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Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug development targeting the PAFR has been limited, partly due to an incomplete understanding of its activation mechanism. Here, we present a 2.9-Å structure of the PAF-bound PAFR-G i complex. Structural and mutagenesis analyses unveil a specific binding mode of PAF, with the choline head forming cation-π interactions within PAFR hydrophobic pocket, while the alkyl tail penetrates deeply into an aromatic cleft between TM4 and TM5. Binding of PAF modulates conformational changes in key motifs of PAFR, triggering the outward movement of TM6, TM7, and helix 8 for G protein coupling. Molecular dynamics simulation suggests a membrane-side pathway for PAF entry into PAFR via the TM4-TM5 cavity. By providing molecular insights into PAFR signaling, this work contributes a foundation for developing therapeutic interventions targeting PAF signal axis. [Display omitted] • 2.9-Å Cryo-EM structure of the PAFR-G i complex activated by PAF • The choline head of PAF forms cation-π interactions within a hydrophobic pocket in PAFR • A membrane-side pathway for PAF entry into PAFR revealed by computational simulation Fan et al. presents the 2.9-Å cryo-EM structure of platelet-activating factor receptor PAFR-G i complex bound to PAF, which reveals the specific binding mode of PAF within PAFR. Structural and computational analyses provide insights into PAFR activation and a membrane entry pathway for PAF to PAFR via the TM4-TM5 cleft. [ABSTRACT FROM AUTHOR]

In this study, we conducted in vitro fermentation with infant faecal inocula dominated by Bifidobacterium longum , Bifidobacterium breve , and Bacteroides enterotypes, and assessed the efficacy of the metabolome associated with 2′-fucosyllactose (2′-FL) fermentation on lipopolysaccharide-induced epithelial cell barrier damage on Caco-2 cells. The results revealed that propionate and butyrate were more prominent in the Bacteroides -dominated group, whereas the Bifidobacterium -dominated group was associated with an increased molar fraction of lactate (∼16 m m). Additionally, our study demonstrated that 2′-FL faecal metabolites (FMs) decreased the production of inflammatory cytokines, and promoted tight junction gene expression by inhibiting the TLR4/NF-κB/MLCK signalling pathway and activating the Nrf2/HO-1 pathway. The 2′-FL FMs from Bacteroides -dominated enterotypes had a unique advantage in regulating the TLR4/NF-κB/MLCK signalling pathway, which can be attributed to the effects of propionate and butyrate. [ABSTRACT FROM AUTHOR]

Note: this figure was drawn by the help of Figdraw (https://www.figdraw.com). [Display omitted] • With the help of the Caco-2 cells and HUVECs model, it is proved that the peptide is taken into the body through active translocation. • The peptide has a potential protective function of HUVECs and can reduce the effect of thrombin on HUVECs. • In animal experiments, the bioavailability of peptides is about 14% because they can be hydrolyzed by enzymes in the digestive tract. • This study provides a theoretical basis for the development and application of the peptide. In the former report, the casein peptide TKLTEEEKNR (PfCN) exhibits strong thrombin inhibitory activity in vitro. Its absorption capabilities, however, are unclear. Therefore, we studied its absorption characteristics both in vivo and in vitro. PfCN was carried by cells from the apical chamber to the basolateral chamber via active translocation in Caco-2 cells. Meanwhile, it can also be transported by HUVECs. We found that PfCN can be taken up by HUVECs using confocal laser imaging. PfCN has been proven to have good absorption properties in in vivo experiments. After five minutes of oral treatment, PfCN was identified in the blood, peaking at 82.75 ± 36.52 ng/mL in 30 min. And PfCN vanished from the blood circulation after 120 min. According to in vivo experiments, excessive concentrations of PfCN will alter the permeability of HUVECs. As a result, there is a foundation for PfCN application in the food sector. Meanwhile, we also hope this article can give an idea to the researchers who studying the absorption of functional peptides. [ABSTRACT FROM AUTHOR]

Microorganisms and organic carbon (C) pool composition are vital in regulating soil organic matter mineralization. However, our understanding of how parent materials and fertilizers affect this process is still limited. In this two-year study, the changes of cumulative soil organic C and nitrogen (N) mineralization and C and N pools (total, labile, and recalcitrant), C- and N-cycling enzymes, bacterial composition, and C- and N-cycling gene and their interactions were analyzed for soils developed on loess and river alluvium. These soils were under rice-rape seed rotation, and no fertilization (Control), NPK (NPK), and NPK plus organic manure (NPKM) were applied; treatments were arranged into a completely randomized design. Soil organic C mineralization was influenced by soil parent material and fertilization, whereas no interactive effects were found for soil N mineralization. The river alluvium promoted 2.24 times higher C and 1.27 times higher N mineralization than loess; fertilization intensified C and N mineralization in 1.70 and 1.22 times only in loess. Soil C and N fractions were influenced by the parent material, with 1.39 and 1.10 times higher effects found in soils formed on river alluvium. NPKM increased the content of total organic C in 1.31 times, labile C in 1.24 times, recalcitrant C in 1.34 times, total N in 1.21 times, and recalcitrant N in 1.17 times in loess soil. Similarly, in river alluvium soil, the increases were 1.41、1.21、1.53、1.23 and 1.28 times. Fertilization with NPKM increased C- and N-cycling enzyme activities in both soils. Parent material and fertilization shifted bacterial composition by changing pH, subsequently influencing N-cycling genes. However, only parent material affected C-cycling genes. Thus, C and N fractions play a direct role in the mineralization process of soil organic C, while bacteria indirectly influenced the C mineralization processes by promoting the enzyme activities. [ABSTRACT FROM AUTHOR]

Antimalarial efficacy in the Plasmodium falciparum differed dramatically for the isomers of C-10 carba analogues of artemisinin. [Display omitted] • Two approaches to obtain the pure isomers of C-10 carba analogues of artemisinin. • Crystallization is an effect way to enrich the minor isomer. • The stereochemistry of C-10 position significantly affects the antimalarial activity. Artemisinin is an endoperoxide bond-containing sesquiterpene lactone showing potent antimalarial effect as well as antitumor and antivirus activities. Inspired by this unique pharmacorphore, researchers around the world developed numerous Artemisinin derivatives. Among these derivatives, the C-10 carba analogues of artemisinin are frequently reported. However, the stereochemistry of C-10 carba analogues of artemisinin is overlooked and the corresponding mixture of stereoisomers are used. Herein, we reported for the first time stereochemistry and antimalarial activity of C-10 carba analogues of artemisinin. We employed two approaches to obtain the pure isomer of C-10 carba analogues and presented an interesting observation about their antimalarial activities. The minor isomer with large-sized substitute and S configuration at C-10 position had much lower antimalarial effect than the major isomer with R configuration. The study will shed light on the development of effective antimalarial drugs based on ART. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is a common complication in clinical inpatients, and it continues a high morbidity and mortality rate despite many clinical treatment measures. AKI is triggered by infections, surgery, heavy metal exposure and drug side effects, but current chemical drugs often fall short of expectations for AKI treatment and have toxic side effects. Therefore, finding new interventions and treatments, especially of natural origin, is of remarkable clinical significance and application. The herbal monomer curcumin is a natural phenolic compound extracted from the plant Curcuma longa and showed various biological activities, including AKI. Furthermore, recent studies have shown that curcumin restores renal function by modulating the immune system and the release of inflammatory mediators, scavenging oxygen free radicals, reducing apoptosis and improving mitochondrial dynamics. However, curcumin has a low bioavailability, which limits its clinical application. For this reason, it is essential to investigate the therapeutic effects and molecular mechanisms of curcumin in AKI, as well as to improve its bioavailability for curcumin formulation development and clinical application.Purpose: This review summarizes the sources, pharmacokinetics, and limitations in the clinical application of curcumin and explores methods to optimize its bioavailability using nanotechnology. In particular, the therapeutic effects and molecular mechanisms of curcumin on AKI are highlighted to provide a theoretical basis for AKI treatment in clinical practices.Methods: This review was specifically searched by means of a search of three databases (Web of Science, PubMed and Science Direct), till December 2021. Search terms were "Curcumin", "Acute kidney injury", "AKI", " Pharmacokinetics", "Mitochondria" and "Nano formulations". The retrieved data followed PRISMA criteria (preferred reporting items for systematic review) RESULTS: Studies have shown that curcumin responded to AKI-induced renal injury and restored renal tubular epithelial cell function by affecting multiple signaling pathways in AKI models induced by factors such as cisplatin, lipopolysaccharide, ischemia/reperfusion, gentamicin and potassium dichromate. Curcumin was able to affect NF-κB signaling pathway and reduce the expression of IL-1β, IL-6, IL-8 and TNF-α, thus preventing renal inflammatory injury. In the prevention of renal tubular oxidative damage, curcumin reduced ROS production by activating the activity of Nrf2, HO-1 and PGC-1α. In addition, curcumin restored mitochondrial homeostasis by upregulating OPA1 and downregulating DRP1 expression, while reducing apoptosis by inhibiting the caspase-3 apoptotic pathway. In addition, due to the low bioavailability and poor absorption of curcumin in vivo, curcumin nanoformulations including nanoparticles, liposomes, and polymeric micelles are formulated to improve the bioavailability.Conclusion: This review provides new ideas for the use of curcumin in the prevention and treatment of AKI by modulating the molecular targets of several different cellular signaling pathways. [ABSTRACT FROM AUTHOR]

[Display omitted] • The high-temperature pyrolysis mechanism for Tetrahydrotricyclopentadiene (THTCPD) is studied using the reactive molecular dynamics method. • The dissociation of the C C bond on the bridge bicycloheptyl structure is the main consumption pathway for THTCPD pyrolysis. • C 2 H 4 is the most abundant species of the initiation reaction process, mainly generated by the dissociation of C 15 H 22 diradicals. • The main production channel of final products (CH 4 and H 2) is the H addition reaction. Tetrahydrotricyclopentadiene (THTCPD) has high density and volumetric heat, but its viscosity is also high, resisting its ignition and combustion, which somewhat limits its applications. Therefore, it is crucial to understand the mechanism of THTCPD pyrolysis. In this study, the ReaxFF reactive molecular dynamics simulations were performed to investigate the thermal dissociation of THTCPD. The detailed description of THTCPD pyrolysis behavior was obtained from the aspects of initial reactions, main species distributions and intermolecular reactions. Initiation of the THTCPD decomposition is mainly through C C bond fission of the bicycloheptyl structure in the middle, leading to the formation of highly active C 15 H 22 diradicals. To give a better description of the pyrolysis behavior, main products related intermolecular reactions should be considered in the mechanism. The simulated pre-exponential factor A (2.30 × 1015 s−1) and activation energy E (55.72 kcal/mol) captured from simulations are found to be reasonably consistent with the experimental values. [ABSTRACT FROM AUTHOR]

The life cycle and occurrence of Haemaphysalis concinna were investigated under field conditions from April 2012 to March 2013 in Eerguna National Natural Reserve Area situated on the China-Russia border in Inner Mongolia, China. Under natural conditions, the whole life cycle of H. concinna was allowed to complete in a natural tick habitat. With domestic rabbits supplied as hosts, the seasonal occurrence and behaviors of H. concinna were also observed in the field plot which was chosen in a natural tick habitat from April to October 2012. Results indicated that the durations of the life cycle from unfed adults to the next generation unfed adults of H. concinna ranged from 124 to 186 days (average periods of 153.1 days). The incubation time of eggs ranged from 39 to 57 days (average periods of 41.3 days), which is the longest period among the four developmental stages, followed by the premolt periods for larvae (averaged 37.7 days) and nymphs (averaged 26.0 days). The number of eggs was positively correlated with the weight of engorged females ( r = 0.8562, p < 0.001). Eggs were laid in high amounts in the first week, subsequently, the egg amount declined gradually with small peaks occasionally observed. The female reproductive efficiency index (REI) and reproductive fitness index (RFI) was 6.2 and 4.3, respectively. Observations on the occurrence of H. concinna indicated that, in the confined plot under field conditions, larvae appeared in late May and peaked in early July, and nymphs were active during July and August. Therefore, there was an overlap in the occurrence of larvae and nymphs in both June and July. [ABSTRACT FROM AUTHOR]

Highlights: [•] There are two reproductive strategies in the hard tick Haemaphysalis longicornis. [•] The chromosomes ratio of bisexual and parthenogenetic populations is close to 2:3. [•] 4× Rule analysis results supported the two populations belong to the same species. [•] Phylogeny analysis revealed that they were in the same monophyletic clade. [•] Parthenogenetic H. longicornis would be metapopulation instead of cryptic species. [ABSTRACT FROM AUTHOR]

To prevent the spread of the COVID-19 epidemic, the Chinese megacity Wuhan has taken emergent lockdown measures starting on January 23, 2020. This provided a natural experiment to investigate the response of air quality to such emission reductions. Here, we decoupled the influence of meteorological and non-meteorological factors on main air pollutants using generalized additive models (GAMs), driven by data from the China National Environmental Monitoring Center (CNEMC) network. During the lockdown period (Jan. 23 – Apr. 8, 2020), PM 2.5 , PM 10 , NO 2 , SO 2 , and CO concentrations decreased significantly by 45 %, 49 %, 56 %, 39 %, and 18 % compared with the corresponding period in 2015–2019, with contributions by S(meteos) of 15 %, 17 %, 13 %, 10 %, and 6 %. This indicates an emission reduction of NO x at least 43 %. However, O 3 increased by 43 % with a contribution by S(meteos) of 6 %. In spite of the reduced volatile organic compound (VOC) emissions by 30 % during the strict lockdown period (Jan. 23 – Feb. 14, 2020), which likely reduced the production of O 3 , O 3 concentrations increased due to a weakening of the titration effect of NO. Our results suggest that conventional emission reduction (NO x reduction only) measures may not be sufficient to reduce (or even lead to an increase of) surface O 3 concentrations, even if reaching the limit, and VOC-specific measures should also be taken. [Display omitted] • COVID-19 lockdown caused a significant reduction in pollutant, except ozone. • GAMs model can explain nonlinear relationship between pollutants and meteorology. • Increasing of ozone mainly due to weakening of titration effect. • Ozone pollution needs to be controlled by a variety of pollutants. [ABSTRACT FROM AUTHOR]

Hydrophilic and hydrophobic peptides were prepared from oyster protein hydrolysates, and zinc-chelating peptides were isolated and characterized. Compared with alcalase hydrolysates, the chelating ability of zinc ions of hydrophilic peptides and hydrophobic peptides was significantly improved, which were respectively 8.09 μg zinc/mg protein and 13.70 μg zinc/mg protein. The structural properties of hydrophobic peptides were identified using ultraviolet spectra, fluorescence spectra and fourier transform infrared spectroscopy, respectively. The results indicated that hydrophobic peptides could form complexes with zinc ions through covalent chelating reactions with carbonyl groups and coordination bonds with amino groups. In addition, molecular docking was performed on the sequences obtained from hydrophobic peptides by NanoLC-Q-TOF. The results indicated that aspartic acid, glutamic acid, and leucine acid of the peptides might play critical roles in the zinc-chelating ability. The findings could be used to make dietary zinc supplements. • New type of zinc-chelating peptides was prepared in this study. • Zinc-chelating ability of hydrophobic peptides was significantly higher than the other two. • The zinc-chelating sites of hydrophobic peptides involved carboxyl, carbonyl and amino ligands. • Asp, Glu and Leu of the peptides might play important roles in the zinc-chelating ability. [ABSTRACT FROM AUTHOR]

Lactoferrin (LF) is a good protein for producing various bioactive peptides, such as those with antimicrobial, immunomodulating, and antihypertensive activities. However, there is no report about a peptide from lactoferrin with both angiotensin I-converting enzyme inhibitory (ACEI) and anticoagulant activities. This study investigated the ACEI and anticoagulant activities of the lactoferrin hydrolysate (LFH) produced using simulated gastrointestinal digestion and identified the potential peptide with both activities, as well as studied its active mechanisms. Results indicated that the LFH showed ACEI activity with an IC 50 value of 0.38 ± 0.06 mg mL−1. Moreover, LFH showed its anticoagulant activity by prolonging the thrombin time from 13.1 ± 0.1 to 20.9 ± 0.5 s at 20 mg mL−1. Nano-scale liquid chromatography-quadrupole time-of-flight mass spectrometry analysis showed that a total of 73 peptides with 7–21 amino acid residues were identified from LFH. The peptide ENLPEKADRD was evaluated for both ACEI and anticoagulant activities. Moreover, the molecular docking results showed that this peptide had strong interactions with ACE and thrombin indicated by "-CDOCKER_Energy" scores of 207 and 171 kcal mol−1, respectively. Twelve ACE amino acid residues interacted with the peptide by forming 13 H-bonds, 7 electrostatic interactions, and 4 hydrophobic interactions. Eight thrombin amino acid residues interacted with peptide ENLPEKADRD by forming 10 H-bonds, 4 electrostatic interactions, and 1 hydrophobic interaction. These results showed that LF may potentially be used as an ingredient in functional food products with both antihypertensive and anticoagulant activities. Image 1 [ABSTRACT FROM AUTHOR]

• AAV based-vaccine could efficiently mediate the RBD protein expression of the SARS-CoV-2 in mammalian cells. • AAV based-vaccine could rapidly induce strong immune responses in mice, which maintaining at least six months. • AAV-3xRBD vaccine could elicit the high level of neutralizing antibodies against SARS-CoV-2 in mice. • AAV-3xRBD vaccine has the ability of inducing the specific antibodies against SARS-CoV-2 in canines. The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in catastrophic damage worldwide. Accordingly, the development of powerful, safe, easily accessible vaccines with long-term effectiveness is understood as an urgently needed countermeasure against this ongoing pandemic. Guided by this strong promise of using AAVs, we here designed, optimized, and developed an AAV-based vaccines (including AAV-RBD(max), AAV-RBD(wt), AAV-2xRBD, and AAV-3xRBD) that elicit strong immune responses against the RBD domain of the SARS-CoV-2 S protein. These immunogenic responses have proven long-lived, with near peak levels for at least six months in mice. Notably, the sera immunized with AAV-3xRBD vaccine contains powerful neutralizing antibodies against the SARS-CoV-2 pseudovirus. Further evidence proven that potent specific antibodies could also be elicited in canines after vaccination with AAV-3xRBD vaccine. [ABSTRACT FROM AUTHOR]

(7 R ,8 S ,7′ E)-9′-O-methyl-5-methoxydehydrodiconiferylalcohol-4-O- β -D-glucopyranoside (1), a novel neolignan glycoside, and twenty-six known compounds (2 – 27) were isolated and characterized from the roots of Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. Regarding the biogenic pathway, they both belong to the phenylpropanoids produced by the shikimate pathway. The structure of compound 1 was elucidated by the analysis of spectroscopic data obtaining from UV, IR, CD, HR-ESI-MS and 1D and 2D NMR experiments (NOESY, HMBC and HSQC). From the current study, compounds 1 – 4 , 16 – 18 were newly isolated from the family Araliaceae, compounds 8 , 13 , 14 and 19 were newly isolated from the genus Eleutherococcu s, and compound 15 was newly isolated from Eleutherococcus senticosus. Furthermore, an insightful discussion of the chemical classification of isolated compounds was presented. [Display omitted] • A new neolignan glycoside and twenty-six known phenylpropanoids from the roots of Eleutherococcus senticosus. • Used literature research in order to investigate the chemical taxonomic significance of the isolated compounds. • From the current study, compounds 1 - 4 , 16 - 18 were newly isolated from the family Araliaceae, compounds 8 , 13 , 14 and 19 were newly isolated from the genus Eleutherococcus , and compound 15 was newly isolated from Eleutherococcus senticosus. [ABSTRACT FROM AUTHOR]

Abstract: In this study, peptidomics and genomics analyses were used to study antimicrobial peptides from the skin of Hylarana spinulosa. Twenty-nine different antimicrobial peptide precursors were characterized from the skin of H. spinulosa, which produce 23 mature antimicrobial peptides belonging to 12 different families. To confirm the actual presence and characteristics of these antimicrobial peptides in the skin tissue extractions from H. spinulosa, we used two distinct methods, one was peptide purification method that combined gel filtration chromatography and reversed-phase high performance liquid chromatography (RP-HPLC), and the other was peptidomics approach based on liquid chromatography in conjunction with tandem mass spectrometry (LC–MS/MS). In the peptidomics approach, incomplete tryptic digestion and gas-phase fractionation (GPF) analysis were used to increase peptidome coverage and reproducibility of peptide ion selection. Multiple species of microorganisms were chosen to test and analyze the antimicrobial activities and spectrum of these antimicrobial peptides. [Copyright &y& Elsevier]

New particle formation (NPF) events are an increasingly interesting topic in air quality and climate science. In this study, the particle number size distributions, and the frequency of NPF events over Hefei were investigated from November 2018 to February 2019. The proportions of the nucleation mode, Aitken mode, and accumulation mode were 24.59%, 53.10%, and 22.30%, respectively, which indicates the presence of abundant ultrafine particles in Hefei. Forty-six NPF events occurred during the observation days, accounting for 41.82% of the entire observation period. Moreover, the favorable meteorological conditions, potential precursor gases, and PM 2.5 range of the NPF events were analyzed. Compared to non-NPF days, the NPF events preferentially occurred on days with lower relative humidity, higher wind speeds, and higher temperatures. When the PM 2.5 was 15–20, 70–80, and 105–115 μg/m3, the frequency of the NPF events was higher. Nucleation mode particles were positively related to atmospheric oxidation indicated by ozone when PM 2.5 ranged from 15 to 20 μg/m3, and related to gaseous precursors like SO 2 and NO 2 when PM 2.5 was located at 70-80 and 105–115 μg/m3. On pollution days, NPF events did not directly contribute to the increase in the PM 2.5 in the daytime, however, NPF events would occur during the night and the growth of particulate matter contributes to the nighttime PM 2.5 contents. This could lead to pollution that lasted into the next day. These findings are significant to the improvement of our understanding of the effects of aerosols on air quality. [Display omitted] [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease that is currently incurable. Clinical practice has shown significant benefits of combined therapies for RA treatment. This study aims to develop and demonstrate an efficient triple therapy for RA in vitro and in vivo. Three anti-inflammatory agents, NF-κB decoy oligodeoxynucleotides (ODNs), gold nanorods (GNRs), and dexamethasone (DEX), were encapsulated into folate (FA) modified liposomes (FA-lip(DEX + GNRs/ODNs)). The FA-lip(DEX + GNRs/ODNs) showed favorable physicochemical properties and efficient intracellular uptake by inflamed macrophages. Combined with laser irradiation, FA-lip(DEX + GNRs/ODNs) greatly reduced the secretion of proinflammatory proteins and oxidative factors in vitro. In adjuvant-induced arthritis (AIA) mice, FA-lip(DEX + GNRs/ODNs) achieved prolonged and enhanced accumulation at inflamed paws. FA-lip(DEX + GNRs/ODNs) + laser treatment reduced clinical arthritis scores and serum cytokine levels and protected cartilage. In summary, the triple therapy demonstrated significantly enhanced anti-inflammatory efficacy and is a promising strategy to treat RA via combined anti-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Bioactive peptides are attractive candidates for drug development. QAW is a tripeptide that is obtained from an anti-inflammatory protein-Annexin A1 (ANXA1). Previous studies showed that QAW alleviated inflammation in experimental colitis and inflammatory bowel disease via NF-κB inhibition. This study establishes adjuvant-induced arthritis (AIA) mouse models and explores the anti-inflammatory efficacy of QAW in AIA mice. To enhance the targeting, responsiveness, and efficacy of QAW to inflammation, QAW (Q) is modified with a cell penetrating peptide (T), a matrix metalloproteases-2/9 (MMP-2/9) digestive peptide (M), and an inflammation targeting peptide-RGD (R). The designed RMTQ demonstrates enhanced delivery to cytoplasm, higher reduction of pro-inflammatory factors, and better efficacy than QAW. The anti-inflammatory efficacy of RMTQ is similar to that of DEX in this study whereas RMTQ treatment shows a higher safety than that of DEX. In sum, this study demonstrates that RMTQ can be a potential therapeutic for inflammatory arthritis. [ABSTRACT FROM AUTHOR]