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Abstract Similar to the physiological importance of gut microbiomes, recent works have shown that insect ectomicrobiotas can mediate defensive colonization resistance against fungal parasites that infect via cuticle penetration. Here we show that engineering the entomopathogenic fungus Metarhizium robertsii with a potent antibacterial moricin gene from silkworms substantially enhances the ability of the fungus to kill mosquitos, locusts, and two Drosophila species. Further use of Drosophila melanogaster as an infection model, quantitative microbiome analysis reveals that engineered strains designed to suppress insect cuticular bacteria additionally disrupt gut microbiomes. An overgrowth of harmful bacteria such as the opportunistic pathogens of Providencia species is detected that can accelerate insect death. In support, quantitative analysis of antimicrobial genes in fly fat bodies and guts indicates that topical fungal infections result in the compromise of intestinal immune responses. In addition to providing an innovative strategy for improving the potency of mycoinsecticides, our data solidify the importance of both the ecto- and endo-microbiomes in maintaining insect wellbeing.

Abstract Background Bletilla striata (Thunb.) Reichb. f. (B. striata) is a perennial herbaceous plant in the Orchidaceae family known for its diverse pharmacological activities, such as promoting wound healing, hemostasis, anti-inflammatory effects, antioxidant properties, and immune regulation. Nevertheless, the microbe-plant-metabolite regulation patterns for B. striata remain largely undetermined, especially in the field of rhizosphere microbes. To elucidate the interrelationships between soil physics and chemistry and rhizosphere microbes and metabolites, a comprehensive approach combining metagenome analysis and targeted metabolomics was employed to investigate the rhizosphere soil and tubers from four provinces and eight production areas in China. Results Our study reveals that the core rhizosphere microbiome of B. striata is predominantly comprised of Paraburkholderia, Methylibium, Bradyrhizobium, Chitinophaga, and Mycobacterium. These microbial species are recognized as potentially beneficial for plants health. Comprehensive analysis revealed a significant association between the accumulation of metabolites, such as militarine and polysaccharides in B. striata and the composition of rhizosphere microbes at the genus level. Furthermore, we found that the soil environment indirectly influenced the metabolite profile of B. striata by affecting the composition of rhizosphere microbes. Notably, our research identifies soil organic carbon as a primary driving factor influencing metabolite accumulation in B. striata. Conclusion Our fndings contribute to an enhanced understanding of the comprehensive regulatory mechanism involving microbe-plant-metabolite interactions. This research provides a theoretical basis for the cultivation of high-quality traditional Chinese medicine B. striata.

Abstract Background Bacterial transfers from plants to insect herbivore guts have been well investigated. However, bacterial exchanges between plant phyllospheres and insect cuticles remain unclear, as does their related biological function. Results Here, we report that the cuticular bacterial loads of silkworm larvae quickly increased after molting and feeding on the white mulberry (Morus alba) leaves. The isolation and examination of silkworm cuticular bacteria identified one bacterium Mammaliicoccus sciuri that could completely inhibit the spore germination of fungal entomopathogens Metarhizium robertsii and Beauveria bassiana. Interestingly, Ma. sciuri was evident originally from mulberry leaves, which could produce a secreted chitinolytic lysozyme (termed Msp1) to damage fungal cell walls. In consistency, the deletion of Msp1 substantially impaired bacterial antifungal activity. Pretreating silkworm larvae with Ma. sciuri cells followed by fungal topical infections revealed that this bacterium could help defend silkworms against fungal infections. Unsurprisingly, the protective efficacy of ΔMsp1 was considerably reduced when compared with that of wild-type bacterium. Administration of bacterium-treated diets had no negative effect on silkworm development; instead, bacterial supplementation could protect the artificial diet from Aspergillus contamination. Conclusions The results of this study evidence that the cross-kingdom transfer of bacteria from plant phyllospheres to insect herbivore cuticles can help protect insects against fungal parasite attacks. Video Abstract

Abstract Background Although stag beetles are a popular saprophytic insect, their gut microbiome has been poorly studied. Here, 16 S rRNA gene sequencing was employed to reveal the gut microbiota composition and functional variations between wild and domestic Dorcus hopei hopei (Dhh) larval individuals. Results The results indicated a significant difference between the wild and domestic Dhh gut microbiota., the domestic Dhh individuals contained more gut microbial taxa (e.g. genera Ralstonia and Methyloversatilis) with xenobiotic degrading functions. The wild Dhh possesses gut microbiota compositions (e.g. Turicibacter and Tyzzerella ) more appropriate for energy metabolism and potential growth. This study furthermore assigned all Dhh individuals by size into groups for data analysis; which indicated limited disparities between the gut microbiota of different-sized D. hopei hopei larvae. Conclusion The outcome of this study illustrated that there exists a significant discrepancy in gut microbiota composition between wild and domestic Dhh larvae. In addition, the assemblage of gut microbiome in Dhh was primarily attributed to environmental influences instead of individual differences such as developmental potential or size. These findings will provide a valuable theoretical foundation for the protection of wild saprophytic insects and the potential utilization of the insect-associated intestinal microbiome in the future.

The Bangiales represent an ancient lineage within red algae that are characterized by a life history featuring a special transitional stage from diploid to haploid known as the conchosporangia stage. However, the regulatory mechanisms governing the initiation of this stage by changes in environmental conditions are not well understood. This study analyzed the changes in phytohormones and H2O2 content during the development of conchosporangia. It also compared the gene expression changes in the early development of conchosporangia through transcriptome analysis. The findings revealed that H2O2 was shown to be the key signal initiating the transition from conchocelis to conchosporangia in Pyropia haitanensis. Phytohormone analysis showed a significant increase in 1-aminocylopropane-1-carboxylic acid (ACC) levels during conchosporangia maturation, while changes in environmental conditions were found to promote the rapid release of H2O2. H2O2 induction led to conchosporangia development, and ACC enhanced both H2O2 production and conchosporangia development. This promotive effect was inhibited by the NADPH oxidase inhibitor diphenylene iodonium and the H2O2 scavenger N, N’-dimethylthiourea. The balance of oxidative–antioxidative mechanisms was maintained by regulating the activities and transcriptional levels of enzymes involved in H2O2 production and scavenging. Transcriptome analysis in conjunction with evaluation of enzyme and transcription level changes revealed upregulation of protein and sugar synthesis along with modulation of energy supply under the conditions that induced maturation, and exogenous ACC was found to enhance the entire process. Overall, this study demonstrates that ACC enhances H2O2 promotion of the life cycle switch responsible for the transition from a vegetative conchocelis to a meiosis-preceding conchosporangia stage in Bangiales species.

Abstract Disease is a major concern in Porphyra aquaculture, particularly during the early shell-borne conchocelis (SBC) seedling stage. To explore prevention strategies for Porphyra diseases, this study explored the potential of using oligoagars (OA) and microbial agents (MA) to treat SBC of Neoporphyra haitanensis in an aquaculture environment. The impact of these treatments on the phycosphere microbial community was analyzed, and the resistance of the treated Porphyra conchocelis to the pathogenic bacterium Vibrio mediterranei 117-T6 (which causes yellow spot disease) was tested in the lab. Results showed that OA reduced α-diversity while enriching Rhodobacteriaceae, and MA increased stability and relative abundance of Bacteroidetes (including Flavobacteria). Furthermore, compared to the control group, the abundance of pathogenic microorganisms and virulence functional genes decreased while defense-related functional gene abundance increased significantly in the groups treated with OA and MA. Most importantly, the OA and MA treatments improved resistance to Vm117-T6, with survival rates of 70% (OA) and 80% (MA), compared to 15% in the control group. Overall, the findings suggest that OA and MA treatments have great potential for preventing Porphyra disease, as they improve phycosphere microorganisms and increase algae resistance to pathogenic bacteria.

ABSTRACTObjective Gain or amplification 1q21 (1q21+) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM). Our aim was to explore the presentation and outcomes of patients with MM harboring 1q21 + .Methods We retrospectively analyzed the clinical features and survival outcomes in 474 consecutive patients with MM receiving immunomodulatory drugs or proteasome inhibitor-based regimens as first-line therapies.Results 1q21 + was detected in 249 (52.5%) patients. Patients with 1q21 + had a higher proportion of subtypes of IgA, IgD, and λ-light chain than non-1q21 + . 1q21 + was associated with more advanced ISS stage and was more frequently accompanied by del(13q), elevated lactate dehydrogenase and lower levels of hemoglobin and platelets. Patients with 1q21 + had shorter PFS (21 months vs. 31 months, P = 0.001) and OS (43 months vs. 72 months, P

ABSTRACTBackground: Although multiple myeloma is still incurable, an abundance of novel treatments have become available for relapsed and or refractory multiple myeloma (RRMM). Direct head-to-head comparisons between the novel treatments are lacking. We performed a network meta-analysis to evaluate immediate effects such as response quality of current novel-drugs combined therapeutic regimens, with the aim to identify treatments that could be more effective than others in RRMM.Methods: We searched Cochrane Library, PubMed, Embase, and Web of Science for randomized controlled clinical trials receiving novel-drugs combined treatments as means of interventions. The primary endpoint was objective response rates (ORRs). We used the surface under the cumulative ranking curve (SUCRA) to sequence treatments. Totally, 22 randomized controlled trials were identified for final evaluation. With the aim to include all regimens within one network analysis, we divided the treatment schemes into 13 categories according to the use of novel drugs.Results: Carfilzomib-, daratumumab-, and isatuximab-based treatments had better ORRs than bortezomib combined dexamethasone and lenalidomide combined dexamethasone. Daratumumab- and isatuximab-based treatments had better ORRs than pomalidomide combined dexamethasone. According to the SUCRA, daratumumab- and isatuximab-based triple-drug regimens had higher probabilities of achieving better ORRs, followed by carfilzomib, elotuzumab, venetoclax, selinexor, ixazomib, vorinostat, pomalidomide, panobinostat, lenalidomide.Conclusions: Our network meta-analysis performed a complete review of the ORRs of all current available novel-drugs based regimens for RRMM. By using the clinical data all from randomized controlled studies, daratumumab- and isatuximab-based treatments were identified to be the best treatments receiving better response quality.

BackgroundsDiabetes nephropathy (DN) is a growing public health concern worldwide. Renal dysfunction impairment in DN is intimately linked to ER stress and its related signaling pathways. Nonetheless, the underlying mechanism and biomarkers for this function of ER stress in the DN remain unknown.MethodsMicroarray datasets were retrieved from the Gene Expression Omnibus (GEO) database, and ER stress-related genes (ERSRGs) were downloaded from the MSigDB and GeneCards database. We identified hub ERSRGs for DN progression by intersecting ERSRGs with differentially expressed genes and significant genes in WGCNA, followed by a functional analysis. After analyzing hub ERSRGs with three machine learning techniques and taking the intersection, we did external validation as well as developed a DN diagnostic model based on the characteristic genes. Immune infiltration was performed using CIBERSORT. Moreover, patients with DN were then categorized using a consensus clustering approach. Eventually, the candidate ERSRGs-specific small-molecule compounds were defined by CMap.ResultsSeveral biological pathways driving pathological injury of DN and disordered levels of immune infiltration were revealed in the DN microarray datasets and strongly related to deregulated ERSRGs by bioinformatics multi-chip integration. Moreover, CDKN1B, EGR1, FKBP5, GDF15, and MARCKS were identified as ER stress signature genes associated with DN by machine learning algorithms, demonstrating their potential as DN biomarkers.ConclusionsOur research sheds fresh light on the function of ER stress in DN pathophysiology and the development of early diagnostic and ER stress-related treatment targets in patients with DN.

Background/objectiveWe retrospectively analyzed the effective and safety of continuous low-dose cyclophosphamide combined with prednisone (CP) in relapsed and refractory multiple myeloma (RRMM) patients with severe complications.MethodsA total of 130 RRMM patients with severe complications were enrolled in this study, among which 41 patients were further given bortezomib, lenalidomide, thalidomide or ixazomib on the basis of CP regimen (CP+X group). The response to therapy, adverse events (AEs), overall survival (OS) and progression-free survival (PFS) were recorded.ResultsAmong the 130 patients, 128 patients received therapeutic response assessment, with a complete remission rate (CRR) and objective response rate (ORR) of 4.7% and 58.6%, respectively. The median OS and PFS time were (38.0 ± 3.6) and (22.9±5.2) months, respectively. The most common AEs were hyperglycemia (7.7%), pneumonia (6.2%) and Cushing’s syndrome (5.4%). In addition, we found the pro-BNP/BNP level was obviously decreased while the LVEF (left ventricular ejection fraction) was increased in RRMM patients following CP treatment as compared with those before treatment. Furthermore, CP+X regimen further improved the CRR compared with that before receiving the CP+X regimen (24.4% vs. 2.4%, P=0.007). Also, both the OS and PFS rates were significantly elevated in patients received CP+X regimen following CP regimen as compared with the patients received CP regimen only.ConclusionThis study demonstrates the metronomic chemotherapy regimen of CP is effective to RRMM patients with severe complications.

Abstract Background Seaweeds in the upper intertidal zone experience extreme desiccation during low tide, followed by rapid rehydration during high tide. Porphyra sensu lato are typical upper intertidal seaweeds. Therefore, it is valuable to investigate the adaptive mechanisms of seaweed in response to dehydration-rehydration stress. Results A reduction in photosynthetic capacity and cell shrinkage were observed when N. haitanensis was dehydrated, and such changes were ameliorated once rehydrated. And the rate and extent of rehydration were affected by the air flow speed, water content before rehydration, and storage temperature and time. Rapid dehydration at high air-flow speed and storage at − 20 °C with water content of 10% caused less damage to N. haitanensis and better-protected cell activity. Moreover, proteomic and metabolomic analyses revealed the abundance members of the differentially expressed proteins (DEPs) and differentially abundant metabolites (DAMs) mainly involved in antioxidant system and osmotic regulation. The ascorbic acid-glutathione coupled with polyamine antioxidant system was enhanced in the dehydration response of N. haitanensis. The increased soluble sugar content, the accumulated polyols, but hardly changed (iso)floridoside and insignificant amount of sucrose during dehydration indicated that polyols as energetically cheaper organic osmolytes might help resist desiccation. Interestingly, the recovery of DAMs and DEPs upon rehydration was fast. Conclusions Our research results revealed that rapid dehydration and storage at − 20 °C were beneficial for recovery of N. haitanensis. And the strategy to resist dehydration was strongly directed toward antioxidant activation and osmotic regulation. This work provided valuable insights into physiological changes and adaptative mechanism in desiccation, which can be applied for seaweed farming.

Abstract Background Red algae Porphyra sensu lato grow naturally in the unfavorable intertidal environment, in which they are exposed to substantial temperature fluctuations. The strategies of Porphyra to tolerate cold stress are poorly understood. Results Herein, investigations revealed that chilling and freezing induced alterations in the physiological properties, gene transcriptional profiles and metabolite levels in the economically important red algae species, Neoporphyra haitanensis. Control samples (kept at 20 °C) were compared to chilled thalli (10 and 4 °C) and to thalli under − 4 °C conditions. Chilling stress did not affect the health or photosynthetic efficiency of gametophytes, but freezing conditions resulted in the arrest of growth, death of some cells and a decrease in photosynthetic activity as calculated by Fv/Fm. Transcriptome sequencing analysis revealed that the photosynthetic system was down-regulated along with genes associated with carbon fixation and primary metabolic biosynthesis. Adaptive mechanisms included an increase in unsaturated fatty acids levels to improve membrane fluidity, an increase in floridoside and isofloridoside content to enhance osmotic resistance, and an elevation in levels of some resistance-associated phytohormones (abscisic acid, salicylic acid, and methyl jasmonic acid). These physiochemical alterations occurred together with the upregulation of ribosome biogenesis. Conclusions N. haitanensis adopts multiple protective mechanisms to maintain homeostasis of cellular physiology in tolerance to cold stress.

IntroductionDiabetic erectile dysfunction (DMED) refers to erectile dysfunction secondary to diabetes. Erectile dysfunction is characterized by a persistent inability to achieve and maintain an erection sufficient to permit satisfactory sexual activity.MethodsBased on the Web of Science core collection database, we firstly analyzed the quantity and quality of publications in the field of DMED, secondly profiled the publishing groups in terms of country, institution, author’s publication and cooperation network, and finally sorted out and summarized the hot topics of research.ResultsFrom 2001 to 2022, a total of 1,403 articles relating to this topic were published in 359 journals. They represent the global research status, potential hotspots, and future research directions. The number of DMED-related publications and citations has steadily increased over the few past decades. Academic institutions from Europe and the United States have played a leading role in DMED research. The country, institution, journal, and author with the most publications were the United States (294), INHA University (39), the Journal of Sexual Medicine (156), and Ryu, Ji-Kan (29), respectively. The most common keywords were erectile dysfunction (796), men (256), diabetes (254), diabetes mellitus (239), prevalence (180), corpus cavernosum (171), dysfunction (155), mellitus (154), nitric-oxide synthase (153), and expression (140). The main keyword-based research topics and hotspots in the DMED field were oral sildenafil, smooth muscle relaxation, nitric oxide synthase, gene therapy, metabolic syndrome, cavernous nerve injury, stem cell, and penile prosthesis.DiscussionThe terms oral sildenafil, smooth muscle relaxation, nitric oxide synthase, gene therapy, metabolic syndrome, cavernous nerve injury, stem cell, and penile prosthesis will be at the forefront of DMED-related research.

The inverted repeat‐lacking clade (IRLC) species are characterized by the loss of an IR region in their plastomes, which has long been of great interest. Wisteriopsis reticulata is one of the members of the tribe Wisterieae, which belongs to Fabaceae and is well-known as IRLC. Here, we reported and characterized the complete chloroplast genome of W. reticulata using the genome skimming approach. The chloroplast genome is 132,477 bp in length and lacks one copy of IR region. The genome encoded 112 unique genes including 89 protein-coding genes, 29 transfer RNA genes and four ribosomal RNA genes. Phylogenetic results supported the monophyly of the tribe Wisterieae (IRLC) and confirmed that W. reticulata belongs to the genus Wisteriopsis.

Abstract Stimulus-responsive therapy that allows precise imaging-guided therapy is limited for osteoarthritis (OA) therapy due to the selection of proper physiological markers as stimulus. Based on that the over-production of Reactive Oxygen Species (ROS) is associated with the progression in OA, we selected ROS as markers and designed a cartilage targeting and ROS-responsive theranostic nanoprobe that can be used for effective bioimaging and therapy of OA. This nanoprobe was fabricated by using PEG micelles modified with ROS-sensitive thioketal linkers (TK) and cartilage-targeting peptide, termed TKCP, which was then encapsulated with Dexamethasone (DEX) to form TKCP@DEX nanoparticles. Results showed that the nanoprobe can smartly “turn on” in response to excessive ROS and “turn off” in the normal joint. By applying different doses of ROS inducer and ROS inhibitor, this nanoprobe can emit ROS-dependent fluorescence according to the degree of OA severity, helpful to precise disease classification in clinic. Specifically targeting cartilage, TKCP@DEX could effectively respond to ROS and sustained release DEX to remarkably reduce cartilage damage in the OA joints. This smart, sensitive and endogenously activated ROS-responsive nanoprobe is promising for OA theranostics. Graphical Abstract

ABSTRACT The nortriterpenoid helvolic acid (HA) has potent antibiotic activities and can be produced by different fungi, yet HA function remains elusive. Here, we report the chemical biology of HA production in the insect pathogen Metarhizium robertsii. After deletion of the core oxidosqualene cyclase gene in Metarhizium, insect survival rates were significantly increased compared to those of insects treated with the wild type and the gene-rescued strain during topical infections but not during injection assays to bypass insect cuticles. Further gnotobiotic infection of axenic Drosophila adults confirmed the HA contribution to fungal infection by inhibiting bacterial competitors in an inoculum-dependent manner. Loss of HA production substantially impaired fungal spore germination and membrane penetration abilities relative to the WT and gene-complemented strains during challenge with different Gram-positive bacteria. Quantitative microbiome analysis revealed that HA production could assist the fungus to suppress the Drosophila cuticular microbiomes by exerting a bacteriostatic rather than bactericidal effect. Our data unveil the chemical ecology of HA and highlight the fact that fungal pathogens have to cope with the host cuticular microbiomes prior to successful infection of hosts. IMPORTANCE Emerging evidence has shown that the plant and animal surface microbiomes can defend hosts against fungal parasite infections. The strategies employed by fungal pathogens to combat the antagonistic inhibition of insect surface bacteria are still elusive. In this study, we found that the potent antibiotic helvolic acid (HA) produced by the insect pathogen Metarhizium robertsii contributes to natural fungal infection of insect hosts. Antibiotic and gnotobiotic infection assays confirmed that HA could facilitate fungal infection of insects by suppression of the host cuticular microbiomes through its bacteriostatic instead of bactericidal activities. The data from this study provide insights into the novel chemical biology of fungal secondary metabolisms.

Intertidal macroalgae have adapted to deal with environmental stresses, in particular desiccation. The phytohormone abscisic acid (ABA) plays an important role in the regulation of a suite of critical responses in plants, including desiccation tolerance. The red alga Neoporphyra haitanensis contains a high level of ABA, but its mechanism of action in N. haitanensis is unknown. In this study, the effect of ABA treatment on the relative water content of thalli during the dehydration-rehydration cycle was evaluated and it was identified that ABA treatment resulted in decreased thalli water loss and an accelerated rehydration process. The effects of addition of ABA upon the activation of antioxidant responses, photosynthetic parameters and gene transcription profiles of N. haitanensis were also evaluated. The results revealed that exogenous ABA regulated the activation of the antioxidant system, including by increasing the activity of antioxidant enzymes, increasing the concentrations of ascorbic acid (AsA) and glutathione (GSH), as well as upregulating the expression of genes encoding antioxidant enzymes and enzymes that synthesize AsA and GSH. ABA treatment also inhibited photosynthesis by reducing light capture and down-regulating the Calvin cycle to save energy; ABA supplementation further simultaneously activated repair mechanisms to avoid excessive DNA and protein damage. The results presented herein demonstrate that ABA plays a crucial role in the regulation of stress tolerance in seaweeds, which may be of great importance when examining the adaptation of this organism to the intertidal environment.

Preeclampsia (PE) is a complex pregnancy-related hypertensive disorder leading to multiorgan dysfunction. It has high maternal, fetal, and neonatal morbidity and mortality rates. The study of gut microbiota and its metabolites in PE deserves further exploration. Thirty-eight pregnant women with PE and 29 healthy pregnant women in the third trimester of their pregnancy were recruited in this study. We used a targeted metabolomics approach to evaluate the short-chain fatty acids (SCFAs) in serum samples. The correlation between SCFAs and clinical characteristics was also explored. The results of mass spectrometry (MS) showed significant differences at the metabolomics level of SCFAs between the PE and healthy control. The metabolic levels of acetate, propionate, isobutyrate, and valerate were significantly increased in the PE group than in the healthy control group. In contrast, caproic acid and butyrate levels were significantly reduced. The correlation analysis showed that urea, systolic, and diastolic blood pressure levels were positively correlated with four types of SCFAs (acetic acid, propionic acid, isobutyric acid, and valeric acid) which increased in the PE group. Furthermore, the neutrophil percentage and the fetal birth weight were negatively correlated with isobutyric acid and valeric acid. In addition, the receiver operating characteristic (ROC) analysis using a generalized linear model showed that multiple SCFAs would be potential diagnostic markers for PE, with high specificity, sensitivity, and area under the curve (AUC). Among them, isobutyric acid (sensitivity: 97.4%, specificity: 100%, AUC = 1.00), propionic acid (sensitivity: 86.8%, specificity: 93.3%, AUC = 0.954) and acetic acid (sensitivity: 86.8%, specificity: 83.3%, AUC = 0.891) depicted significantly higher diagnostic value and potential clinical applications. In summary, the results of this study indicate that SCFAs have the potential to become effective biomarkers for early screening of PE.

Gastric carcinoma is a frequently detected malignancy worldwide, while its mainstream drugs usually result in some adverse reactions, including immunosuppression. λ-carrageenan oligosaccharides (COS) have attracted increasing attention as potential anticancer agents due to their ability to enhance immune function. Our current work assessed the antitumor mechanism of λ-COS using BGC-823 cells. Our findings indicated that λ-COS alone did not have a significant impact on BGC-823 cells in vitro; however, it was effective in inhibiting tumor growth in vivo. When THP-1 cells were pre-incubated with λ-COS and used to condition the medium, BGC-823 cells in vitro displayed a concentration-dependent induction of cell apoptosis, nuclear damage, and the collapse of mitochondrial transmembrane potential. These findings suggested that the antineoplastic effect of λ-COS was primarily due to its immunoenhancement property. Treatment with λ-COS was found to significantly enhance the phagocytic capability of macrophages, increase the secretion of TNF-α and IFN-γ, and improve the indexes of spleen and thymus in BALB/c mice. In addition, λ-COS was found to inhibit the growth of BGC-823-derived tumors in vitro by activating the Par-4 signaling pathway, which may be stimulated by the combination of TNF-α and IFN-γ. When used in combination with 5-FU, λ-COS demonstrated enhanced anti-gastric carcinoma activity and improved the immunosuppression induced by 5-FU alone. These findings suggested that λ-COS could be used as an immune-modulating agent for chemotherapy.

Abstract Drug therapy of osteoarthritis (OA) is limited by the short retention and lacking of stimulus-responsiveness after intra-articular (IA) injection. The weak acid microenvironment in joint provides a potential trigger for controlled drug release systems in the treatment of OA. Herein, we developed an pH-responsive metal − organic frameworks (MOFs) system modified by hyaluronic acid (HA) and loaded with an anti-inflammatory protocatechuic acid (PCA), designated as MOF@HA@PCA, for the therapy of OA. Results demonstrated that MOF@HA@PCA could smartly respond to acidic conditions in OA microenvironment and gradually release PCA, which could remarkably reduce synovial inflammation in both IL-1β induced chondrocytes and the OA joints. MOF@HA@PCA also down-regulated the expression of inflammatory markers of OA and promoted the expression of cartilage-specific makers. This work may provide a new insight for the design of efficient nanoprobes for precision theranostics of OA .

Abstract Stimulus-responsive therapy permits precise control of therapeutic effect only at lesion of interest, which determines it a promising method for diagnosis and imaging-guided precision therapy. The acid environment and overexpressed matrix metalloproteinases-13 (MMP-13) are typical markers in osteoarthritis (OA), which enables the development of stimulus-responsive drug delivery system with high specificity for OA. We herein demonstrate a nano-micelle based stimuli-responsive theranostic strategy with reporting and drug release controlled by acidic pH and MMP-13 for OA therapy. Such nanoplatform is incorporated with a motif specifically targeting on cartilage, a motif responsive to matrix metalloproteinases-13 to specifically report OA condition and biodynamics of nano-micelles, an anti-inflammatory drug (e.g., psoralidin (PSO)) from traditional Chinese medicine, and a biocompatible polymeric skeleton for sustainable drug release in response to the acidic OA condition. The high effectiveness of this targeted precision therapy is demonstrated comprehensively by both in vitro and vivo evidences.

Abstract Background This study aimed to explore the heterogeneity of circRNA expression pattern via microarray, and further evaluate the potential of 10 specific circRNAs as diagnostic and prognostic biomarkers in multiple myeloma (MM). Methods In exploration stage (stage I), circRNA expression profiles were detected by the microarray in bone marrow plasma cells from 4 MM patients and 4 healthy controls (HCs), and bioinformatic analyses were performed. In validation stage (stage II), top 10 upregulated and top 10 downregulated circRNAs identified in stage I were detected in 60 MM patients and 30 HCs for further validation; the diagnostic and prognostic values of these circRNAs in MM patients were analyzed. Results In stage I, 122 upregulated and 260 downregulated circRNAs were identified in MM patients compared with HCs. GO, KEGG and pathway enrichment analyses revealed that these circRNAs were implicated in neoplastic pathways such as MAPK and VEGF signaling pathways. In stage II, circ-PTK2, circ-RNF217, circ-RERE, circ-NAGPA and circ-KCNQ5 were validated to be upregulated and circ-AFF2, circ-WWC3, circ-DNAJC5, circ-KLHL2, circ-IQGAP1 and circ-AL137655 were validated to be downregulated in MM compared with controls. Circ-PTK2 and circ-RNF217 were correlated with poor treatment response and survival, while circ-AFF2 predicted good treatment response and survival in MM patients. Conclusions This study provides valuable reference for profound understanding about circRNA expression patterns in MM, and validates that circ-PTK2, circ-RNF217 and circ-AFF2 might serve as potential prognostic biomarkers in MM.

Objective: To identify the effect of spirulina supplementation on the immune cells’ indicators of young soccer players during the preparation period of a tournament. Methods: 39 undergraduate male soccer players were recruited and randomly allocated into a spirulina supplementation group (SP group, n = 20) and the placebo supplementation group (PB group, n = 19). Their elbow venous blood samples were collected before and after the preparation period of a tournament, which included 8 weeks total. The differences within the group and between groups were recorded and analyzed. Results: The ratio of the basophils in the SP group between the pre-test and post-test were statistically significantly different (p < 0.05). In the PB group, the percentage of before and after in leukocytes and monocytes were statistically significantly different (p < 0.05). In the data of the post-test, the percentage of monocytes and basophils between the SP group and PB group were statistically significantly different. The delta variations of monocytes between groups were significantly different (p < 0.05). Conclusions: Intense long-duration exercise can reduce the ratio of leukocytes and monocytes in young athletes, yet the spirulina supplement can inhibit the change. It also might improve immunity to parasites, pathogenic bacterium, and rapid-onset allergies.

Our previous study observed that circular RNA protein tyrosine kinase 2 (circ-PTK2) was upregulated and correlated with worse clinical features and unfavorable prognosis in multiple myeloma (MM) patients. Thus, this study aimed to further characterize the regulatory function of circ-PTK2 on cell malignant activities and its target microRNA-638 (miR-638) as well as downstream MEK/ERK, WNT/β-catenin signaling pathways in MM. The effect of circ-PTK2 on MM cell proliferation, apoptosis, migration, invasion and its potential target miRNAs was assessed by transfecting circ-PTK2 overexpression plasmids into U226 cells and circ-PTK2 knock-down plasmids into LP-1 cells. Furthermore, the interaction between circ-PTK2 and miR-638 mediated MEK/ERK and WNT/β-catenin signaling pathways was validated by rescue experiments. Circ-PTK2 was overexpressed in most MM cell lines compared to normal plasma cells. Overexpressing circ-PTK2 promoted proliferation and migration, inhibited apoptosis in U266 cells, but did not affect cell invasion; knocking down circ-PTK2 achieved opposite effect in LP-1 cells. Besides, circ-PTK2 reversely regulated miR-638 expression but not miR-4690, miR-6724, miR-6749 or miR-6775. The following luciferase reporter assay illustrated the direct bind of circ-PTK2 towards miR-638. In rescue experiments, overexpressing miR-638 suppressed proliferation, migration, while promoted apoptosis in both wild U266 cells and circ-PTK2-overexpressed U266 cells; meanwhile, overexpressing miR-638 also suppressed MEK/ERK and WNT/β-catenin pathways in both wild U266 cells and circ-PTK2-overexpressed U266 cells. Knocking down miR-638 achieved opposite effect in both wild LP-1 cells and circ-PTK2-knocked-down LP-1 cells. In conclusion, circ-PTK2 promotes cell proliferation, migration, suppresses cell apoptosis via miR-638 mediated MEK&ERK and WNT&β-catenin signaling pathways in MM.

The Bangiales represent an ancient lineage within red algae that are characterized by a life history featuring a special transitional stage from diploid to haploid known as the conchosporangia stage. However, the regulatory mechanisms governing the initiation of this stage by changes in environmental conditions are not well understood. This study analyzed the changes in phytohormones and H2O2 content during the development of conchosporangia. It also compared the gene expression changes in the early development of conchosporangia through transcriptome analysis. The findings revealed that H2O2 was shown to be the key signal initiating the transition from conchocelis to conchosporangia in Pyropia haitanensis. Phytohormone analysis showed a significant increase in 1- aminocylopropane-1-carboxylic acid (ACC) levels during conchosporangia maturation, while changes in environmental conditions were found to promote the rapid release of H2O2. H2O2 induction led to conchosporangia development, and ACC enhanced both H2O2 production and conchosporangia development. This promotive effect was inhibited by the NADPH oxidase inhibitor diphenylene iodonium and the H2O2 scavenger N, N'-dimethylthiourea. The balance of oxidative-antioxidative mechanisms was maintained by regulating the activities and transcriptional levels of enzymes involved in H2O2 production and scavenging. Transcriptome analysis in conjunction with evaluation of enzyme and transcription level changes revealed upregulation of protein and sugar synthesis along with modulation of energy supply under the conditions that induced maturation, and exogenous ACC was found to enhance the entire process. Overall, this study demonstrates that ACC enhances H2O2 promotion of the life cycle switch responsible for the transition from a vegetative conchocelis to a meiosispreceding conchosporangia stage in Bangiales species. [ABSTRACT FROM AUTHOR]

Abstract Background The heteroside floridoside is a primary photosynthetic product that is known to contribute to osmotic acclimation in almost all orders of Rhodophyta. However, the encoding genes and enzymes responsible for the synthesis of floridoside and its isomeric form, l- or d-isofloridoside, are poorly studied. Results Here, four putative trehalose-6-phosphate synthase (TPS) genes, designated as PhTPS1, PhTPS2, PhTPS3, and PhTPS4, were cloned and characterized from the red alga Pyropia haitanensis (Bangiophyceae). The deduced amino acid sequence is similar to the annotated TPS proteins of other organisms, especially the UDP-galactose substrate binding sites of PhTPS1, 2, which are highly conserved. Of these, PhTPS1, 4 are involved in the biosynthesis of floridoside and isofloridoside, with isofloridoside being the main product. PhTPS3 is an isofloridoside phosphate synthase, while PhTPS2 exhibits no activity. When challenged by desiccation, high temperature, and salt stress, PhTPS members were expressed to different degrees, but the responses to thermal stress and desiccation were stronger. Conclusions Thus, in P. haitanensis, PhTPSs encode the enzymatical activity of floridoside and isofloridoside phosphate synthase and are crucial for the abiotic stress defense response.

Abstract Background SLC25A22, a member of mitochondrial carrier system (MCS) family encoding a mitochondrial glutamate transporter, has been reported to have vital roles in promoting proliferation and migration in cancer. Gallbladder cancer (GBC) is the most common biliary tract malignancy and has a poor prognosis. We aimed to determine the expression and function of SLC25A22 in GBC. Methods Immunohistochemistry (IHC) staining analysis and quantitative real-time PCR (qRT-PCR) were conducted to determine the expression of SLC25A22 in GBC tissues. Human NOZ and GBC-SD cells were used to perform the experiments. The protein expression was detected by western-blot analysis. Cell viability was evaluated via CCK-8 assay and colony formation assay. Cell migration and invasion in vitro were investigated by wound healing and transwell assay. Annexin V/PI staining assay for apoptosis were measured by flow cytometry. The effect of SLC25A22 in vivo was conducted with subcutaneous xenograft. Results We indicated that the expression of SLC25A22 was significantly upregulated in GBC tumor tissues as well as cell lines. Downregulation of SLC25A22 inhibited GBC cell growth and proliferation in vitro and in vivo and also had an effect on metastasis of GBC cells through the EMT processes. In addition, inhibition of SLC25A22 promoted mitochondrial apoptosis via downregulating BCL-2 and upregulating cleaved PARP, Cytochrome-c, and BAX mediated by MAPK/ERK pathway. Conclusions Our study identified that SLC25A22 promoted development of GBC activating MAPK/ERK pathway. SLC25A22 has a potential to be used as a target for cancer diagnosis of GBC and related therapies.

Abstract Background Hepatic portal vein gas (HPVG) is a rare acute abdomen, which is not an independent disease. Meanwhile, HPVG combined with appendicitis has been rarely reported. We found only a similar report by looking for literature, but no intestinal necrosis occurred. We report a patient with HPVG, appendicitis and intestinal necrosis was reported in the current study. The patient was given frequent monitoring and had been conducted operation in time. Case presentation An 86-year-old female with appendicitis complicated by HPVG was reported in the present study. Abdominal examination revealed rebound tenderness at the McBurney’s point. Moreover, abdominal computed tomography (CT) revealed gas in portal and mesenteric veins in addition to appendicitis. An emergency operation was planned on the appendix. However, the patient refused surgical treatment. Therefore, conservative treatment of antibiotics and frequent imaging observation was conducted for this patient. Although imaging results suggested disappeared gas in intra- and extra-hepatic portal veins, the small intestine was dilated, after conservative treatment of antibiotics. In addition, signs of diffused peritonitis could also be observed and an exploratory laparotomy was performed. Intra-operative findings had confirmed suppurated appendix, mesenteric ischemia and small intestinal necrosis. Conclusions Frequent monitoring benefits us in observing the progress of intestinal diseases. When there exist other possible causes of HPVG such as infection, it is not easy for us to ignore the possibility of intestinal necrosis.

Abstract Background Short chain oxylipins in plants as the main volatile organic carbon have been speculated to playing an important role for plant innate immunity, however, not yet intensively studied and far away established as the fully recognized algae defense signals. Results The production of 1-octen-3-ol is self-amplified via the fatty acid-oxylipin metabolic cycle through positive feedback loop. Production of 1-octen-3-ol may act as a messenger that induces P. haitanensis to be in a “primed” state and ready for defense by upregulating the synthesis of methyl jasmonic acid, indole-3-acetic acid, and gibberellin A3. Production of these oxylipins also adjust the redox state in cells, resulting in host defense activation. Conclusions We provide the first demonstration that 1-octen-3-ol from P. haitanensis, can act as a self-stimulating community messenger. The multiple effects of 1-octen-3-ol may explain why P. haitanensis, a very ancient lineage within plant kingdom, thrives in the niche of intertidal zones.

As the most abundant marine carotenoid extracted from seaweeds, fucoxanthin is considered to have neuroprotective activity via its excellent antioxidant properties. Oxidative stress is regarded as an important starting factor for neuronal cell loss and necrosis, is one of the causes of Parkinson’s disease (PD), and is considered to be the cause of adverse reactions caused by the current PD commonly used treatment drug levodopa (l-DA). Supplementation with antioxidants early in PD can effectively prevent neurodegeneration and inhibit apoptosis in dopaminergic neurons. At present, the effect of fucoxanthin in improving the adverse effects triggered by long-term l-DA administration in PD patients is unclear. In the present study, we found that fucoxanthin can reduce cytotoxicity and suppress the high concentration of l-DA (200 μM)-mediated cell apoptosis in the 6-OHDA-induced PC12 cells through improving the reduction in mitochondrial membrane potential, suppressing ROS over-expression, and inhibiting active of ERK/JNK-c-Jun system and expression of caspase-3 protein. These results were demonstrated by PD mice with long-term administration of l-DA showing enhanced motor ability after intervention with fucoxanthin. Our data indicate that fucoxanthin may prove useful in the treatment of PD patients with long-term l-DA administration.

Abstract In vitro expansion of mesenchymal stem cells (MSCs) has been implicated in loss of multipotency, leading to impaired chondrogenic potential and an eventual therapeutic effect, as reported in our previous study. However, the precise regulatory mechanism is still unclear. Here, we demonstrate that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were involved in transformation of MSCs induced by in vitro culture based on the comparative profiling of in vitro cultured bone marrow MSCs at passage 3 (P3 BMSCs) vs. fresh P0 BMSCs by microarray analysis. Indeed, RT-PCR and Western blot analysis showed significantly lower expression levels of three key UPR-related molecules, ATF4, ATF6 and XBP1, in P3 BMSCs than P0 BMSCs. Further, we found that UPR suppression by 4-phenylbutyrate (4-PBA) reduced the chondrogenic potential of P0 BMSCs and further cartilage regeneration. Conversely, UPR induction by tunicamycin (TM) enhanced the chondrogenic differentiation of P3 BMSCs and the therapeutic effect on cartilage repair. Thus, the decline in the chondrogenic potential of stem cells after in vitro culture and expansion may be due to changes in ER stress and the UPR pathway.

Floridoside is a low-molecular-weight organic compound, which can be accumulated by red algae under stressful conditions to protect cells via its excellent antioxidant properties. In the present study, we investigated the antioxidant mechanism of floridoside toward human hepatocyte L-02 cells. We found that floridoside had no toxicity to L-02 cells, and no reactive oxidative species were induced by it either. However, the expression of hemoxygenase-1 (HO-1) protein was up-regulated upon exposure to floridoside, and two antioxidant enzymes, superoxide dismutase (SOD) and GSH-Px, were activated by floridoside. Moreover, we investigated the pathway involved in the production of these antioxidants, p38/extracellular signal-regulated kinase (ERK) MAPK-nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway. ERK1/2 and p38 phosphorylation, nuclear translocation of Nrf2, and activation of ARE luciferase activity were observed upon exposure to floridoside. siRNA interference and inhibitor treatment suppressed the HO-1 expression and the phosphorylation of ERK1/2 and p38, respectively. These results indicated that floridoside exerted its antioxidant activity by activating HO-1 expression via p38/ERK MAPK-Nrf2 pathway in human hepatocyte L-02 cells.

The Mediator complex is at the core of transcriptional regulation and plays a central role in plant immunity. The MEDIATOR25 (MED25) subunit of Arabidopsis thaliana regulates jasmonate-dependent resistance to Botrytis cinerea through interacting with the basic helix-loop-helix (bHLH) transcription factor of jasmonate signaling, MYC2. Another Mediator subunit, MED8, acts independently or together with MED25 in plant immunity. However, unlike MED25, the underlying action mechanisms of MED8 in regulating B. cinerea resistance are still unknown. Here, we demonstrated that MED8 regulated plant immunity to B. cinerea through interacting with another bHLH transcription factor, FAMA, which was previously shown to control the final proliferation/differentiation switch during stomatal development. Our research demonstrates that FAMA is also an essential component of B. cinerea resistance. The fama loss-of-function mutants (fama-1 and fama-2) increased susceptibility to B. cinerea infection and reduced defense-gene expression. On the contrary, transgenic lines constitutively overexpressing FAMA showed opposite B. cinerea responses compared with the fama loss-of-function mutants. FAMA-overexpressed plants displayed enhanced resistance to B. cinerea infection and increased expression levels of defensin genes following B. cinerea treatment. Genetic analysis of MED8 and FAMA suggested that FAMA-regulated pathogen resistance was dependent on MED8. In addition, MED8 and FAMA were both associated with the G-box region in the promoter of ORA59. Our findings indicate that the MED8 subunit of the A. thaliana Mediator regulates plant immunity to B. cinerea through interacting with the transcription factor FAMA, which was discovered to be a key component in B. cinerea resistance.