n-butanol fraction, were found to display hepatoprotective and antioxidant activities. Further chemical investigation of the active fractions led to the isolation of its main constituents, including 11 flavonoids (1⁻11) and 8 indole alkaloids (12⁻19). There were 9 flavonoids (1⁻9) that were obtained from the ethyl acetate fraction, and 2 flavonoids (10 and 11) and 8 alkaloids (12⁻19) from the n-butanol fraction. Compounds 1⁻11 and 16⁻19 were isolated for the first time from P. pulchellum, and 1, 2, 8, 11, and 18 were obtained from the genus Phyllodium initially. Subsequently, the isolated compounds were evaluated for their in vitro hepatoprotective effects on the human normal hepatocyte cell line L-O2 injured by d-galactosamine and radical scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH). The flavonoids (-)-epigallocatechin (5) and (-)-epicatechin (6) exhibited prominent hepatoprotective activities with higher cell viability values (65.53% and 62.40% at 10 µM·mL-1, respectively) than the positive control, silymarin (61.85% at 10 µM·mL-1). In addition, compared with the positive control of vitamin C (IC50: 5.14 µg·mL-1), (-)-gallocatechin (3) and (-)-epigallocatechin (5) exhibited stronger antioxidant activities with IC50 values of 3.80 and 3.97 µg·mL-1, respectively. Furthermore, the total flavonoids from P. pulchellum were characterized using a high-performance liquid chromatography-linear ion trap quadrupole-Orbitrap-mass spectrometry (HPLC-LTQ-Orbitrap-MS). In total, 34 flavonoids were tentatively identified, which had not been previously reported from P. pulchellum. In addition, we performed a semi-quantitative analysis of the isolated flavonoids. The contents of compounds 1⁻11 were 3.88, 17.73, 140.35, 41.93, 27.80, 4.34, 0.01, 0.20, 9.67, 795.85, and 5.23 µg·g-1, respectively. In conclusion, this study revealed that the flavonoids that were isolated from P. pulchellum showed hepatoprotective and antioxidant activities, indicating that, besides alkaloids, the flavonoids should be the potential pharmacodynamic ingredients that are responsible for the hepatoprotective and antioxidant activities of P. pulchellum.

Effects of renal denervation on blood-pressure response to hemorrhagic shock in spontaneously hypertensive rats.

PURPOSE: Renal denervation (RD) has been demonstrated to be an effective approach to reduce blood pressure for those with resistant hypertension. Yet, we aimed to explore the effect and possible mechanism of RD on blood-pressure response to hemorrhagic shock in spontaneously hypertensive rats. METHODS: A total of 48 male spontaneously hypertensive rats were randomized to three groups: study group, sham-operation group and control group. RD was achieved by cutting off renal nerves and swabbing phenol on it. Ten weeks after RD, 8 rats in each group were sacrificed to collect the kidney and heart tissues. The remaining rats were subjected to an operation to induce hemorrhagic shock which would lead to 40% loss of total blood volume, and observed for 120 min. The serum concentration of norepinephrine was measured before and three weeks after RD. RESULTS: The blood-pressure and norepinephrine levels were reduced significantly after RD (p < 0.05). Systolic blood pressure and diastolic blood pressure of the surgery group were higher than those in the sham and control groups at 15, 30 and 45 min after hemorrhagic shock (p < 0.05), while no significant difference was observed at 60, 90 and 120 min (p > 0.05). Additionally, the beta-1 adrenergic receptor (ß1-AR) in the study group was significantly higher than those in the other two groups (p < 0.05) after hemorrhagic shock. CONCLUSION: This study demonstrated that RD could to some extent improve blood-pressure response to hemorrhagic shock in an established model of severe hemorrhagic shock in spontaneously hypertensive rats. The mechanism might be associated with up-regulation of ß1-AR.

Naphthalenones and Depsidones from a Sponge-Derived Strain of the Fungus Corynespora cassiicola.

Two new naphthalenones, corynenones A and B (1 and 2), and one new depsidone, corynesidone E (3), together with one known depsidone, corynesidone A (4) and two known diphenyl ethers, corynethers A (5) and B (6), were isolated from the sponge-derived fungus Corynespora cassiicola XS-20090I7. Their structures including absolute configurations were determined by spectroscopic data and electronic circular dichroism (ECD) spectra. Compounds 4 and 5 showed cytotoxicity against human promyelocytic leukemia HL-60 and human cervical carcinoma HeLa cell lines.

[Prevalence and risk factors for hepatitis B in Hua County, Henan Province].

OBJECTIVE: To determine the epidemiological characteristics and associated risk factors of hepatitis B surface antigens (HBsAg) prevalence in rural areas of Hua County, Henan Province, and to provide scientific evidence for Hepatitis B prevention and control in local areas. METHODS: On the basis of an ongoing esophageal cancer cohort study in rural Anyang, a total of 5 104 subjects aged 25-65 years were clustered and selected from 5 targeted villages for this study in rural areas of Hua County, Henan Province. HBsAg was detected in their blood samples and a questionnaire was completed by all the subjects in a manner of one-on-one interview. All statistical analyses were conducted using SPSS for Windows version 13.0. RESULTS: Of the 5 104 studied subjects (overall participation rate: 92.05%), 5.17% were positive for HBsAg. The detection rate was significantly higher in males than in females (6.54% vs. 3.87%, P<0.001) and the highest detection rates were observed in the 25-29 and 55-59 years groups in both males and females. Multiple Logistic analyses showed unmarried status (OR=1.80, 95% CI: 1.00-3.25) and high frequency of sexual intercourse (Ptrend=0.049) were associated with higher the risk for hepatitis B virus (HBV) infection. CONCLUSION: The prevalence of HBsAg in rural Hua County, Henan Province, was slightly lower than the national average of the same time period. More attention should be attached to high risk groups of HBV infection in this population, i.e. males aged 25-29 years and 55-59 years and sexually active population. Immunization and health education projects against hepatitis B should be carried out in this population to further reduce the overall prevalence of hepatitis B.

Multifunctional Metal-Organic Framework (MOF)-Based Nanoplatforms for Crop Protection and Growth Promotion.

Phytopathogen, pest, weed, and nutrient deficiency cause severe losses to global crop yields every year. As the core engine, agrochemicals drive the continuous development of modern agriculture to meet the demand for agricultural productivity and increase the environmental burden due to inefficient use. With new advances in nanotechnology, introducing nanomaterials into agriculture to realize agrochemical accurate and targeted delivery has brought new opportunities to support the sustainable development of green agriculture. Metal-Organic frameworks (MOFs), which weave metal ions/clusters and organic ligands into porous frameworks, have exhibited significant advantages in constructing biotic/abiotic stimuli-responsive nanoplatforms for controlled agrochemical delivery. This review emphasizes the recent developments of MOF-based nanoplatforms for crop protection, including phytopathogen, pest, and weed control, and crop growth promotion, including fertilizer/plant hormone delivery. Finally, forward-looking perspectives and challenges on MOF-based nanoplatforms for future applications in crop protection and growth promotion are also discussed.

A Lesion Microenvironment-Responsive Fungicide Nanoplatform for Crop Disease Prevention and Control.

Controlled fungicide delivery in response to the specific microenvironment produced by fungal pathogens is an advisable strategy to improve the efficacy of fungicides. Herein, the authors construct a smart fungicide nanoplatform, using mesoporous silica nanoparticles (MSNs) as nanocarriers loaded with eugenol (EU) and Ag+ coordinated polydopamine (Ag+ -PDA) as a coating to form Ag+ -PDA@MSNs-EU NPs for Botrytis cinerea (B. cinerea) control. As a botanical fungicide, EU offers an eco-friendly alternative to synthetic fungicides and can upregulate several defense-related genes in the tomato plant. The Ag+ -PDA coating can lock the EU inside the nanocarriers and respond to the oxalic acid produced by B. cinerea to corelease the loaded EU and Ag+ . The results demonstrate that Ag+ -PDA@MSNs-EU NPs can effectively inhibit the mycelial growth of B. cinerea on detached and potted tomato leaves. The construction of such a smart fungicide nanoplatform provides new guidance to design controlled fungicides release systems, which can respond to the microenvironment associated with plant pathogen to realize fungus control.

2,5-Diketopiperazines From a Sponge-Derived Fungus Aspergillus sclerotiorum.

Three new 2,5-diketopiperazines, speramide C (1), 3,21-epi-taichunamide F (2), and 2-epi-amoenamide C (3), along with four known analogs (4-7), were obtained from the sponge-derived fungus Aspergillus sclerotiorum GDST-2013-0501 collected from the South China Sea. The chemical structures of new compounds were elucidated by analyzing NMR and MS spectroscopy data, and their absolute configurations were determined by electronic circular dichroism (ECD) calculations. Compound 1 represents the first prenylated indole alkaloid with an ethylene oxide ring at the isopentenyl side chain. Compound 4 displayed DNA topoisomerase I inhibitory activity and antibacterial activity against Staphylococcus epidermidis. The low cytotoxic or non-cytotoxic compound 4 displayed DNA topoisomerase I inhibitory activity, which could provide a starting point for the development of antitumor agents.

Eco-Friendly Nanoplatforms for Crop Quality Control, Protection, and Nutrition.

Agricultural chemicals have been widely utilized to manage pests, weeds, and plant pathogens for maximizing crop yields. However, the excessive use of these organic substances to compensate their instability in the environment has caused severe environmental consequences, threatened human health, and consumed enormous economic costs. In order to improve the utilization efficiency of these agricultural chemicals, one strategy that attracted researchers is to design novel eco-friendly nanoplatforms. To date, numerous advanced nanoplatforms with functional components have been applied in the agricultural field, such as silica-based materials for pesticides delivery, metal/metal oxide nanoparticles for pesticides/mycotoxins detection, and carbon nanoparticles for fertilizers delivery. In this review, the synthesis, applications, and mechanisms of recent eco-friendly nanoplatforms in the agricultural field, including pesticides and mycotoxins on-site detection, phytopathogen inactivation, pest control, and crops growth regulation for guaranteeing food security, enhancing the utilization efficiency of agricultural chemicals and increasing crop yields are highlighted. The review also stimulates new thinking for improving the existing agricultural technologies, protecting crops from biotic and abiotic stress, alleviating the global food crisis, and ensuring food security. In addition, the challenges to overcome the constrained applications of functional nanoplatforms in the agricultural field are also discussed.

Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive cancer with poor prognosis. The lack of effective targeted therapies for TNBC remains a profound clinical challenge. Fusion transcripts play critical roles in carcinogenesis and serve as valuable diagnostic and therapeutic targets in cancer. The present study aimed to identify novel fusion transcripts in TNBC. METHODS: We analyzed the RNA sequencing data of 360 TNBC samples to identify and filter fusion candidates through SOAPfuse and ChimeraScan analysis. The characteristics, including recurrence, fusion type, chromosomal localization, TNBC subgroup distribution, and clinicopathological correlations, were analyzed in all candidates. Furthermore, we selected the promising fusion transcript and predicted its fusion type and protein coding capacity. RESULTS: Using the RNA sequencing data, we identified 189 fusion transcripts in TNBC, among which 22 were recurrent fusions. Compared to para-tumor tissues, TNBC tumor tissues accumulated more fusion events, especially in high-grade tumors. Interestingly, these events were enriched at specific chromosomal loci, and the distribution pattern varied in different TNBC subtypes. The vast majority of fusion partners were discovered on chromosomes 1p, 11q, 19p, and 19q. Besides, fusion events mainly clustered on chromosome 11 in the immunomodulatory subtype and chromosome 19 in the luminal androgen receptor subtype of TNBC. Considering the tumor specificity and frameshift mutation, we selected MFGE8-HAPLN3 as a novel biomarker and further validated it in TNBC samples using PCR and Sanger sequencing. Further, we successfully identified three types of MFGE8-HAPLN3 (E6-E2, E5-E3, and E6-E3) and predicted the ORF of E6-E2, which could encode a protein of 712 amino acids, suggesting its critical role in TNBC. CONCLUSIONS: Improved bioinformatic stratification and comprehensive analysis identified the fusion transcript MFGE8-HAPLN3 as a novel biomarker with promising clinical application in the future.

Supramolecular Nanoplatform Based on Mesoporous Silica Nanocarriers and Pillararene Nanogates for Fungus Control.

Synthetic fungicides have been widely used to protect crops from fungal diseases. However, excessive use of synthetic fungicides leads to the generation of fungicide resistance in fungal pathogens. Recently, smart cargo delivery systems have been introduced for the construction of a pesticide delivery nanoplatform, benefiting from their controlled release performance. Herein, a fungal pathogen microenvironment-responsive supramolecular fungicide nanoplatform has been designed and constructed, using quaternary ammonium salt (Q)-modified mesoporous silica nanoparticles (MSN-Q NPs) as nanocarriers loaded with berberine hydrochloride (BH) and carboxylatopillar[5]arene (CP[5]A) as nanogates to form BH-loaded CP[5]A@MSN-Q NPs for effective inhibition of Botrytis cinerea. CP[5]A as nanogates can endow the fungicide nanoplatform with pH stimuli-responsive release features for the control of fungicide release. The loaded BH, as a natural plant fungicide, provides an ecofriendly alternative to synthetic fungicides for controlling B. cinerea. Interestingly, we use oxalic acid (OA) secreted by B. cinerea as a trigger so that BH can be released from the fungicide nanoplatform on demand under pathogen microenvironments for controlling B. cinerea. The experimental results indicate that the fabricated fungicide nanoplatform could effectively inhibit the mycelial growth and spore germination, providing a new way for the management of B. cinerea in actual application.

Potent Phytotoxic Harziane Diterpenes from a Soft Coral-Derived Strain of the Fungus Trichoderma harzianum XS-20090075.

Two new harziane diterpene lactones, possessing a 6/5/7/5-fused carbocyclic core containing a lactone ring system, harzianelactones A and B (1 and 2), and five new harziane diterpenes, harzianones A-D (3-6) and harziane (7), were isolated from the soft coral-derived fungus Trichoderma harzianum XS-20090075. Their structures were determined by extensive NMR spectroscopic data, ECD and OR calculations, as well as X-ray diffraction. The isolated compounds exhibited potent phytotoxicity against seedling growth of amaranth and lettuce. Harziane diterpenes were rarely reported for their remarkably bioactivities, and it was the first report to study the phytotoxicity of harziane diterpenes, which provide a new application of such compounds in agriculture for future research.

[Patterns of hepatic cells death during hepatic ischemia/reperfusion injury in cirrhotic rats].

OBJECTIVE: To research on the main pattern of hepatic cells death during hepatic ischemia/ reperfusion (I/R) injury in cirrhotic rat. METHODS: Cirrhotic rat model was established by carbon tetrachloride replication. These rats were randomly divided into sham operation group and I/R group. In the I/R group, 70% i/R injury model was established and then the liver samples were taken 0, 1, 6, 24, and 48 hours after reperfusion. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, Na+ - K+ ATPase, and Ca2+ ATPase were compared. the percentage of apoptotic/oncotic hepatic cells was measured with flow cytometry, and the changes in hepatic cellular structures were observed under transmission electron microscope. RESULTS: Compared with the sham operation group, the levels of serum AST and ALT significantly increased in the I/R group (P < 0.05), reaching their peak levels at the 6th hour. The activities of Na+ - K+ ATPase and Ca2+ ATPase dramatically decreased one hour after reperfusion and then gradually recovered (P < 0.05). Hepatic cells mainly suffered oncosis at the early stage after reperfusion (within 6 hours); at the late stage (around 24 hours after reperfusion), apoptosis became the main death pattern. CONCLUSION: Oncosis is the main pattern of hepatic cells death during I/R injury in cirrhotic rat, and the severity of hepatic injury correlates with the oncosis.

Use of a Bayesian approach in the design and evaluation of NCE2s.

Taiwan's regulatory agency defines New Chemical Entity 2 (NCE2) as a compound drug that has been approved and marketed for ten years in a top-ten pharmaceutically-advanced country but which is new in Taiwan. To apply for registration of NCE2 in Taiwan, a clinical trial may be conducted in Taiwan to evaluate the efficacy and safety. Since the NCE2 has been approved in at least one of the top-ten pharmaceutically-advanced countries, we can borrow the information from all of the observed data from other countries to synthesize the data from both Taiwan and other countries to assess the NCE2 efficacy. In this paper, we propose a Bayesian approach that uses a mixture of prior information to help evaluate an NCE2's efficacy. Numerical examples illustrate applications of the proposed approach in different scenarios. A method for sample-size determination for such trials is also proposed.

Antifouling phenyl ethers and other compounds from the invertebrates and their symbiotic fungi collected from the South China Sea.

Marine organism-derived secondary metabolites are promising potential sources for discovering environmentally safe antifouling agents. In present study, 55 marine secondary metabolites and their synthesized derivatives were tested and evaluated for their antifouling activities and security. These compounds include 44 natural products isolated from marine invertebrates and their symbiotic microorganisms collected from the South China Sea and 11 structural modified products derived from the isolated compounds. The natural secondary metabolites, covering phenyl ether derivatives, terpenoids, 9, 11-secosteroids, anthraquinones, alkaloids, nucleoside derivatives and peptides, were isolated from two corals, one sponge and five symbiotic fungi. All of the isolated and synthesized compounds were tested for their antifouling activities against the cyprids of barnacle Balanus (Amphibalanus) amphitrite Darwin. Noticeably, five phenyl ether derivatives (9, 11, 13-15) exhibited potent anti-larval settlement activity with the EC50 values lower than 3.05 µM and the LC50/EC50 ratios higher than 15. The study of structure-activity relationship (SAR) revealed that the introduction of acetoxy groups and bromine atoms to phenyl ether derivatives could significantly improve their antifouling activities. This is the first report on the SAR of phenyl ether derivatives on antifouling activity against barnacle B. amphitrite. The polybrominated diphenyl ether derivative, 2, 4, 6, 2', 4', 6'-hexabromo-diorcinol (13), which displayed excellent antifouling activity, was considered as a promising candidate of environmentally friendly antifouling agents.

General Principles for the Education and Training of GCP Inspectors: The Outcome of Discussions by International Regulatory Experts in the Discussion Group on the ICH E6 Guideline.

In response to the globalization of drug development, regulatory inspection of Good Clinical Practice (GCP) has recently been conducted not only by International Conference on Harmonisation (ICH) regions but also non-ICH regions. To promote the international implementation of GCP, consistent understanding and interpretation of its concept among regions are important. This article summarizes the background and past activities of the E6 Discussion Group, established under the Regulators Forum.

Differential alterations of GABA(A) receptor (α1, ß2, γ2 subunit) expression and increased seizure susceptibility in rat offspring from morphine-addicted mothers: beneficial effect of dextromethorphan.

Although prenatal morphine exposure experimentally induces seizures in rat offspring, underlying mechanisms remain unclear. This study addresses whether prenatal morphine exposure altered subunit compositions of γ-aminobutyric acid receptor subtype A (GABA(A)R) in the hippocampal CA1 area and temporal cortex and increased seizure susceptibility of young rat offspring, at a representative age (postneonatal days 14; P14). Therapeutic efficacy of dextromethorphan (a noncompetitive antagonist of N-methyl-d-aspartate receptors (NMDARs)), in such offspring was also evaluated. From P7 to 14, Sprague-Dawley rat offspring were intraperitoneally (ip) injected a representative dose of dextromethorphan (3mg/kg) twice a day. At P14, some offspring were ip injected pentylenetetrazol to estimate seizure susceptibility, while the others were studied for GABA(A)R subunit (α1, ß2, γ2) expression. Prenatal morphine exposure caused the up-regulated α1 subunit and down-regulated ß2/γ2 subunit expression of GABA(A)R within hippocampus and temporal cortex in rat offspring associated to increase seizure susceptibility. The magnitudes of upregulated α1 subunit and downregulated ß2 subunit expression in the hippocampus were greater than which in the temporal cortex. The use of dextromethorphan markedly reversed the prenatal morphine-induced alterations, indicating the possible therapeutic actions of dextromethorphan. These results suggest that the altered subunit compositions (α1, ß2, γ2) of GABA(A)R in the hippocampal CA1 area and temporal cortex may contribute, at least in part, to the increased seizure susceptibility of rat offspring subjected to prenatal morphine exposure. More importantly, dextromethorphan may be a promising clinical agent acting against these alterations.