Interleukin (IL)-8 plays a vital role in regulating inflammation and breast cancer formation by activating CXCR1/2. We previously designed an antagonist peptide, (RF16), to inhibits the activation of ...downstream signaling pathways by competing with IL-8 in binding to CXCR1/2, thereby inhibiting IL-8-induced chemoattractant monocyte binding. To evaluate the effect of the RF16 peptide on breast cancer progression, triple-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells were used to investigate whether RF16 can inhibit the IL-8-induced breast cancer metastasis. Using growth, proliferation, and invasiveness assays, the results revealed that RF16 reduced cell proliferation, migration, and invasiveness in MDA-MB-231 cells. The RF16 peptide also regulated the protein and mRNA expressions of epithelial–mesenchymal transition (EMT) markers in IL-8-stimulated MDA-MB-231 cells. It also inhibited downstream IL-8 signaling and the IL-8-induced inflammatory response via the mitogen-activated protein kinase (MAPK) and Phosphoinositide 3-kinase (PI3K) pathways. In the xenograft tumor mouse model, RF16 synergistically reinforces the antitumor efficacy of docetaxel by improving mouse survival and retarding tumor growth. Our results indicate that RF16 significantly inhibited IL-8-stimulated cell growth, migration, and invasion in MDA-MB-231 breast cancer cells by blocking the activation of p38 and AKT cascades. It indicated that the RF16 peptide may serve as a new supplementary drug for breast cancer.
Stereocontrolled chemical glycosylation remains a major challenge despite vast efforts reported over many decades and so far still mainly relies on trial and error. Now it is shown that the relative ...reactivity value (RRV) of thioglycosides is an indicator for revealing stereoselectivities according to four types of acceptors. Mechanistic studies show that the reaction is dominated by two distinct intermediates: glycosyl triflates and glycosyl halides from N‐halosuccinimide (NXS)/TfOH. The formation of glycosyl halide is highly correlated with the production of α‐glycoside. These findings enable glycosylation reactions to be foreseen by using RRVs as an α/β‐selectivity indicator and guidelines and rules to be developed for stereocontrolled glycosylation.
Selectivity rev‐counter: The relative reactivity value (RRV) of thioglycosides is an indicator for revealing stereoselectivities for chemical glycosylation.
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has now become a pandemic, but there is currently very little understanding ...of the antigenicity of the virus. We therefore determined the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein at 3.1-angstrom resolution. CR3022 targets a highly conserved epitope, distal from the receptor binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBDs on the trimeric S protein are in the "up" conformation and slightly rotated. These results provide molecular insights into antibody recognition of SARS-CoV-2.
This research investigates the bidirectional cointegration relationship between environmental, social, and governance (ESG) performance and corporate green innovation with a panel of 770 Chinese ...listed firms during the 2011–2020. We find that there exists a long‐run bidirectional comovement between ESG performance and corporate green innovation output. ESG performance exerts a short‐run and long‐run causal link with green innovation output. The panel cointegration test and VECM estimation also support that ESG performance moves together with green innovation output for clean industries, while ESG performance only presents a long‐run relationship to green invention patents output for pollution industries. Our findings offer important value for policymakers and enterprises to propose an effective strategy to stimulate green innovation and improve ESG score.
The enzyme‐resistant thioglycosides are highly valuable immunogens because of their enhanced metabolic stability. We report the first synthesis of a family of thiooligosaccharides related to the ...capsular polysaccharides (CPS) of Campylobacter jejuni HS:4 for potential use in conjugate vaccines. The native CPS structures of the pathogen consist of a challenging repeating disaccharide formed with β(1→4)‐linked 6‐deoxy‐β‐D‐ido‐heptopyranoside and N‐acetyl‐D‐glucosamine; the rare 6‐deoxy‐ido‐heptopyranosyl backbone and β‐anomeric configuration of the former monosaccharide makes the synthesis of this family of antigens very challenging. So far, no synthesis of the thioanalogs of the CPS antigens have been reported. The unprecedented synthesis presented in this work is built on an elegant approach by using β‐glycosylthiolate as a glycosyl donor to open the 2,3‐epoxide functionality of pre‐designed 6‐deoxy‐β‐D‐talo‐heptopyranosides. Our results illustrated that this key trans‐thioglycosylation can be designed in a modular and regio and stereo‐selective manner. Built on the success of this novel approach, we succeeded the synthesis of a family of thiooligosaccharides including a thiohexasaccharide which is considered to be the desired antigen length and complexity for immunizations. We also report the first direct conversion of base‐stable but acid‐labile 2‐trimethylsilylethyl glycosides to glycosyl‐1‐thioacetates in a one‐pot manner.
Enzyme‐resistant thioglycosides have the potential to be used as potent immunogens in vaccinations. The regio‐ and stereoselective opening of pyranosyl epoxides has been taken advantage of to obtain a family of very challenging thiooligosaccharide antigens related to Campylobacter jejuni HS:4 with unprecedented efficiency.
Molecular understanding of neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could accelerate vaccine design and drug discovery. We analyzed 294 ...anti-SARS-CoV-2 antibodies and found that immunoglobulin G heavy-chain variable region 3-53 (IGHV3-53) is the most frequently used IGHV gene for targeting the receptor-binding domain (RBD) of the spike protein. Co-crystal structures of two IGHV3-53-neutralizing antibodies with RBD, with or without Fab CR3022, at 2.33- to 3.20-angstrom resolution revealed that the germline-encoded residues dominate recognition of the angiotensin I converting enzyme 2 (ACE2)-binding site. This binding mode limits the IGHV3-53 antibodies to short complementarity-determining region H3 loops but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency, which is promising for vaccine design. Knowledge of these structural motifs and binding mode should facilitate the design of antigens that elicit this type of neutralizing response.
Background
Age‐related muscle dysfunctions are common disorders resulting in poor quality of life in the elderly. Probiotic supplementation is a potential strategy for preventing age‐related ...sarcopenia as evidence suggests that probiotics can enhance muscle function via the gut–muscle axis. However, the effects and mechanisms of probiotics in age‐related sarcopenia are currently unknown. In this study, we examined the effects of Lactobacillus casei Shirota (LcS), a probiotic previously reported to improve muscle function in young adult mice.
Methods
We administered LcS (1 × 108 or 1 × 109 CFU/mouse/day) by oral gavage to senescence‐accelerated mouse prone‐8 mice for 12 weeks (16‐ to 28‐week‐old). Sixteen‐week‐old and 28‐week‐old SMAP8 mice were included as non‐aged and aged controls, respectively. Muscle condition was evaluated using dual‐energy X‐ray absorptiometry for muscle mass, holding impulse and grip strength tests for muscle strength, and oxygen consumption rate, gene expressions of mitochondrial biogenesis, and mitochondrial number assays for mitochondria function. Inflammatory cytokines were determined using enzyme‐linked immunosorbent assay. Gas chromatography–mass spectrometry was utilized to measure the short‐chain fatty acid levels. The gut microbiota was analysed based on the data of 16S rRNA gene sequencing of mouse stool.
Results
The LcS supplementation reduced age‐related declines in muscle mass (>94.6%, P < 0.04), strength (>66% in holding impulse and >96.3% in grip strength, P < 0.05), and mitochondrial function (P < 0.05). The concentration of short‐chain fatty acids (acetic, isobutyric, butyric, penic, and hexanoic acid) was recovered by LcS (>65.9% in the mice given high dose of LcS, P < 0.05) in the aged mice, and LcS attenuated age‐related increases in inflammation (P < 0.05) and reactive oxygen species (>89.4%, P < 0.001). The high dose of LcS supplementation was also associated with distinct microbiota composition as indicated by the separation of groups in the beta‐diversity analysis (P = 0.027). LcS supplementation altered predicted bacterial functions based on the gut microbiota. Apoptosis (P = 0.026), p53 signalling (P = 0.017), and non‐homologous end‐joining (P = 0.031) were significantly reduced, whereas DNA repair and recombination proteins (P = 0.043), RNA polymerase (P = 0.008), and aminoacyl‐tRNA biosynthesis (P = 0.003) were increased. Finally, the genera enriched by high‐dose LcS linear discriminant analysis (LDA) score > 2.0 were positively correlated with healthy muscle and physiological condition (P < 0.05), while the genera enriched in aged control mice (LDA score > 2.0) were negatively associated with healthy muscle and physiological condition (P < 0.05).
Conclusions
Lactobacillus casei Shirota represents an active modulator that regulates the onset and progression of age‐related muscle impairment potentially via the gut–muscle axis.
This research examines the effect of environmental policy stringency on green innovation in renewable energy technology and whether the green innovation response differs with varying degrees of ...environmental policy. Based on panel data of 33 countries over the period 1990–2015, we show that a stringent environmental policy does encourage green innovation in renewable energy technology, and this impact is more pronounced in OECD countries and high-income countries. More specifically, a stringent non-market-based environmental policy induces more patents in renewable energy generation. The findings also show that a stringent environmental policy yields green innovation for geothermal energy, hydro energy, and marine energy, but not for wind energy and solar energy. Heterogeneity analysis suggests that innovation capacity and environmental pressure enhance the impact of environmental policy stringency on green innovation in the renewable energy field. Finally, the paper presents that clean energy investment plays the role of a mechanism through which environmental policy stringency spurs green innovation in the renewable energy field, offering insights into the influence of environmental policy stringency on green innovation.
Climate change may affect energy consumption and thus bring shocks to clean energy investment. By employing instrumental variable quantile regression model, this research investigates the effects of ...climate change on clean energy investment according to global panel data spanning a long period. In addition to the sample of all countries, we also carry out investigations of sub-samples for OECD and non-OECD countries to analyze whether there exists heterogeneity in development levels. Overall, we provide a diversified exploration on how climate change shocks impact clean energy investment. More specifically, we find that effects of climate change on clean energy investment vary significantly in countries with different levels of clean energy investment; i.e., climate change is likely to promote clean energy investment in countries whose clean investments are greater, and there exists significant heterogeneity in the subsamples. From these results, we offer policy implications such as carrying out differentiated clean energy plans based on the specific environment, implementing policies on clean energy, and copying the practices in some OECD countries that have high levels of clean energy investment.
•This research investigates the effects of climate change on clean energy investment according to global panel data.•We provide a diversified exploration on how climate change shocks impact clean energy investment.•We find that effects of climate change on clean energy investment vary significantly in countries with different levels of clean energy investment.•The effects of climate change on clean energy investment show significant heterogeneity in the subsamples of OECD and non-OECD countries.
Nanogels (or nanohydrogels) have been extensively investigated as one of the most promising nanoparticulate biomedical platforms owing to their advantageous properties that combine the ...characteristics of hydrogel systems with nanoparticles. Among them, smart nanogels that have the ability to respond to external stimuli, such as pH, redox, temperature, enzymes, light, magnetic field and so forth, are most attractive in the area of drug delivery. Besides, numerous multifunctionalized nanogels with high sensitivity and specificity were designed for diagnostic applications. In this feature article, we have reviewed and discussed the recent progress of biodegradable nanogels as smart nanocarriers of anticancer drugs and biomedical diagnostic agents for cancer.
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