Treatment-related adverse events of antibody-drug conjugates in clinical trials: A systematic review and meta-analysis.

BACKGROUND: Antibody-drug conjugates (ADCs) have complex molecular structures and have been tested in numerous clinical trials. Therefore, understanding the mechanisms of their toxicity when applied in medical practice is of high importance. METHODS: In a systematic review and meta-analysis of data gathered from different scientific databases (PubMed, Embase, Cochrane, and Web of Science) between January 1, 2000, and June 7, 2022, the authors applied a random-effects model with logit transformation and evaluated the heterogeneity between studies using I2 statistics. The primary outcome was the incidence and 95% confidence interval (CI) for all-grade and grade ≥3 treatment-related adverse events and differences between different drugs, molecular structures, and cancer types. RESULTS: In total, 2511 records were identified that included 169 clinical trials involving 22,492 patients. The overall incidence of treatment-related adverse events was 91.2% (95% CI, 90.7%-91.7%; I2  = 95.9%) for all-grade adverse events and 46.1% (95% CI, 45.2%-47.0%; I2  = 96.3%) for grade ≥3 adverse events. The most common all-grade adverse events were lymphopenia (53.0%; 95% CI, 48.7%-57.3%), nausea (44.1%; 95% CI, 43.2%-44.9%), neutropenia (43.7%; 95% CI, 42.6%-44.9%), blurred vision (40.5%; 95% CI, 37.4%-43.6%), and peripheral neuropathy (39.6%; 95% CI, 38.2%-41.1%); and the most common grade ≥3 adverse events were neutropenia (31.2%; 95% CI, 30.2%-32.3%), hypoesthesia (23.3%; 95% CI, 10.6%-35.9%), thrombocytopenia (22.6%; 95% CI, 21.3%-23.9%), febrile neutropenia (21.2%; 95% CI, 19.3%-23.1%), and lymphopenia (21.0%; 95% CI, 18.2%-23.7%). CONCLUSIONS: Different ADCs appear to affect various treatment-related adverse events and provide comprehensive data on treatment-related adverse events for ADCs. The current results provide an important reference for clinicians and patients on how to care for toxicities from ADCs in clinical practice. LAY SUMMARY: Unique anticancer drugs called antibody-drug conjugates (ADCs) have made significant progress in oncology in recent years because of their great success, and they are rapidly being used in the clinic as well as in hundreds of ongoing trials exploring their further use. The occurrence of serious side effects (adverse events) related to the receipt of ADCs was studied using data from 169 clinical trials involving 22,492 patients to determine the treatment-related causes of higher toxicity and adverse events in patients who receive ADCs, because these data are crucial for informing physicians how to safely treat patients using ADCs. The results indicate that different ADCs appear to affect various adverse events related to their use, providing comprehensive data on these ADCs that provide an important reference for clinicians and patients on how to care for toxicities from ADCs in clinical practice.

Interaction of E2F3a and CASP8AP2 Regulates Histone Expression and Chemosensitivity of Leukemic Cells.

Low expression levels of E2F3a and caspase 8-associated protein 2 (CASP8AP2) are associated with poor outcomes in children with acute lymphoblastic leukemia. Our previous study showed that a combined assessment of E2F3a and CASP8AP2 expression was more accurate in predicting relapse in children with acute lymphoblastic leukemia. However, the underlying mechanism remains unclear. In this study, the interaction between E2F3a and CASP8AP2 and its role in the regulation of histone expression, cell proliferation, the cell cycle, and chemosensitivity were investigated. Exogenous E2F3a-GST was coprecipitated with CASP8AP2-FLAG in HEK-293T cells. E2F3a was colocalized with CASP8AP2-GFP in the nucleus. The replication-dependent histones H2A and H2B were significantly upregulated when E2F3a or CASP8AP2 was overexpressed in HEK-293T or 697 cells and downregulated by E2F3a or CASP8AP2 knockdown. E2F3a and CASP8AP2 could collaboratively enhance the transcriptional activity of HIST1H2AG and HIST1H2BK . Both CASP8AP2 and E2F3a are involved in S phase progression. E2F3a and CASP8AP2 also affected the sensitivity of leukemic cells to daunorubicin. Therefore, CASP8AP2 and E2F3a collaboratively regulated replication-dependent histone expression, cell cycle progression, and chemosensitivity of leukemic cells.

Anti-Larval and Anti-Algal Natural Products from Marine Microorganisms as Sources of Anti-Biofilm Agents.

Bacteria growing inside biofilms are more resistant to hostile environments, conventional antibiotics, and mechanical stresses than their planktonic counterparts. It is estimated that more than 80% of microbial infections in human patients are biofilm-based, and biofouling induced by the biofilms of some bacteria causes serious ecological and economic problems throughout the world. Therefore, exploring highly effective anti-biofilm compounds has become an urgent demand for the medical and marine industries. Marine microorganisms, a well-documented and prolific source of natural products, provide an array of structurally distinct secondary metabolites with diverse biological activities. However, up to date, only a handful of anti-biofilm natural products derived from marine microorganisms have been reported. Meanwhile, it is worth noting that some promising antifouling (AF) compounds from marine microbes, particularly those that inhibit settlement of fouling invertebrate larvae and algal spores, can be considered as potential anti-biofilm agents owing to the well-known knowledge of the correlations between biofilm formation and the biofouling process of fouling organisms. In this review, a total of 112 anti-biofilm, anti-larval, and anti-algal natural products from marine microbes and 26 of their synthetic analogues are highlighted from 2000 to 2021. These compounds are introduced based on their microbial origins, and then categorized into the following different structural groups: fatty acids, butenolides, terpenoids, steroids, phenols, phenyl ethers, polyketides, alkaloids, flavonoids, amines, nucleosides, and peptides. The preliminary structure-activity relationships (SAR) of some important compounds are also briefly discussed. Finally, current challenges and future research perspectives are proposed based on opinions from many previous reviews.

Magnetic-assisted laparoscopic liver transplantation in swine.

BACKGROUND: Although laparoscopic technology has achieved rapid development in the surgical field, it has not been applied to liver transplantation, primarily because of difficulties associated with laparoscopic vascular anastomosis. In this study, we introduced a new magnetic-assisted vascular anastomosis technique and explored its application in laparoscopic liver transplantation in pigs. METHODS: Two sets of magnetic vascular anastomosis rings (MVARs) with different diameters were developed. One set was used for anastomosis of the suprahepatic vena cava (SHVC) and the other set was used for anastomosis of the infrahepatic vena cava (IHVC) and portal vein (PV). Six laparoscopic orthotopic liver transplantations were performed in pigs. Donor liver was obtained via open surgery. Hepatectomy was performed in the recipients through laparoscopic surgery. Anastomosis of the SHVC was performed using hand-assisted magnetic anastomosis, and the anastomosis of the IHVC and PV was performed by magnetic anastomosis with or without hand assistance. RESULTS: Liver transplants were successfully performed in five of the six cases. Postoperative ultrasonographic examination showed that the portal inflow was smooth. However, PV bending and blood flow obstruction occurred in one case because the MVARs were attached to each other. The durations of loading of MVAR in the laparoscope group and manual assistance group for IHVC and PV were 13 ± 5 vs. 5 ± 1 min (P < 0.01) and 10 ± 2 vs. 4 ± 1 min (P < 0.05), respectively. The durations of MVAR anastomosis in the laparoscope group and manual assistance group for IHVC and PV were 5 ± 1 vs. 1 ± 1 min (P < 0.01), and 5 ± 1 vs. 1 ± 1 min (P < 0.01), respectively. The anhepatic phase was 43 ± 4 min in the laparoscope group and 23 ± 2 min in the manual assistance group (P < 0.01). CONCLUSIONS: Our study showed that magnetic-assisted laparoscopic liver transplantation can be successfully carried out in pigs.

[Chemical constituents of steroidal saponins in rhizome of Paris polyphylla var. yunnanensis cultured in vitro].

In this study, liquid chromatography-mass spectrometry(LC-MS) and high performance liquid chromatography(HPLC) were employed for qualitative and quantitative analysis of the steroidal saponins in rhizomes of Paris polyphylla var. yunnanensis from three different habitats cultured in vitro, in an attempt to explore whether the rhizomes of the medicinal herb cultured in vitro can synthesize the steroidal saponins, including polyphyllinsⅠ, Ⅱ, and Ⅶ, the quality markers specified in Chinese Pharmacopoeia(2020 edition). A total of 20 steroidal saponins were identified in the rhizomes from Changxin, Yunlong(S1), Fengyi, Dali(S2), and Niujie, Eryuan(S3): parisyunnanoside A and parisyunnanoside D or E, proto-polyphyllin Ⅱ, polyphyllins G and H, polyphyllinsⅠ, Ⅱ, Ⅴ, Ⅵ, and Ⅶ, dioscin, gracillin, prosapogenin A, Tg, isomer of Th, saponin Th, reclinatoside, proto-pairs D, pseudoproto-dioscin, and 23-O-glc-(23S,25R)-spirost-5-en-3ß,23α,27-triol-3-O-rha-(1→2)-[ara(1→4)]-glc or 27-O-glc-(23S,25R)-spirost-5-en-3ß,27α-diol-3-O-rha-(1→2)-[ara(1→4)]-glc. Among them, polyphyllinsⅠ, Ⅱ, and Ⅶ were detected in the rhizomes from S1, with the mass fraction of 0.109 1%, 0.165 2%, and 0.051 03%, respectively(total 0.325 3%). Polyphyllins Ⅱ and Ⅶ were identified in the rhizomes from S2 with the respective mass fraction of 0.192 2% and 0.074 23% and total content of 0.266 5%. Moreover, polyphyllins Ⅱ and Ⅶ were also found in the rhizomes from S3, which had the mass fraction of 0.207 7% and 0.186 9%, separately, with the total content of 0.394 6%. Thus, steroidal saponins, including the quality makers polyphyllins Ⅰ, Ⅱ, and Ⅶ recorded in Chinese Pharmacopoeia(2020 edition) can be synthesized in rhizomes of Paris polyphylla var. yunnanensis cultured in vitro, but their total content fails to meet the standard(0.60% in Chinese Pharmacopoeia). Therefore, in vitro culture of the Paris polyphylla var. yunnanensis is feasible, but the culture conditions need to be further improved.

Algoriphagus kandeliae sp. nov., isolated from mangrove rhizosphere soil.

Strain XY-J91T, a Gram-stain-negative, reddish orange, non-spore-forming and short-rod-shaped marine bacterium, was isolated from rhizosphere soil of the mangrove plant Kandelia candel (L.) Druce in Mai Po Nature Reserve, Hong Kong. The strain showed growth at 15-50 °C (optimum 40 °C), at pH 5.5-9.5 (optimum 7.0-8.0) and with 0-8 % (w/v) NaCl (optimum 1-2 %). The only respiratory quinone was MK-7 and the major fatty acids were iso-C15 : 0 and iso-C17 : 0 3-OH. The major polar lipids were phosphatidylethanolamine, an unidentified aminolipid and an unidentified phospholipid. The G+C content of strain XY-J91T was 40.4 mol%. Strain XY-J91T exhibited highest 16S rRNA gene sequence similarities to the type strains of Algoriphagus marincola SW-2T (96.66 %), Algoriphagus taiwanensis CC-PR-82T (96.21%), Algoriphagus ornithinivorans JC2052T (96.16%), Algoriphagus confluentis HJM-2T (95.73%) and Algoriphagus zhangzhouensis 12C11T (95.52 %). Based on the phylogenetic, phenotypic and chemotaxonomic evidence presented, strain XY-J91T represents a novel species of the genus Algoriphagus, for which the name Algoriphagus kandeliae sp. nov. is proposed. The type strain is XY-J91T (=MCCC 1K03612T=KCTC 72216T).

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.

Isolation and Structure-Activity Relationship of Subergorgic Acid and Synthesis of Its Derivatives as Antifouling Agent.

In this study, as part of our continuous search for environmentally-friendly antifoulants from natural resources, subergorgic acid (SA) was identified from the gorgonian coral Subergorgia suberosa, demonstrating non-toxic, significant inhibitory effects (EC50 1.25 µg/mL, LC50 > 25 µg/mL) against the settlement of Balanus amphitrite. To further explore the bioactive functional groups of SA and synthesize more potent antifouling compounds based on the lead SA, the structure-activity relationships of SA were studied, followed by rational design and synthesis of two series of SA derivatives (one being benzyl esters of SA and another being SA derivatives containing methylene chains of various lengths). Our results indicated that (1) both the double bond and ketone carbonyl are essential elements responsible for the antifouling effect of SA, while the acid group is not absolutely necessary for maintaining the antifouling effect; (2) all benzyl esters of SA displayed good antifouling effects (EC50 ranged from 0.30 to 2.50 µg/mL) with the most potent compound being 5 (EC50 0.30 µg/mL, LC50 > 25 µg/mL), which was over four-fold more potent than SA; and (3) the introduction of a methylene chain into SA reduces the antifouling potency while the length of the methylene chain may differently influence the antifouling effect, depending on the functional group at the opposite site of the methylene chain. Not only has this study successfully revealed the bioactive functional groups of SA, contributing to the mechanism of SA against the settlement of B. amphitrite, but it has also resulted in the identification of a more potent compound 5, which might represent a non-toxic, high-efficiency antifoulant.

miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin.

Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS-induced ALI. Here, we have investigated the potential roles of PGRN-targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS-induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR-34b-5p in ALI was determined by transfection of a miR-34b-5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT-PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR-34b-5p levels were closely associated with PGRN expression in the lung homogenates. The gain- and loss-of-function analysis, dual-luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR-34b-5p. Intravenous injection of miR-34b-5p antagomir in vivo significantly inhibited miR-34b-5p up-regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR-34b-5p knockdown attenuates lung inflammation and apoptosis in an LPS-induced ALI mouse model by targeting PGRN. This study shows that miR-34b-5p and PGRN may be potential targets for ALI treatments.

HMGB1-containing nucleosome mediates chemotherapy-induced metastasis of human lung cancer.

While chemotherapy is an important and widely used therapeutic for cancer, it may facilitate cancer metastasis. Herein, we report that human lung cancer cells exert higher invasion and metastasis after chemotherapy. In a human lung cancer xenograft model, chemotherapy promotes the cancer invasion and metastasis in HMGB1-dependent manner. Further studies identify HMGB1-containing nucleosome from chemotherapy-induced apoptotic cancer cells as an effective factor. Such nucleosome functions through TLR4 and TLR9 to drive cancer invasion and metastasis. In lung cancer patients, circulating HMGB1-containing nucleosome is higher in those under chemotherapy, predicting poorly cancer cell differentiation state, enhanced cancer invasion and advanced TNM stages. These findings provide a novel mechanism by which the tumor metastasis is propagated in lung cancer patients, especially in those under chemotherapy, and a clue for developing therapeutic strategies against chemotherapy-induced metastasis.

Epigenetic Switch Driven by DNA Inversions Dictates Phase Variation in Streptococcus pneumoniae.

DNA methylation is an important epigenetic mechanism for phenotypic diversification in all forms of life. We previously described remarkable cell-to-cell heterogeneity in epigenetic pattern within a clonal population of Streptococcus pneumoniae, a leading human pathogen. We here report that the epigenetic diversity is caused by extensive DNA inversions among hsdSA, hsdSB, and hsdSC, three methyltransferase hsdS genes in the Spn556II type-I restriction modification (R-M) locus. Because hsdSA encodes the sequence recognition subunit of this type-I R-M DNA methyltransferase, these site-specific recombinations generate pneumococcal cells with variable HsdSA alleles and thereby diverse genome methylation patterns. Most importantly, the DNA methylation pattern specified by the HsdSA1 allele leads to the formation of opaque colonies, whereas the pneumococci lacking HsdSA1 produce transparent colonies. Furthermore, this HsdSA1-dependent phase variation requires intact DNA methylase activity encoded by hsdM in the Spn556II (renamed colony opacity determinant or cod) locus. Thus, the DNA inversion-driven ON/OFF switch of the hsdSA1 allele in the cod locus and resulting epigenetic switch dictate the phase variation between the opaque and transparent phenotypes. Phase variation has been well documented for its importance in pneumococcal carriage and invasive infection, but its molecular basis remains unclear. Our work has discovered a novel epigenetic cause for this significant pathobiology phenomenon in S. pneumoniae. Lastly, our findings broadly represents a significant advancement in our understanding of bacterial R-M systems and their potential in shaping epigenetic and phenotypic diversity of the prokaryotic organisms because similar site-specific recombination systems widely exist in many archaeal and bacterial species.

Transcription factor E2F3a regulates CASP8AP2 transcription and enhances sensitivity to chemotherapeutic drugs in acute lymphoblastic leukemia.

BACKGROUND: Low expression of E2F3a and caspase 8 associated protein 2 (CASP8AP2) are associated with poor prognosis of childhood acute lymphoblastic leukemia (ALL). METHODS: Dual-luciferase reporter assay and wild type as well as four mutated types of reporter plasmids were used to demonstrate the activation of E2F3a on CASP8AP2 transcription. The direct binding of E2F3a with the promoter of CASP8AP2 was shown by Chromatin Immunoprecipitation (ChIP). Cell proliferation activity and cell cycle were determined by MTS and flow cytometry in leukemic cells after treating with common chemotherapeutic drugs vincristine and daunorubicin. RESULTS: In this study, we found that up-regulation of E2F3a in leukemic cells led to increased fraction of cells in S and G2/M phase, accelerated proliferation, and enhanced sensitivity to vincristine and daunorubicin. ChIP and luciferase assay indicated that E2F3a could directly bind to two fragments in the wild type of CASP8AP2 promotor (- 206 to - 69 and - 677 to - 507), and activate its transcription activity which was reduced in mutated promotors. The effect of E2F3a on chemotherapeutic sensitivity of leukemic cells could be reversed by down-regulating CASP8AP2. CONCLUSIONS: E2F3a could promote transcription and expression of CASP8AP2. The effect of E2F3a on chemotherapeutic sensitivity of ALL cells was implemented by regulating CASP8AP2 expression to a great extent.

Ruegeria kandeliae sp. nov., isolated from the rhizosphere soil of a mangrove plant Kandelia candel.

A Gram-negative, rod-shaped and motile bacterium, designated strain J95T, was isolated from the rhizosphere soil of a mangrove plant Kandeliacandel (L.) Druce in Mai Po Nature Reserve, Hong Kong. Growth of strain J95T was observed at pH 5.0-8.5 (optimum, 6.0-7.0), between 10-40 °C (30-37 °C) and in the presence of 0-9 % (w/v) NaCl (0.5-3 %). Chemotaxonomic analysis showed ubiquinone-10 as the predominant respiratory quinone and C18 : 1ω7c and C19 : 0 cycloω8c as the major fatty acids. The major polar lipids were lipid, aminolipid, phospholipid, phosphatidylcholine, phosphatidylglycerol and phosphatidylethanolamine. The genomic contained a circular chromosome of 5.48 Mb with a DNA G+C content of 65.7 mol%. The genome included 5299 genes. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain J95T belongs to the genus Ruegeria with highest sequence similarity (96.8 %) to the type strain Ruegeria marina ZH17T. The combined phenotypic, chemotaxonomic and phylogenetic data suggested that strain J95T represents a novel species of the genus Ruegeria, for which the name Ruegeria kandeliae sp. nov. is proposed. The type strain is J95T (=MCCC 1K03284T=DSM 104293T).

Kandeliimicrobium roseum gen. nov., sp. nov., a new member of the family Rhodobacteraceae isolated from mangrove rhizosphere soil.

A Gram-stain-negative, non-flagellated, short rod-shaped bacterium, designated XY-R6T, was isolated from the rhizosphere soil of a mangrove plant, Kandelia candel (L.) Druce, in Mai Po Nature Reserve, Hong Kong. Growth of strain XY-R6T was observed at pH 5.0-9.5 (optimum 6.5-8.0), between 8 and 42 °C (optimum 28-34 °C), and in the presence of 0-9.5 % (w/v) NaCl (optimum 1-4 %). The predominant isoprenoid quinone was ubiquinone-10. The major fatty acids were summed feature 8 (C18 : 1ω6c and/or C18 : 1ω7c) (55.61 %), C19 : 0cycloω8c (21.59 %) and C16 : 0 (11.24 %). The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, aminolipid, phosphatidylcholine and diphosphatidylglycerol. The genomic DNA G+C content of strain XY-R6T was 69.3 mol%. Phylogenetic analyses, based on 16S rRNA gene sequences, revealed that strain XY-R6T belonged to the family Rhodobacteraceae of the class Alphaproteobacteria and formed a distinct lineage, showing the highest gene sequence similarities to the members of genus Wenxinia(94.5-94.3 %), followed by the genera Profundibacterium (94.3 %), Defluviimonas(93.8-92.5 %), Oceanicola (93.8 %) and Cereibacter (93.7 %). Similarities to other genera within the family Rhodobacteraceae were below 94.0 %. Based on comprehensive phenotypic, phylogenetic and chemotaxonomic characterization, it is indicated that strain XY-R6T represents a novel species of a new genus in the family Rhodobacteraceae, for which the name Kandeliimicrobium roseum gen. nov., sp. nov. is proposed, with XY-R6T (=MCCC 1K01498T=KCTC 52266T=DSM 104294T) as the type strain.

Altererythrobacter salegens sp. nov., a slightly halophilic bacterium isolated from surface sediment.

A Gram-negative, rod-shaped and slightly halophilic bacterium, strain XY-R17T, was isolated from the surface sediment of Mai Po Inner Deep Bay Ramsar Site birdwatch in Hong Kong. The 16S rRNA gene sequence of strain XY-R17T exhibited 96.5 % similarity to that of the type strain of Altererythrobacter atlanticus. Optimal growth occurred at pH 7.0-7.5, 3-8 % (w/v) NaCl and at 30 °C. The major respiratory quinone was ubiquinone-10. The principal fatty acids were summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c), summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), 11-methyl C18 : 1ω7c and C17 : 1ω6c .The polar lipid profile consisted of the major compounds sphingoglycolipid, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine and two unknown lipids. The DNA G+C content was 64.7 mol%. Based on its phenotypic properties, chemotaxonomic characteristics and phylogenetic distinctiveness, strain XY-R17T should be designated as a novel species of the genus Altererythrobacter. Therefore, the name Altererythrobacter salegens sp. nov. (type strain XY-R17T=KCTC 52267T=MCCC 1K01500T) is proposed.

Mini-Review: Antifouling Natural Products from Marine Microorganisms and Their Synthetic Analogs.

Biofouling causes huge economic loss and generates serious ecological issues worldwide. Marine coatings incorporated with antifouling (AF) compounds are the most common practices to prevent biofouling. With a ban of organotins and an increase in the restrictions regarding the use of other AF alternatives, exploring effective and environmentally friendly AF compounds has become an urgent demand for marine coating industries. Marine microorganisms, which have the largest biodiversity, represent a rich and important source of bioactive compounds and have many medical and industrial applications. This review summarizes 89 natural products from marine microorganisms and 13 of their synthetic analogs with AF EC50 values ≤ 25 µg/mL from 1995 (the first report about marine microorganism-derived AF compounds) to April 2017. Some compounds with the EC50 values < 5 µg/mL and LC50/EC50 ratios > 50 are highlighted as potential AF compounds, and the preliminary analysis of structure-relationship (SAR) of these compounds is also discussed briefly. In the last part, current challenges and future research perspectives are proposed based on opinions from many previous reviews. To provide clear guidance for the readers, the AF compounds from microorganisms and their synthetic analogs in this review are categorized into ten types, including fatty acids, lactones, terpenes, steroids, benzenoids, phenyl ethers, polyketides, alkaloids, nucleosides and peptides. In addition to the major AF compounds which targets macro-foulers, this review also includes compounds with antibiofilm activity since micro-foulers also contribute significantly to the biofouling communities.

Biological and Chemical Diversity of Bacteria Associated with a Marine Flatworm.

The aim of this research is to explore the biological and chemical diversity of bacteria associated with a marine flatworm Paraplanocera sp., and to discover the bioactive metabolites from culturable strains. A total of 141 strains of bacteria including 45 strains of actinomycetes and 96 strains of other bacteria were isolated, identified and fermented on a small scale. Bioactive screening (antibacterial and cytotoxic activities) and chemical screening (ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)) yielded several target bacterial strains. Among these strains, the ethyl acetate (EA) crude extract of Streptomyces sp. XY-FW47 fermentation broth showed strong antibacterial activity against methicillin-resistant Staphylococcus aureus ATCC43300 (MRSA ATCC43300) and potent cytotoxic effects on HeLa cells. The UPLC-MS spectral analysis of the crude extract indicated that the strain XY-FW47 could produce a series of geldanamycins (GMs). One new geldanamycin (GM) analog, 4,5-dihydro-17-O-demethylgeldanamycin (1), and three known GMs (2-4) were obtained. All of these compounds were tested for antibacterial, cytotoxic, and antifungal activities, yet only GM (3) showed potent cytotoxic (HeLa cells, EC50 = 1.12 µg/mL) and antifungal (Setosphaeria turcica MIC = 2.40 µg/mL) activities. Their structure-activity relationship (SAR) was also preliminarily discussed in this study.

Cochliomycin A inhibits the larval settlement of Amphibalanus amphitrite by activating the NO/cGMP pathway.

Cochliomycin A is a compound with anti-barnacle settlement activity and low toxicity, but the molecular mechanism of the compound is unknown. Here, isobaric tags for the relative or absolute quantitation (iTRAQ) labeling proteomic method were applied to analyze changes in the proteome of Amphibalanus (=Balanus) amphitrite cyprids in response to cochliomycin A treatment. Cochliomycin A affected the cytochrome P450, glutathione S-transferase (GST) and NO/cGMP pathways, among which the NO/cGMP pathway was considered to play a key role in barnacle larval settlement, while the cytochrome P450 and the GST pathways are mainly for detoxification. The results of real-time PCR further suggested the NO/cGMP pathway was activated in response to cochliomycin A. Larval settlement assays revealed that S-methylisothiourea sulfate (SMIS) and 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) rescued cyprids from cochliomycin A-induced inhibition of larval settlement. The findings supported the hypothesis that cochliomycin A inhibited barnacle larval settlement by stimulating the NO/cGMP pathway.

Azaphilone and Diphenyl Ether Derivatives from a Gorgonian-Derived Strain of the Fungus Penicillium pinophilum.

Three new azaphilone derivatives, pinophilins D-F (1-3), and one new diphenyl ether derivative, hydroxypenicillide (10), together with nine known compounds (4-9, 11-13), were isolated from the gorgonian-derived fungus Penicillium pinophilum XS-20090E18. Their structures including absolute configurations were determined by spectroscopic data, chemical conversions, the ECD exciton chirality method, and ECD calculations. Compounds 10-13 exhibited inhibitory activity against the larval settlement of the barnacle Balanus amphitrite at nontoxic concentrations. Compounds 10 and 11 showed cytotoxicity against Hep-2, RD, and HeLa cell lines.

Bioactive steroid derivatives and butyrolactone derivatives from a gorgonian-derived Aspergillus sp. fungus.

Six steroid derivatives, 1-6, and five butyrolactone derivatives, 7-11, were isolated from the fermentation broth of a gorgonian-derived Aspergillus sp. fungus. Their structures were elucidated on the basis of NMR and MS spectral data. Compound 1 is a new, highly conjugated steroid. The NMR and MS data of 7 and 8 are reported for the first time, as their structures were listed in SciFinder Scholar with no associated reference. Compounds 1, 4, 5, and 8-11 inhibited the larval settlement of barnacle Balanus amphitrite with EC50 values ranging from 0.63 to 18.4 µg ml(-1) . Butyrolactone derivatives 7 and 8 showed pronounced antibacterial activities against Staphylococcus aureus with the same MIC values as the positive control ciprofloxacin (MIC 1.56 µM for all three compounds).