A conserved protein inhibitor brings under check the activity of RNase E in cyanobacteria.

The bacterial ribonuclease RNase E plays a key role in RNA metabolism. Yet, with a large substrate spectrum and poor substrate specificity, its activity must be well controlled under different conditions. Only a few regulators of RNase E are known, limiting our understanding on posttranscriptional regulatory mechanisms in bacteria. Here we show that, RebA, a protein universally present in cyanobacteria, interacts with RNase E in the cyanobacterium Anabaena PCC 7120. Distinct from those known regulators of RNase E, RebA interacts with the catalytic region of RNase E, and suppresses the cleavage activities of RNase E for all tested substrates. Consistent with the inhibitory function of RebA on RNase E, depletion of RNase E and overproduction of RebA caused formation of elongated cells, whereas the absence of RebA and overproduction of RNase E resulted in a shorter-cell phenotype. We further showed that the morphological changes caused by altered levels of RNase E or RebA are dependent on their physical interaction. The action of RebA represents a new mechanism, potentially conserved in cyanobacteria, for RNase E regulation. Our findings provide insights into the regulation and the function of RNase E, and demonstrate the importance of balanced RNA metabolism in bacteria.

A c-di-GMP binding effector controls cell size in a cyanobacterium.

Cyclic-di-GMP (c-di-GMP) is a ubiquitous bacterial signaling molecule. It is also a critical player in the regulation of cell size and cell behaviors such as cell aggregation and phototaxis in cyanobacteria, which constitute an important group of prokaryotes for their roles in the ecology and evolution of the Earth. However, c-di-GMP receptors have never been revealed in cyanobacteria. Here, we report the identification of a c-di-GMP receptor, CdgR, from the filamentous cyanobacterium Anabaena PCC 7120. Crystal structural analysis and genetic studies demonstrate that CdgR binds c-di-GMP at the dimer interface and this binding is required for the control of cell size in a c-di-GMP-dependent manner. Different functions of CdgR, in ligand binding and signal transmission, could be separated genetically, allowing us to dissect its molecular signaling functions. The presence of the apo-form of CdgR triggers cell size reduction, consistent with the similar effects observed with a decrease of c-di-GMP levels in cells. Furthermore, we found that CdgR exerts its function by interacting with a global transcription factor DevH, and this interaction was inhibited by c-di-GMP. The lethal effect triggered by conditional depletion of DevH or by the production of several point-mutant proteins of CdgR in cells indicates that this signaling pathway plays critical functions in Anabaena. Our studies revealed a mechanism of c-di-GMP signaling in the control of cell size, an important and complex trait for bacteria. CdgR is highly conserved in cyanobacteria, which will greatly expand our understanding of the roles of c-di-GMP signaling in these organisms.

A proteolytic pathway coordinates cell division and heterocyst differentiation in the cyanobacterium Anabaena sp. PCC 7120.

The filamentous, multicellular cyanobacterium Anabaena sp. PCC 7120 (Anabaena) is a prokaryotic model for the study of cell differentiation and cell-cell interactions. Upon combined-nitrogen deprivation, Anabaena forms a particular cell type, heterocyst, for aerobic nitrogen fixation. Heterocysts are semiregularly spaced among vegetative cells. Heterocyst differentiation is coupled to cell division, but the underlying mechanism remains unclear. This mechanism could be mediated by the putative protease HetF, which is a divisome component and is necessary for heterocyst differentiation. In this study, by suppressor screening, we identified PatU3, as a negative regulator acting downstream of HetF for cell division and heterocyst development. The inactivation of patU3 restored the capacity of cell division and heterocyst differentiation in the ΔhetF mutant, and overexpression of patU3 inhibited both processes in the wild-type background. We demonstrated that PatU3 was a specific substrate of the protease activity of HetF. Consequently, PatU3 accumulated in the hetF-deficient mutant, which was responsible for the resultant mutant phenotype. The cleavage site of PatU3 by HetF was mapped after the Arg117 residue, whose mutation made PatU3 resistant to HetF processing, and mimicked the effect of hetF deletion. Our results provided evidence that HetF regulated cell division and heterocyst differentiation by controlling the inhibitory effects of PatU3. This proteolytic pathway constituted a mechanism for the coordination between cell division and differentiation in a prokaryotic model used for studies on developmental biology and multicellularity.

Computational models, databases and tools for antibiotic combinations.

Antibiotic combination is a promising strategy to extend the lifetime of antibiotics and thereby combat antimicrobial resistance. However, screening for new antibiotic combinations is both time-consuming and labor-intensive. In recent years, an increasing number of researchers have used computational models to predict effective antibiotic combinations. In this review, we summarized existing computational models for antibiotic combinations and discussed the limitations and challenges of these models in detail. In addition, we also collected and summarized available data resources and tools for antibiotic combinations. This study aims to help computational biologists design more accurate and interpretable computational models.

Identification of Robust Antibiotic Subgroups by Integrating Multi-Species Drug-Drug Interactions.

Previous studies have shown that antibiotics can be divided into groups, and drug-drug interactions (DDI) depend on their groups. However, these studies focused on a specific bacteria strain (i.e., Escherichia coli BW25113). Existing datasets often contain noise. Noisy labeled data may have a bad effect on the clustering results. To address this problem, we developed a multi-source information fusion method for integrating DDI information from multiple bacterial strains. Specifically, we calculated drug similarities based on the DDI network of each bacterial strain and then fused these drug similarity matrices to obtain a new fused similarity matrix. The fused similarity matrix was combined with the T-distributed stochastic neighbor embedding algorithm, and hierarchical clustering algorithm can effectively identify antibiotic subgroups. These antibiotic subgroups are strongly correlated with known antibiotic classifications, and group-group interactions are almost monochromatic. In summary, our method provides a promising framework for understanding the mechanism of action of antibiotics and exploring multi-species group-group interactions.

[Application of traditional Chinese medicine theory in modern traditional Chinese medicine nano-preparation: taking tumor treatment as an example].

With Zang-Fu organs, meridians, Qi and blood, and body fluid as the physiological and pathological basis, traditional Chinese medicine(TCM) theory is guided by the holistic concept and characterized by syndrome differentiation. It has made significant contributions to human health maintenance and disease prevention. Modern TCM preparation is developed on the basis of inheriting and developing TCM preparations using modern science and technology under the guidance of TCM theory. At present, the incidence and mortality of common tumors are increasing. TCM has rich clinical experience in the treatment of tumors. However, in the current stage, some TCM preparations have a tendency to deviate from the guidance of TCM theory. With the modernization of TCM, it is worth considering how TCM theory guides modern TCM preparations. Taking tumor treatment as an example, this paper introduced the development of TCM nano-preparation under the influence of modern nanotechnology, summarized the research on the development of modern TCM nano-preparation from the aspects of TCM holistic concept, TCM treatment principles, and TCM theory application, and discussed the application prospect of TCM nano-preparation in overall therapy, drug pairing, carrier selection, and targeted substance selection under the guidance of TCM theory. This paper provides new references for further developing the combination of tradition and modernization of TCM nano-preparation.

The developmental regulator PatD modulates assembly of the cell-division protein FtsZ in the cyanobacterium Anabaena sp. PCC 7120.

FtsZ is a tubulin-like GTPase that polymerizes to initiate the process of cell division in bacteria. Heterocysts are terminally differentiated cells of filamentous cyanobacteria that have lost the capacity for cell division and in which the ftsZ gene is downregulated. However, mechanisms of FtsZ regulation during heterocyst differentiation have been scarcely investigated. The patD gene is NtcA dependent and involved in the optimization of heterocyst frequency in Anabaena sp. PCC 7120. Here, we report that the inactivation of patD caused the formation of multiple FtsZ-rings in vegetative cells, cell enlargement, and the retention of peptidoglycan synthesis activity in heterocysts, whereas its ectopic expression resulted in aberrant FtsZ polymerization and cell division. PatD interacted with FtsZ, increased FtsZ precipitation in sedimentation assays, and promoted the formation of thick straight FtsZ bundles that differ from the toroidal aggregates formed by FtsZ alone. These results suggest that in the differentiating heterocysts, PatD interferes with the assembly of FtsZ. We propose that in Anabaena FtsZ is a bifunctional protein involved in both vegetative cell division and regulation of heterocyst differentiation. In the differentiating cells PatD-FtsZ interactions appear to set an FtsZ activity that is insufficient for cell division but optimal to foster differentiation.

Discovery of novel indolin-2-one compounds as potent inhibitors of HsClpP for cancer treatment.

Human caseinolytic protease proteolytic subunit (HsClpP) is a highly conserved serine protease that plays an essential role in cell homeostasis through removal of the damaged and/or misfolded proteins. Recently, due to its critical role in cancer proliferation and metastasis, HsClpP has been considered as a promising target for the cancer treatment. In this paper, through a random screening toward a library of 2086 bioactive chemicals, a novel compound I, 3-(3,5-dibromo-4-hydroxybenzylidene) -5-iodoindolin-2-one, was identified as a potent suppressor of HsClpP. Herein, a series of compound I derivatives were synthesized, and evaluated for their anti-cancer activities on a variety of cancers cells. Through the preliminary biological assay in vitro, including MTT assay and proteolytic activity assay, compound I was identified as the most potent inhibitor. Treatment with compound I impaired the migration of Hela cells. In addition, compound I disrupted the mitochondrial function, and reduced the level of the SDHB and induced the production of the ATF4. In general, compound I is a promising probe of HsClpP for cancer treatment, and is a good lead compound for the development of novel anti-cancer agent.

Coordinating carbon and nitrogen metabolic signaling through the cyanobacterial global repressor NdhR.

The coordination of carbon and nitrogen metabolism is essential for bacteria to adapt to nutritional variations in the environment, but the underlying mechanism remains poorly understood. In autotrophic cyanobacteria, high CO2 levels favor the carboxylase activity of ribulose 1,5 bisphosphate carboxylase/oxygenase (RuBisCO) to produce 3-phosphoglycerate, whereas low CO2 levels promote the oxygenase activity of RuBisCO, leading to 2-phosphoglycolate (2-PG) production. Thus, the 2-PG level is reversely correlated with that of 2-oxoglutarate (2-OG), which accumulates under a high carbon/nitrogen ratio and acts as a nitrogen-starvation signal. The LysR-type transcriptional repressor NAD(P)H dehydrogenase regulator (NdhR) controls the expression of genes related to carbon metabolism. Based on genetic and biochemical studies, we report here that 2-PG is an inducer of NdhR, while 2-OG is a corepressor, as found previously. Furthermore, structural analyses indicate that binding of 2-OG at the interface between the two regulatory domains (RD) allows the NdhR tetramer to adopt a repressor conformation, whereas 2-PG binding to an intradomain cleft of each RD triggers drastic conformational changes leading to the dissociation of NdhR from its target DNA. We further confirmed the effect of 2-PG or 2-OG levels on the transcription of the NdhR regulon. Together with previous findings, we propose that NdhR can sense 2-OG from the Krebs cycle and 2-PG from photorespiration, two key metabolites that function together as indicators of intracellular carbon/nitrogen status, thus representing a fine sensor for the coordination of carbon and nitrogen metabolism in cyanobacteria.

[Analysis on quality value transmitting of substance benchmark of Houpo Wenzhong Decoction].

By preparing 15 batches of lyophilized powder samples of substance benchmark in Houpo Wenzhong Decoction,the fingerprint,index component content and extract rate were determined,and the characteristic peaks,the range of similarity with the reference map,the content range and transfer rate range of magnolol,hesperidin,glycyrrhizic acid and pinocembrin,the extract rate range and the change range were clarified. The results showed that the similarity between the fingerprint of substance benchmark and the reference map R generated from the 15 batches of substance benchmark samples was higher than 0. 90. The assignment of the characteristic peaks in the full prescription's fingerprint of the herbs except Poria cocos was clarified. Nineteen characteristic peaks were assigned,and 12 characteristic peaks were assigned by the reference substance,of which 4 were from Magnolia ocinalis Cortex,5 from Exocarpium Citri Rubrum,2 from Radix aucklandiae,3 from Glycyrrhiza Radix et Rhizoma,4 from Semen Alpiniae Katsumadai,and one from Rhizoma Zingiberis and Zingiber officinale Roscoe. The index component content range and transfer rate range were 0. 80%-1. 14% and 20. 25%-39. 61% for hesperidin,0. 49%-0. 79% and 23. 09%-33. 87%for glycyrrhizic acid,0. 03%-0. 07% and 3. 55%-10. 09% for pinocembrin,0. 15%-0. 38% and 8. 08%-24. 35% for magnolol. The extract rate range and the change range were22. 60%-25. 57% and 12. 67%-23. 68% respectively. In this study,we introduced the concepts of index component content,fingerprint,extract rate,explored the transfer relation of quality value transmitting of substance benchmark in Houpo Wenzhong Decoction,and initially established the quality standard of Houpo Wenzhong Decoction,all of which would provide ideas for the development and research of similar prescriptions.

A numerical simulation method of natural fragment formation and injury to human thorax.

OBJECTIVE: Fragment injury is a type of blast injury that is becoming more and more common in military campaigns and terrorist attacks. Numerical simulation methods investigating the formation of natural fragments and injuries to biological targets are expected to be developed. METHODS: A cylindrical warhead model was established and the formation process of natural fragments was simulated using the approach of tied nodes with failure through the explicit finite element (FE) software of LS-DYNA. The interaction between the detonation product and the warhead shell was simulated using the fluid-structure interaction algorithm. A method to simulate the injury of natural fragments to a biological target was presented by transforming Lagrange elements into smooth particle hydrodynamics (SPH) particles after the natural fragments were successfully formed. A computational model of the human thorax was established to simulate the injury induced by natural fragments by the node-to-surface contact algorithm with erosion. RESULTS: The discontinuous velocities of the warhead shell at different locations resulted in the formation of natural fragments with different sizes. The velocities of natural fragments increased rapidly at the initial stage and slowly after the warhead shell fractured. The initial velocities of natural fragments at the central part of the warhead shell were the largest, whereas those at both ends of the warhead shell were the smallest. The natural fragments resulted in bullet holes that were of the same shape as that of the fragments but slightly larger in size than the fragments in the human thorax after they penetrated through. Stress waves propagated in the ribs and enhanced the injury to soft tissues; additionally, ballistic pressure waves ahead of the natural fragments were also an injury factor to the soft tissues. CONCLUSION: The proposed method is effective in simulating the formation of natural fragments and their injury to biological targets. Moreover, this method will be beneficial for simulating the combined injuries of natural fragments and shock waves to biological targets.

[HPLC fingerprint of famous traditional formula Sanpian Decoction and quality value transmitting of Chuanxiong Rhizoma].

Famous traditional formula Sanpian Decoction(SPD)comes from Dialectical Records of Chen Shiduo of the Qing Dynasty,and ranks among 100 classic prescriptions of Classic Famous Traditional Formula catalogue(the First Batch). SPD was prepared according to Management Standards for Traditional Chinese Medicine Decoction Room in Medical Institutions. According to the polarity of different components in SPD,two HPLC fingerprints were established, in which six herbs, namely Chuanxiong Rhizoma, Paeoniae Randix Alba, Sinapis Semen, Glycyrrhizae Radix et Rhizoma, Pruni Semen, Angelicae Dahuricae Radix,are all reflected in the fingerprints; The dry extract rate, transfer rate and similarities of fingerprints were used as indicators to study the relationship between the quality value transmitting of medicinal herbs-decoction pieces-whole decoction of Chuanxiong Rhizoma. Experiment result shows that,the transfer rate of ferulic acid from medicinal herbs to decoction pieces is between 72.00% and 108.36%; the transfer rate of ferulic acid from decoction pieces to SPD is between 31.76% and 64.09%; the dry extract rate of the whole decoction is between 14.69% and 20.16%;The similarity range of fingerprint 1 of 15 batches of SPD is between 0.971 and 0.998, and the similarity range of fingerprint 2 is between 0.980 and 0.996. The established fingerprint has rich information,and the established quality evaluation method is suitable for the quality control of medicinal herbs-decoction pieces-whole decoction of Chuanxiong Rhizoma, which can provide a certain reference for developing the quality control evaluation method for formulated granules, famous formulae and other terminal products derived from traditional Chinese medicine decoction.

patD, a Gene Regulated by NtcA, Is Involved in the Optimization of Heterocyst Frequency in the Cyanobacterium Anabaena sp. Strain PCC 7120.

In the filamentous multicellular cyanobacterium Anabaena sp. strain PCC 7120, 5 to 10% of the cells differentiate into heterocysts, which are specialized in N2 fixation. Heterocysts and vegetative cells are mutually dependent for filament growth through nutrient exchange. Thus, the heterocyst frequency should be optimized to maintain the cellular carbon and nitrogen (C/N) balance for filament fitness in the environment. Here, we report the identification of patD, whose expression is directly activated in developing cells by the transcription factor NtcA. The inactivation of patD increases heterocyst frequency and promotes the upregulation of the positive regulator of heterocyst development hetR, whereas its overexpression decreases the heterocyst frequency. The change in heterocyst frequency resulting from the inactivation of patD leads to the reduction in competitiveness of the filaments under combined-nitrogen-depleted conditions. These results indicate that patD regulates heterocyst frequency in Anabaena sp. PCC 7120, ensuring its optimal filament growth.IMPORTANCE Microorganisms have evolved various strategies in order to adapt to the environment and compete with other organisms. Heterocyst differentiation is a prokaryotic model for studying complex cellular regulation. The NtcA-regulated gene patD controls the ratio of heterocysts relative to vegetative cells on the filaments of Anabaena sp. strain PCC 7120. Such a regulation provides a mechanism through which carbon fixation by vegetative cells and nitrogen fixation by heterocysts are properly balanced to ensure optimal growth and keep a competitive edge for long-term survival.

[Study on benchmark preparation technology of boiled and powdered classical prescriptions by taking Houpo Wenzhong Decoction as an example].

In recent years,the development and application of classical famous prescriptions have attracted much attention. However,the differences between ancient and modern conditions lead to difficulties in carrying out practical work. In this paper,with Houpu Wenzhong Decoction as an example,the key technologies of boiling granularity,water addition,boiling time and sample pretreatment methods were investigated on the basis of sufficient literature research. The experimental results showed that there was no significant difference in the concentration of index components between those with different granularity( 2 mm and 3-5 mm) and different decocting time( 30 min and 60 min),but the extraction rate of index components was relatively high when the granularity of powder was 2 mm and decocting time was 30 min. With the increase of water content,the concentration of index components and the extraction rate were increased in varying degrees. A certain proportion of methanol aqueous solution was used as the resolvent before content determination of the reference sample of Houpu Wenzhong Decoction,which could take into account both the spectral information of water-soluble components and fat-soluble components in the prescription,and help to display the overall information of the prescription' s chemical components more comprehensively. At the same time,the boiling and dispersing classical prescriptions in the Catalogue of Ancient Classical Prescriptions( the first batch) were collected and summarized in this study; the key influencing factors of decocting process were analyzed from different angles,and preliminary research suggestions were put forward,so as to provide a certain direction and reference for the establishment of quality standard of Houpu Wenzhong Decoction,as well as for the development,research and clinical application of boiling and dispersing classical prescriptions.

[Analysis on quality value transmitting of substance benchmarks of Linggui Zhugan Decoction].

By preparing 10 batches of the material reference of Linggui Zhugan Decoction,the methodology of the characteristic spectrum of the material reference was created. The creaming rate range,the contents and the transfer rate range of cinnamaldehyde,glycyrrhizin and glycyrrhizic acid,the characteristic peaks and the similarity range of the characteristic spectrum of Linggui Zhugan Decoction were determined to clarify key quality attributes of the material reference of Linggui Zhugan Decoction. In the 10 batches of the material reference of Linggui Zhugan Decoction,the similarity of characteristic spectrum was higher than 0. 9. Furthermore,after summarizing the characteristic peak information,we knew that Fuling had two characteristic peaks,Guizhi had six characteristic peaks,Baizhu had two characteristic peaks and Gancao had 11 characteristic peaks. The average creaming rate of the material reference of the ten batches was( 12. 13 ± 0. 35) %. The average content of cinnamaldehyde was 0. 32%,the average transfer rate was 10. 69%,the content of cinnamaldehyde in the different batches was between 0. 22% and 0. 42%,and the transfer rate was between 7. 48% and13. 90%. The average content of glycyrrhizin was 0. 84%,the average transfer rate was 50. 39%,the content of glycyrrhizin in the different batches was between 0. 42% and 1. 26%,and the transfer rate was between 35. 27% and 65. 51%. The average content of glycyrrhizic was 1. 88%,the average transfer rate was 40. 74%,the content of glycyrrhizic in the different batches was between 0. 94% and2. 82%,and the transfer rate was between 28. 52% and 52. 96%. In this paper,the quality value transmitting of substance benchmarks of Linggui Zhugan Decoction was analyzed by the combination of characteristic spectrum,creaming rate and the content of index component. A scientific and stable method was preliminarily established,which provided scientific basis for the quality control and formulation development of Linggui Zhugan Decoction.

Design, synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis.

In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H37Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated forin vitrostudies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H37Ra, respectively.

RNase E forms a complex with polynucleotide phosphorylase in cyanobacteria via a cyanobacterial-specific nonapeptide in the noncatalytic region.

RNase E, a central component involved in bacterial RNA metabolism, usually has a highly conserved N-terminal catalytic domain but an extremely divergent C-terminal domain. While the C-terminal domain of RNase E in Escherichia coli recruits other components to form an RNA degradation complex, it is unknown if a similar function can be found for RNase E in other organisms due to the divergent feature of this domain. Here, we provide evidence showing that RNase E forms a complex with another essential ribonuclease-the polynucleotide phosphorylase (PNPase)-in cyanobacteria, a group of ecologically important and phylogenetically ancient organisms. Sequence alignment for all cyanobacterial RNase E proteins revealed several conserved and variable subregions in their noncatalytic domains. One such subregion, an extremely conserved nonapeptide (RRRRRRSSA) located near the very end of RNase E, serves as the PNPase recognition site in both the filamentous cyanobacterium Anabaena PCC7120 and the unicellular cyanobacterium Synechocystis PCC6803. These results indicate that RNase E and PNPase form a ribonuclease complex via a common mechanism in cyanobacteria. The PNPase-recognition motif in cyanobacterial RNase E is distinct from those previously identified in Proteobacteria, implying a mechanism of coevolution for PNPase and RNase E in different organisms.

Mechanism of enhanced oral absorption of morin by phospholipid complex based self-nanoemulsifying drug delivery system.

Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.

Antidepressant activity of astilbin: involvement of monoaminergic neurotransmitters and BDNF signal pathway.

Depression and related mood disorders are among the world's greatest public health problems. Previous studies have demonstrated that astilbin (AST) has broad pharmacological functions which may modulate numerous pathways, such as antioxidant, scavenging free radicals, anti-inflammatory and so on, similarly to some of other flavonoids. In this study, the antidepressant-like effect of AST was investigated using chronic unpredictable mild stress (CUMS) model of depression in mice. The results showed that chronic administration of AST at doses of 10, 20 and 40 mg/kg (intraperitoneally (i.p.), 21 d) reduced depressive-like behaviors of mice in the forced swim test (FST), tail suspension test (TST) and sucrose preference test (SPT) without affecting locomotor activity. AST increased the contents of serotonin (5-HT) and dopamine (DA) in the frontal cortex of CUMS mice. Additionally, it was shown that AST treatment restored the CUMS-induced inhibition of extracellular signal-regulated kinase (ERK) 1/2 and AKT phosphorylation in the frontal cortex, conformed to the brain-derived neurotrophic factor (BDNF) expression. Our findings suggest that AST has antidepressant activities and the mechanisms, at least in part, relate to up-regulation of monoaminergic neurotransmitters (5-HT and DA) and activation of the BDNF signaling pathway.

Sarcopenia in systemic sclerosis: prevalence and impact-a systematic review and meta-analysis.

OBJECTIVE: This review aims to provide an estimate of sarcopenia prevalence and its impact on clinical characteristics in patients with systemic sclerosis (SSc). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Embase, Medline, Web of Science and the Cochrane Central Register of Controlled Trials were systemically searched from inception to 24 May 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included observational studies that reported the prevalence of sarcopenia in patients with SSc. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently performed study selection and data extraction using standardised methods. Risk of bias was assessed using the Agency for Healthcare Research and Quality Scale and the Newcastle-Ottawa Scale. Meta-analysis was conducted using random effects models. RESULTS: A total of 4583 articles were screened and 9 studies with data from 815 patients were included in the analysis (8 cross-sectional studies and 1 retrospective cohort study). The overall prevalence of sarcopenia in patients with SSc was 22% (95% CI 17% to 28%). Patients with SSc with sarcopenia had a poorer quality of life (mean difference -12.02; 95% CI -19.11 to -4.93) and higher C reactive protein (CRP) levels (standardised mean difference 0.67; 95% CI 0.35 to 1.00). CONCLUSIONS: Sarcopenia is common in patients with SSc. Patients with SSc with sarcopenia had a worse quality of life and higher CRP levels, based on our findings. Given the detrimental impact of sarcopenia on quality of life, future efforts aimed at early identification of sarcopenia in the clinical assessment of patients with SSc may have significance. PROSPERO REGISTRATION NUMBER: CRD42022368326.