Prevalence and molecular characterization of Cryptosporidium spp., Enterocytozoon bieneusi, and Giardia duodenalis in dairy cattle in Ningxia, northwestern China.

Cryptosporidium spp., Enterocytozoon bieneusi, and Giardia duodenalis are common intestinal pathogens that infect humans and animals. To date, research regarding these three protozoa in the Ningxia Hui Autonomous Region (Ningxia) has mostly been limited to a single pathogen, and comprehensive data on mixed infections are unavailable. This study aimed to evaluate the zoonotic potential of these three protozoa. In this study, small subunit ribosomal RNA (SSU rRNA) and 60 kDa glycoprotein (gp60) genes of Cryptosporidium; internal transcribed spacer (ITS) gene of E. bieneusi; and SSU rRNA, glutamate dehydrogenase (gdh), triosephosphate isomerase (tpi), and beta-giardin (bg) genes of G. duodenalis were examined. DNA extraction, polymerase chain reaction, and sequence analysis were performed on fecal samples collected from 320 dairy cattle at three intensive dairy farms in Ningxia in 2021 to determine the prevalence and genetic characteristics of these three protozoa. The findings revealed that 61.56% (197/320) of the samples were infected with at least one protozoan. The overall prevalence of Cryptosporidium was 19.38% (62/320), E. bieneusi was 41.56% (133/320), and G. duodenalis was 29.38% (94/320). This study identified four Cryptosporidium species (C. bovis, C. andersoni, C. ryanae, and C. parvum) and the presence of mixed infections with two or three Cryptosporidium species. C. bovis was the dominant species in this study, while the dominant C. parvum subtypes were IIdA15G1 and IIdA20G1. The genotypes of E. bieneusis were J, BEB4, and I alongside the novel genotypes NX1-NX8, all belonging to group 2, with genotype J being dominant. G. duodenalis assemblages were identified as assemblages E, A, and B, and a mixed infection involving assemblages A + E was identified, with assemblage E being the dominant one. Concurrently, 11 isolates formed 10 different assemblage E multilocus genotypes (MLGs) and 1 assemblage A MLG and assemblage E MLGs formed 5 subgroups. To the best of our knowledge, this is the first report on mixed infection with two or three Cryptosporidium species in cattle in Ningxia and on the presence of the C. parvum subtype IIdA20G1 in this part of China. This study also discovered nine genotypes of E. bieneusis and novel features of G. duodenalis assemblages in Ningxia. This study indicates that dairy cattle in this region may play a significant role in the zoonotic transmission of Cryptosporidium spp., E. bieneusi, and G. duodenalis.

Telomere dysfunction alters intestinal stem cell dynamics to promote cancer.

Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3ß inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres.

Chelativorans salis sp. nov., a slightly halophilic bacterium isolated from an enrichment system with saline lake sediment.

A Gram-stain-negative, non-motile, and slightly halophilic alphaproteobacterium, designated strain EGI FJ00035T, was isolated from enrichment sediment samples of a saline lake in Xinjiang Uygur Autonomous Region, PR China. The taxonomic position of the isolate was determined using the polyphasic taxonomic and phylogenomic analyses. Phylogenetic analysis based on the 16S rRNA gene sequences indicated that strain EGI FJ00035T formed a distinct clade with 'Chelativorans alearense' UJN715 and 'Chelativorans xinjiangense' lm93 with sequence similarities of 98.44 and 98.22 %, respectively, while sharing less than 96.7 % with other valid type strains. The novel isolate could be distinguished from other species of the genus Chelativorans by its distinct phenotypic, physiological, and genotypic characteristics. Optimal growth of strain EGI FJ00035T occurred on marine agar 2216 at pH 7.0 and 30 °C. The major respiratory quinone was Q-10, while the major fatty acids (>5 %) were C19 : 0 cyclo ω8c, summed feature 8 (C17 : 1 ω6c and/or C17 : 1 ω7c), C16 : 0, C18 : 0, and iso-C17 : 0. The detected polar lipids included diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, unidentified aminophospholipids, unidentified glycolipids, and an unidentified lipid. Based on its genome sequence, the G+C content of strain EGI FJ00035T was 63.2 mol%. The average nucleotide identity, average amino acid identity, and digital DNA-DNA hybridization values of strain EGI FJ00035T against related members of the genus Chelativorans were below the thresholds for delineation of a novel species. According our polyphasic taxonomic data, strain EGI FJ00035T represents a new species of the genus Chelativorans, for which the name Chelativorans salis sp. nov. is proposed. The type strain of the proposed novel isolate is EGI FJ00035T (=KCTC 92251T=CGMCC 1.19480T).

Peripheral nerve injury associated with JEV infection in high endemic regions, 2016-2020: a multicenter retrospective study in China.

Previously, we reported a cohort of Japanese encephalitis (JE) patients with Guillain-Barré syndrome. However, the evidence linking Japanese encephalitis virus (JEV) infection and peripheral nerve injury (PNI) remains limited, especially the epidemiology, clinical presentation, diagnosis, treatment, and outcome significantly differ from traditional JE. We performed a retrospective and multicenter study of 1626 patients with JE recorded in the surveillance system of the Chinese Center for Disease Control and Prevention, spanning the years 2016-2020. Cases were classified into type 1 and type 2 JE based on whether the JE was combined with PNI or not. A comparative analysis was conducted on demographic characteristics, clinical manifestations, imaging findings, electromyography data, laboratory results, and treatment outcomes. Among 1626 laboratory confirmed JE patients, 230 (14%) were type 2 mainly located along the Yellow River in northwest China. In addition to fever, headache, and disturbance of consciousness, type 2 patients experienced acute flaccid paralysis of the limbs, as well as severe respiratory muscle paralysis. These patients presented a greater mean length of stay in hospital (children, 22 years [range, 1-34]; adults, 25 years [range, 0-183]) and intensive care unit (children, 16 years [range, 1-30]; adults, 17 years [range, 0-102]). The mortality rate was higher in type 2 patients (36/230 [16%]) compared to type 1 (67/1396 [5%]). The clinical classification of the diagnosis of JE may play a crucial role in developing a rational treatment strategy, thereby mitigating the severity of the disease and potentially reducing disability and mortality rates among patients.

Genomic survey and expression analysis of cellulose synthase superfamily and COBRA-like gene family in Zanthoxylum bungeanum stipule thorns.

The Cellulose Synthase gene (CS) superfamily and COBRA-like (COBL) gene family are essential for synthesizing cellulose and hemicellulose, which play a crucial role in cell wall biosynthesis and the hardening of plant tissues. Our study identified 126 ZbCS and 31 ZbCOBL genes from the Zanthoxylum bungeanum (Zb) genome. Phylogenetic analysis and conservative domain analysis unfolded that ZbCS and ZbCOBL genes were divided into seven and two subfamilies, respectively. Gene duplication data suggested that more than 75% of these genes had tandem and fragment duplications. Codon usage patterns analysis indicated that the ZbCS and ZbCOBL genes prefer ending with A/T base, with weak codon preference. Furthermore, seven key ZbCS and five key ZbCOBL genes were identified based on the content of cellulose and hemicellulose and the expression characteristics of ZbCS and ZbCOBL genes in various stages of stipule thorns. Altogether, these results improve the understanding of CS and COBL genes and provide valuable reference data for cultivating Zb with soft thorns. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01432-x.

Peniditerpenoids A and B: Oxidized Indole Diterpenoids with Osteoclast Differentiation Inhibitory Activity from a Mangrove-Sediment-Derived Penicillium sp.

An unprecedented di-seco-indole diterpenoid, peniditerpenoid A (1), and a rare N-oxide-containing indole diterpenoid derivative, peniditerpenoid B (2), together with three known ones (3-5), were obtained from the mangrove-sediment-derived fungus Penicillium sp. SCSIO 41411. Their structures were determined by the analysis of spectroscopic data, quantum chemical calculations, and X-ray diffraction analyses. Peniditerpenoid A (1) inhibited lipopolysaccharide-induced NF-κB with an IC50 value of 11 µM and further effectively prevented RANKL-induced osteoclast differentiation in bone marrow macrophages. In vitro studies demonstrated that 1 exerted significant inhibition of NF-κB activation in the classical pathway by preventing TAK1 activation, IκBα phosphorylation, and p65 translocation. Furthermore, 1 effectively reduced the level of NFATc1 activation, resulting in the attenuation of osteoclast differentiation. Our findings suggest that 1 holds promise as an inhibitor with significant potential for the treatment of diseases related to osteoporosis.

Transcranial alternating current stimulation improves quality of life in Parkinson's disease: study protocol for a randomized, double-blind, controlled trial.

BACKGROUND: The neural cells in the brains of patients with Parkinson's disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson's disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson's disease based on the central-peripheral-central theory. METHODS: The present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson's disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes. DISCUSSION: The objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023.

Structural characterization of a Chlorella heteropolysaccharide by analyzing its depolymerized product and finding an inducer of human dendritic cell maturation.

Chlorella polysaccharides have been gaining increasing attention because of their high yield from dried Chlorella powder and their remarkable immunomodulatory activity. In this study, the major polysaccharide fraction, CPP-3a, in Chlorella pyrenoidosa, was isolated, and its detailed structure was investigated by analyzing the low-molecular-weight product prepared via free radical depolymerization. The results indicated that CPP-3a with a molecular weight of 195.2 kDa was formed by →2)-α-L-Araf-(1→, →2)-α-D-Rhap-(1→, →5)-α-L-Araf-(1→, →3)-ß-D-Glcp-(1→, →4)-α-D-Glcp-(1→, →4)-α-D-GlcpA-(1→, →2,3)-α-D-Manp-(1→, →3,4)-α-D-Manp-(1→, →3,4)-ß-D-Galp-(1→, →3,6)-ß-D-Galp-(1→, and →2,3,6)-α-D-Galp-(1→ residues, branched at C2, C3, C4, or C6 of α/ß-D-Galp and α-D-Manp, and terminated by α/ß-L-Araf, α-L-Arap, α-D-Galp, and ß-D-Glcp. Biological assays showed that CPP-3a significantly altered the dendritic morphology of immature dendritic cells (DCs). Enhanced CD80, CD86, and MHC I expression on the cell surface and decreased phagocytic ability indicated that CPP-3a could induce the maturation of DCs. Furthermore, CPP-3a-stimulated DCs not only stimulated the proliferation of allogeneic naïve CD4+ T cells and the secretion of IFN-γ, but also directly stimulated the activation and proliferation of CD8+ T cells through cross-antigen presentation. These findings indicate that CPP-3a can promote human DC maturation and T-cell stimulation and may be a novel DC maturation inducer with potential developmental value in DC immunotherapy.

An Enzymatic Carbon-Carbon Bond Cleavage and Aldol Reaction Cascade Converts an Angular Scaffold into the Linear Tetracyclic Core of Ochraceopones.

Meroterpenoids of the ochraceopones family featuring a linear tetracyclic scaffold exhibit exceptional antiviral and anti-inflammatory activities. The biosynthetic pathway and chemical logic to generate this linear tetracycle, however, remain unknown. In this study, we identified and characterized all biosynthetic enzymes to afford ochraceopones and elucidated the complete biosynthetic pathway. We demonstrated that the linear tetracyclic scaffold of ochraceopones was derived from an angular tetracyclic precursor. A multifunctional cytochrome P450 OchH was validated to catalyze the free-radical-initiated carbon-carbon bond cleavage of the angular tetracycle. Then, a new carbon-carbon bond was verified to be constructed using a new aldolase OchL, which catalyzes an intramolecular aldol reaction to form the linear tetracycle. This carbon-carbon bond fragmentation and aldol reaction cascade features an unprecedented strategy for converting a common angular tetracycle to a distinctive linear tetracyclic scaffold in meroterpenoid biosynthesis.

First report of Giardia duodenalis in dairy cattle and beef cattle in Shanxi, China.

BACKGROUND: Giardia duodenalis is an important intestinal parasitic protozoan that infects several vertebrates, including humans. Cattle are considered the major source of giardiasis outbreak in humans. This study aimed to investigate the prevalence and multilocus genotype (MLG) of G. duodenalis in Shanxi, and lay the foundation for the prevention and control of Giardiosis. METHODS AND RESULTS: DNA extraction, nested polymerase chain reaction, sequence analysis, MLG analysis, and statistical analysis were performed using 858 bovine fecal samples from Shanxi based on three gene loci: ß-giardin (bg), glutamate dehydrogenase (gdh), and triosephosphate isomerase (tpi). The overall prevalence of G. duodenalis was 28.3%, while its prevalence in Yingxian and Lingqiu was 28.1% and 28.5%, respectively. The overall prevalence of G. duodenalis in dairy cattle and beef cattle was 28.0% and 28.5%, respectively. G. duodenalis infection was detected in all age groups evaluated in this study. The overall prevalence of G. duodenalis in diarrhea and nondiarrhea samples was 32.4% and 27.5%, respectively, whereas that in intensively farmed and free-range cattle was 35.0% and 19.9%, respectively. We obtained 83, 53, and 59 sequences of bg, gdh, and tpi in G. duodenalis, respectively. Moreover, assemblage A (n = 2) and assemblage E (n = 81) by bg, assemblage A (n = 1) and assemblage E (n = 52) by gdh, and assemblage A (n = 2) and assemblage E (n = 57) by tpi were identified. Multilocus genotyping yielded 29 assemblage E MLGs, which formed 10 subgroups. CONCLUSIONS: To the best of our knowledge, this is the first study to report cattle infected with G. duodenalis in Shanxi, China. Livestock-specific G. duodenalis assemblage E was the dominant assemblage genotype, and zoonotic sub-assemblage AI was also detected in this region.

Tongue Biting Event in Patients with Sleep-Related Facial Mandibular Myoclonus: A Case Series Study.

Background: Sleep-related facial mandibular myoclonus (SRFMM) remains rare in clinical practice. The aim of this study was to provide a comprehensive understanding of the electroclinical manner, therapeutic regimen, and prognosis of SRFMM. Methods: Twenty-three patients who were diagnosed with SRFMM by clinical manifestation, video-electroencephalography (EEG) and electromyography over bilateral masseter and temporalis muscles were enrolled. Clinical and electrophysiological evaluation as well as follow-up information were recorded and analyzed. Results: The cohort involved 4 infants and 19 adults with a mean onset age of 43.5 years for SRFMM, among whom 19 were male. Twenty-one patients complained of tongue injuries and disturbed night-time sleep. SRFMM in 4 patients were ascribed to oral aripiprazole, brainstem ischemia and brain trauma. In 62 SRFMM episodes, 93.5% occurred in NREM sleep and 6.5% in REM sleep, and all events were associated with EEG arousals. In 13 patients with or without clonazepam, the motor events gradually disappeared, and the rest turned to be sporadic. Conclusion: SRFMM is a characteristic parasomnia manifested by tongue biting and accompanying facial mandibular myoclonus, leading to disrupted sleep. Besides adults, infants can also experience SRFMM with spontaneous remission. Most patients respond well to clonazepam, eventually with favorable prognosis.

Diversified Chemical Structures and Bioactivities of the Chemical Constituents Found in the Brown Algae Family Sargassaceae.

Sargassaceae, the most abundant family in Fucales, was recently formed through the merging of the two former families Sargassaceae and Cystoseiraceae. It is widely distributed in the world's oceans, notably in tropical coastal regions, with the exception of the coasts of Antarctica and South America. Numerous bioactivities have been discovered through investigations of the chemical diversity of the Sargassaceae family. The secondary metabolites with unique structures found in this family have been classified as terpenoids, phlorotannins, and steroids, among others. These compounds have exhibited potent pharmacological activities. This review describes the new discovered compounds from Sargassaceae species and their associated bioactivities, citing 136 references covering from March 1975 to August 2023.

Carneusones A-F, Benzophenone Derivatives from Sponge-Derived Fungus Aspergillus carneus GXIMD00543.

Six benzophenone derivatives, carneusones A-F (1-6), along with seven known compounds (7-13) were isolated from a strain of sponge-derived marine fungus Aspergillus carneus GXIMD00543. Their chemical structures were elucidated by detailed spectroscopic data and quantum chemical calculations. Compounds 5, 6, and 8 exhibited moderate anti-inflammatory activity on NO secretion using lipopolysaccharide (LPS)-induced RAW 264.7 cells with EC50 values of 34.6 ± 0.9, 20.2 ± 1.8, and 26.8 ± 1.7 µM, while 11 showed potent effect with an EC50 value of 2.9 ± 0.1 µM.

New Alkaloids and Steroids from Hydranth of Goniopora columna Corals and Their Inhibiting Lung Cancer Cell Activities.

A new alkaloids, aplysingoniopora A (1), and new configuration pregnane type steroid compound, 9,17-α-pregn-1,4,20-en-3-one (2), and two known pregnane type steroid compounds (3 and 4) were isolated from hydranth of Goniopora columna corals. The compounds structures and absolute configurations were determined by extensive spectroscopic analysis, MS data, single-crystal X-ray diffraction analysis and quantum chemical calculation. The anticancer effect of the compounds were explored in human non-small-cell lung cancer (NSCLC) A549 cell lines. As the results, the compound 3 and 4 induces toxicity and has proliferation inhibitory effects on A549 cells (IC50=58.99 µM and 58.77 µM, respectively) in vitro.

Discovery of Enzyme Inhibitors from Mangrove Sediment Derived Fungus Trichoderma harzianum SCSIO 41051.

One new fatty acid derivative, (2E,4E)-6,7-dihydroxy-2-methylocta-2,4-dienoic acid (1), and 16 known compounds (2-17) were isolated from the mangrove sediment derived fungus Trichoderma harzianum SCSIO 41051. Their structures were established by spectroscopic methods, computational ECD, and Mo2(OAc)4-induced ECD experiment. All the compounds were evaluated for their acetylcholinesterase (AChE) and pancreatic lipase (PL) inhibition. Compounds 9 and 14 exhibited moderate AChE inhibitory activities with IC50 values of 2.49 and 2.92 µM, respectively, which compounds 8 and 9 displayed moderate inhibition on PL with IC50 value of 2.30 and 2.34 µM, respectively.

Identifying Marine-Derived Tanzawaic Acid Derivatives as Novel Inhibitors against Osteoclastogenesis and Osteoporosis via Downregulation of NF-κB and NFATc1 Activation.

To discover novel osteoclast-targeting antiosteoporosis leads from natural products, we identified 40 tanzawaic acid derivatives, including 22 new ones (1-8, 14-19, 27-32, 37, and 38), from the South China Sea mangrove-derived fungus Penicillium steckii SCSIO 41025. Penicisteck acid F (2), one of the new derivatives showing the most potent NF-κB inhibitory activity, remarkably inhibited osteoclast generation in vitro. Mechanistically, 2 reduced RANKL-induced IκBα degradation, NF-κB p65 nuclear translocation, the activation and nuclear translocation of NFATc1, and the relevant mRNA expression. NF-κB p65 could be a potential molecular target for 2, which has been further determined by the cellular thermal shift assay, surface plasmon resonance, and the gene knock-down assay. Moreover, 2 could also alleviate osteoporosis in ovariectomized mice by reducing the quantities of osteoclasts. Our finding offered a novel potential inhibitor of osteoclastogenesis and osteoporosis for further development of potent antiosteoporosis agents.

Genome Mining Uncovers a Flavoenzyme-Catalyzed Isomerization Process during the Maturation of Pyrenophorol Dilactones.

The biosynthetic gene cluster responsible for the production of C2-asymmetric 16-membered dilactones, including pyrenophorol and its derivatives, was discovered through genome mining of polyketides from a sponge-derived fungus. The biosynthetic pathway of the pyrenophorol dilactones was subsequently elucidated. A distinctive flavoenzyme PylE was identified to catalyze the isomerization of the 4-alcohol-2,3-unsaturated moiety within the dilactone scaffold, resulting in the formation of a 1,4-diketone. Further insights into the catalytic mechanism of PylE were obtained through mutagenesis experiments combined with molecular docking.

Austin-Type Meroterpenoids from Fungi Reported in the Last Five Decades: A Review.

Austin was first isolated as a novel polyisoprenoid mycotoxin from Aspergillus ustus in 1976. Subsequently, some new austin-type meroterpenoids (ATMTs) have been continually found. This review attempts to give a comprehensive summary of progress on the isolation, chemical structural features, biological activities, and fungal biodiversity of 104 novel ATMTs from 5 genera of terrestrial- and marine-derived fungi reported from October 1976 to January 2023. The genera of Penicillium and Aspergillus are the two dominant producers, producing 63.5% and 30.8% of ATMTs, respectively. Moreover, about 26.9% of ATMTs display various pronounced bioactivities, including insecticidal, anti-inflammatory, cytotoxicity, antibacterial, and PTP1B inhibitory activities. The chemical diversity and potential activities of these novel fungal ATMTs are reviewed for a better understanding, and a relevant summary focusing on the source fungi and their taxonomy is provided to shed light on the future development and research of austin-type meroterpenoids.

Structural modification of natural axinelline A: Achieving reduced colitis side effects through balanced COX inhibition.

Marine natural products continue to hold great promise as potential candidates for the discovery of anti-inflammatory drug. In our previous investigation, we successfully synthesized axinelline A, a naturally occurring cyclooxygenase-2 (COX-2) inhibitor, as a promising anti-inflammatory lead compound. This study was to discover novel COX inhibitors with balanced inhibition, aiming to mitigate the severe adverse effects through further structural modification of axinelline A. Of the synthetic derivatives, compound 5e showed highest COX-2 inhibitory activity and balanced COX inhibition (IC50 = 1.74 µM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 16.32). The in vitro anti-inflammatory results indicated that 5e effectively suppressed the expression of pro-inflammatory mediators via the NF-κB signaling pathway rather than the MAPK signaling pathway. The in vivo ulcerative colitis assay demonstrated 5e significantly ameliorated the histological damages and showed strong protection against DSS-induced acute colitis. Therefore, our findings suggest that compound 5e exhibits potential as a promising anti-inflammatory agent with attenuated colitis-related adverse effects.

Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products.

A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.