Suppression of SIRT1/FXR signaling pathway contributes to oleanolic acid-induced liver injury.

Oleanolic acid (OA) is a pentacyclic triterpenoid compound used clinically for acute and chronic hepatitis. However, high dose or long-term use of OA causes hepatotoxicity, which limits its clinical application. Hepatic Sirtuin (SIRT1) participates in the regulation of FXR signaling and maintains hepatic metabolic homeostasis. This study was designed to determine whether SIRT1/FXR signaling pathway contributes to the hepatotoxicity caused by OA. C57BL/6J mice were administered with OA for 4 consecutive days to induce hepatotoxicity. The results showed that OA suppressed the expression of FXR and its downstream targets CYP7A1, CYP8B1, BSEP and MRP2 at both mRNA and protein levels, breaking the homeostasis of bile acid leading to hepatotoxicity. However, treatment with FXR agonist GW4064 noticeably attenuated hepatotoxicity caused by OA. Furthermore, it was found that OA inhibited protein expression of SIRT1. Activation of SIRT1 by its agonist SRT1720 significantly improved OA-induced hepatotoxicity. Meanwhile, SRT1720 significantly reduced the inhibition of protein expression of FXR and FXR-downstream proteins. These results suggested that OA may cause hepatotoxicity through SIRT1 dependent suppression of FXR signaling pathway. In vitro experiments confirmed that OA suppressed protein expressions of FXR and its targets through inhibition of SIRT1. It was further revealed that silencing of HNF1α with siRNA significantly weakened regulatory effects of SIRT1 on the expression of FXR as well as its target genes. In conclusion, our study reveals that SIRT1/FXR pathway is crucial in OA-induced hepatotoxicity. Activation of SIRT1/HNF1α/FXR axis may represent a novel therapeutic target for ameliorating OA and other herb-induced hepatotoxicity.

Study on Photochemical Properties of a Sr-SnS2/CaIn2S4 Heterostructure to Improve Cr(VI) Removal.

Compound semiconductor photocatalysis technology is considered to be a promising treatment for solving water problems efficiently. The point of designing high-efficiency catalysts is to optimize the band gap structure and facilitate the separation of charge carriers by establishing new electron migration pathways. Recently, 3D porous CaIn2S4 was found to have good photocatalytic ability. However, the quick recombination and agglomeration of carriers still limit its application. Herein, we prepared a heterostructure by introducing 2D Sr-doped SnS2 to 3D CaIn2S4 by a hydrothermal synthesis method. The optimal dosage of Sr-SnS2 is 3%, and the photocatalytic Cr(VI) removal efficiency of 3% Sr-SnS2/CaIn2S4 (SSCS-3) is 5.82 and 10.83 times those of pure CaIn2S4 and SnS2, respectively. According to the results of characterization tests and calculation verification, we inferred that the enhanced photocatalytic removal of Cr(VI) is due to the introduction of Sr-SnS2 that can promote the rapid transfer of photogenerated electrons to the surface of CaIn2S4, and the heterostructure formed between 2D Sr-SnS2 and 3D CaIn2S4 can also provide abundant reaction sites. The promotion of carrier separation is mainly due to the formation of a built-in electric field of the Sr-SnS2/CaIn2S4 heterostructure. This work provides new ideas and technologies for the treatment of Cr(VI) in wastewater.

circSSPO boosts growth of esophageal squamous cell carcinoma through upregulation of micrRNA-6820-5p-mediated KLK8 and PKD1 expression.

Investigation on a competitive endogenous RNA (ceRNA) network attracted lots of attention due its function in cancer regulation. Here, we probed into the possible molecular mechanism of circSSPO/microRNA-6820-5p (miR-6820-5p)/kallikrein-related peptidase 8 (KLK8)/PKD1 network in the esophageal squamous cell carcinoma (ESCC). Following whole-transcriptome sequencing and differential analysis in collected ESCC tissue samples, circRNA-miRNA-mRNA regulatory network affecting ESCC was investigated. After interaction measurement among circSSPO/miR-6820-5p/KLK8/PKD1, their regulatory roles in ESCC cell functions in vitro and xenograft tumor growth and lung metastasis in vivo were analyzed. The bioinformatics prediction and sequencing results screened that circSSPO, miR-6820-5p, KLK8, and PKD1 were associated with ESCC development. In ESCC, miR-6820-5p was expressed at very low levels, while circSSPO, KLK8, and PKD1 were highly expressed. In vitro cell experiments further proved that circSSPO competitively inhibited miR-6820-5p to induce ESCC cell malignant properties. Moreover, knockdown of KLK8 or PKD1 inhibited ESCC cell malignant properties. circSSPO also promoted the tumorigenic and metastasis of ESCC through the upregulation of KLK8 and PKD1 expression in vivo. We found that circSSPO was an oncogenic circRNA that was significantly abundant in ESCC tissues and circSSPO exhibited an oncogenic activity in ESCC by elevating expression of KLK8 and PKD1 through suppressing miR-6820-5p expression.

AMP-activated protein kinase-farnesoid X receptor pathway contributes to oleanolic acid-induced liver injury.

Natural pentacyclic triterpenoid oleanolic acid (OA) is used as an over-the-counter drug for acute and chronic hepatitis. However, clinical use of OA-containing herbal medicines has been reported to cause cholestasis, and the specific mechanism is unknown. The purpose of this study was to explore how OA causes cholestatic liver injury via the AMP-activated protein kinase (AMPK)-farnesoid X receptor (FXR) pathway. In animal experiments, it was found that OA treatment activated AMPK and decreased FXR and bile acid efflux transport proteins expression. When intervened with the specific inhibitor Compound C (CC), it was observed that AMPK activation was inhibited, the reduction of FXR and bile acid efflux transport protein expression was effectively alleviated, serum biochemical indicators were significantly reduced, and liver pathological damage brought about by OA was effectively ameliorated. In addition, OA was found to downregulate the expression of FXR and bile acid efflux transport proteins by activating the ERK1/2-LKB1-AMPK pathway in cellular experiments. The ERK1/2 inhibitor U0126 was used to pretreat primary hepatocytes, and this drastically reduced the phosphorylation levels of LKB1 and AMPK. The inhibition effects of OA on FXR and bile acid efflux transport proteins were also effectively alleviated after pretreatment with CC. In addition, OA-induced downregulation of FXR gene and protein expression levels was significantly prevented after silencing AMPKα1 expression in AML12 cells. Our study demonstrated that OA inhibited FXR and bile acid efflux transporters through the activation of AMPK, thus leading to cholestatic liver injury.

Characterizing environmental pollution with civil complaints and social media data: A case of the Greater Taipei Area.

Environmental pollution is a major cause of nuisance and ill health among urban residents. Complaints are traditionally self-reported through phone-based systems. Social media provide novel channels to detect pollution-related incidents; however, their reliability has not been sufficiently evaluated. This study aimed to compare pollution incidents expressed on Twitter with those extracted from phone-based systems and to identify the built environment and socioeconomic attributes that can predict the likelihood of pollution incidents. A total of 639,746 tweets were retrieved from the Greater Taipei Area in 2017 and 110,716 self-reported pollution incidents were extracted from the Public Nuisance Petition system during the same period. The results suggest that complaints collected from phone-based systems and Twitter were found to have correlated with each other spatially, albeit they differ in temporal profiles and by the proportion of pollution categories. Catering businesses and the entertainment activities they attract appear to be the main sources of pollution complaints and can be precisely captured by geotagged tweets. This can serve as a strong predictor for pollution incidents, more than traditional indicators such as population density or industrial activities, as suggested by earlier studies. Social media analytics, with their ability to monitor and analyze online discussions in a timely manner, can be a valuable supplement to existing phone-based pollution monitoring procedures. The methodologies developed in this study have the potential to support the proactive management of urban environmental pollution, in which resources can be prioritized in key areas to further enhance the quality of urban services.

Hydrophobicity Effects of γ-Glutamyl Transpeptidase-Responsive Polymers on the Catalytic Activity and Transcytosis Efficacy.

Active transcytosis has recently sparked great interest in drug delivery as a novel route for tumor extravasation and infiltration. However, the rational design of transcytosis-inducing nanomedicines remains challenging. We recently demonstrated that the γ-glutamyl transpeptidase (GGT)-responsive polymer cationization induced efficient adsorption-mediated transcytosis (AMT). However, it remains unclear how the nanomedicines' physicochemical properties influence the GGT-responsive cationization and induced transcytosis behaviors. Herein, through a combination of experimental techniques and molecular dynamics (MD) simulations, we find that the random copolymers with high hydrophobic monomers tend to form compact structures accessible to the catalytic site of GGT, leading to a fast cationization and thus high transcytosis efficiency, while the homopolymers of the hydrophilic GGT-sensitive monomers have elongated structures unable to enter the active site and thus exhibit poor GGT sensitivity. As a result, the more hydrophobic polymer-drug conjugates with high camptothecin contents exhibit higher GGT-responsive activity, which in turn leads to faster cationization and cellular internalization, enhanced tumor infiltration, and more potent antitumor activity. These findings indicate the hydrophobicity is a main parameter determining the GGT catalytic activity and transcytosis efficiency of the GGT-activatable co(homo)polymers, providing guidelines for the rational design of GGT-induced charge reversal carriers for transcytotic nanomedicines.

Distinct lipid membrane interaction and uptake of differentially charged nanoplastics in bacteria.

BACKGROUND: Nanoplastics have been recently found widely distributed in our natural environment where ubiquitously bacteria are major participants in various material cycles. Understanding how nanoplastics interact with bacterial cell membrane is critical to grasp their uptake processes as well as to analyze their associated risks in ecosystems and human microflora. However, little is known about the detailed interaction of differentially charged nanoplastics with bacteria. The present work experimentally and theoretically demonstrated that nanoplastics enter into bacteria depending on the surface charges and cell envelope structural features, and proved the shielding role of membrane lipids against nanoplastics. RESULTS: Positively charged polystyrene nanoplastics (PS-NH2, 80 nm) can efficiently translocate across cell membranes, while negatively charged PS (PS-COOH) and neutral PS show almost no or much less efficacy in translocation. Molecular dynamics simulations revealed that the PS-NH2 displayed more favourable electrostatic interactions with bacterial membranes and was subjected to internalisation through membrane penetration. The positively charged nanoplastics destroy cell envelope of Gram-positive B. subtilis by forming membrane pore, while enter into the Gram-negative E. coli with a relatively intact envelope. The accumulated positively charged nanoplastics conveyed more cell stress by inducing a higher level of reactive oxygen species (ROS). However, the subsequently released membrane lipid-coated nanoplastics were nearly nontoxic to cells, and like wise, stealthy bacteria wrapped up with artifical lipid layers became less sensitive to the positively charged nanoplastics, thereby illustrating that the membrane lipid can shield the strong interaction between the positively charged nanoplastics and cells. CONCLUSIONS: Our findings elucidated the molecular mechanism of nanoplastics' interaction and accumulation within bacteria, and implied the shielding and internalization effect of membrane lipid on toxic nanoplastics could promote bacteria for potential plastic bioremediation.

Outdoor light at night and risk of coronary heart disease among older adults: a prospective cohort study.

AIMS: We estimated the association between outdoor light at night at the residence and risk of coronary heart disease (CHD) within a prospective cohort of older adults in Hong Kong. METHODS AND RESULTS: Over a median of 11 years of follow-up, we identified 3772 incident CHD hospitalizations and 1695 CHD deaths. Annual levels of outdoor light at night at participants' residential addresses were estimated using time-varying satellite data for a composite of persistent night-time illumination at ∼1 km2 scale. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between outdoor light at night at the residence and risk of CHD. The association between light at night and incident CHD hospitalization and mortality exhibited a monotonic exposure-response function. An interquartile range (IQR) (60.0 nW/cm2/sr) increase in outdoor light at night was associated with an HR of 1.11 (95% CI: 1.03, 1.18) for CHD hospitalizations and 1.10 (95% CI: 1.00, 1.22) for CHD deaths after adjusting for both individual and area-level risk factors. The association did not vary across strata of hypothesized risk factors. CONCLUSION: Among older adults, outdoor light at night at the residence was associated with a higher risk of CHD hospitalizations and deaths. We caution against causal interpretation of these novel findings. Future studies with more detailed information on exposure, individual adaptive behaviours, and potential mediators are warranted to further examine the relationship between light at night and CHD risk.

Airborne transmission of the Delta variant of SARS-CoV-2 in an auditorium.

The Delta variant of SARS-CoV-2 has inflicted heavy burdens on healthcare systems globally, although direct evidence on the quantity of exhaled viral shedding from Delta cases is lacking. The literature remains inconclusive on whether existing public health guidance, based on earlier evidence of COVID-19, should respond differently to more infectious viral strains. This paper describes a study on an outbreak of the Delta variant of COVID-19 in an auditorium, where one person contracted the virus from three asymptomatic index cases sitting in a different row. Field inspections were conducted on the configuration of seating, building and ventilation systems. Numerical simulation was conducted to retrospectively assess the exhaled viral emission, decay, airborne dispersion, with a modified Wells-Riley equation used to calculate the inhalation exposure and disease infection risks at the seat level. Results support the airborne disease transmission. The viral emission rate for Delta cases was estimated at 31 quanta per hour, 30 times higher than those of the original variant. The high quantity of viral plume exhaled by delta cases can create a high risk zone nearby, which, for a mixing ventilation system, cannot be easily mitigated by raising mixing rates or introducing fresh air supply. Such risks can be reduced by wearing an N95 respirator, less so for social distancing. A displacement ventilation system, through which the air is supplied at the floor and returned from the ceiling, can reduce risks compared with a mixing system. The study has implications for ventilation guidelines and hygiene practices in light of more infectious viral strains of COVID-19.

Metallo-Helicoid with Double Rims: Polymerization Followed by Folding by Intramolecular Coordination.

In this study, we established a feasible strategy to construct a new type of metallo-polymer with helicoidal structure through the combination of covalent polymerization and intramolecular coordination-driven self-assembly. In the design, a tetratopic monomer (M) was prepared with two terminal alkynes in the outer rim for polymerization, and two terpyridines (TPYs) in the inner rim for subsequent folding by selective intramolecular coordination. Then, the linear covalent polymer (P) was synthesized by polymerization of M via Glaser-Hay homocoupling reaction. Finally, intramolecular coordination interactions between TPYs and Zn(II) folded the backbone of P into a right- or left-handed metallo-helicoid (H) with double rims. Owing to multiple positive charges on the inner rim of helicoid, double-stranded DNA molecules (dsDNA) could interact with H through electrostatic interactions. Remarkably, dsDNA allowed exclusive formation of H with right handedness by means of chiral induction.

Drug-binding albumins forming stabilized nanoparticles for efficient anticancer therapy.

Albumin is a serum transport protein, which has been utilized as a carrier for a variety of drugs to improve their delivery efficiency and to obtain favorable pharmacokinetic profiles. However, natural albumin possesses only a few high-affinity binding sites for a limited number of drugs. This results in deficiencies in drug-loading and serum stability, and consequently, in impaired therapeutic efficacy. Herein, BSA was modified with different isothiocyanate conjugates (BSA-ITCs), which self-assembled with paclitaxel (PTX) to produce BSA-ITCs/PTX nanoparticles. Among these BSA-ITCs, phenethyl isothiocyanate (PEITC)-modified BSA (BSA-PEITC35) conjugates effectively loaded PTX and formed highly stable BSA-PEITC35/PTX nanoparticles. Molecular modeling studies suggested that PEITC groups in BSA-PEITC35 can significantly lower the PTX binding free energy. BSA-PEITC35/PTX showed enhanced stability, prolonged blood circulation and increased tumor accumulation than unmodified BSA/PTX, and exerted more potent antitumor activity than both BSA/PTX and Abraxane in subcutaneous mouse tumor models after intravenous administration.

Extracellular Vesicles Derived from Human Adipose-Derived Mesenchymal Stem Cells Alleviate Sepsis-Induced Acute Lung Injury through a MicroRNA-150-5p-Dependent Mechanism.

Extracellular vesicles (EVs) derived from human adipose mesenchymal stem cells (hADSCs) may exert a therapeutic benefit in alleviating sepsis-induced organ dysfunction by delivering cargos that include RNAs and proteins to target cells. The current study aims to explore the protective effect of miR-150-5p delivered by hADSC-EVs on sepsis-induced acute lung injury (ALI). We noted low expression of miR-150-5p in plasma and bronchoalveolar lavage fluid samples from patients with sepsis-induced ALI. The hADSC-EVs were isolated and subsequently cocultured with macrophages. It was established that hADSC-EVs transferred miR-150-5p to macrophages, where miR-150-5p targeted HMGA2 to inhibit its expression and, consequently, inactivated the MAPK pathway. This effect contributed to the promotion of M2 polarization of macrophages and the inhibition of proinflammatory cytokines. Further, mice were made septic by cecal ligation and puncture in vivo and treated with hADSC-EVs to elucidate the effect of hADSC-EVs on sepsis-induced ALI. The in vivo experimental results confirmed a suppressive role of hADSC-EVs in sepsis-induced ALI. Our findings suggest that hADSC-EV-mediated transfer of miR-150-5p may be a novel mechanism underlying the paracrine effects of hADSC-EVs on the M2 polarization of macrophages in sepsis-induced ALI.

Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury.

Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.

Therapeutic potential of ADSC-EV-derived lncRNA DLEU2: A novel molecular pathway in alleviating sepsis-induced lung injury via the miR-106a-5p/LXN axis.

This study investigates the molecular mechanisms by which extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (ADSCs) promote M2 polarization of macrophages and thus reduce lung injury caused by sepsis. High-throughput sequencing was used to identify differentially expressed genes related to long non-coding RNA (lncRNA) in ADSC-derived EVs (ADSC-EVs) in sepsis lung tissue. Weighted gene co-expression network analysis (WGCNA) was employed to predict the downstream target genes of the lncRNA DLEU2. The RNAInter database predicted miRNAs that interact with DLEU2 and LXN. Functional and pathway enrichment analyses were performed using GO and KEGG analysis. A mouse model of sepsis was established, and treatment with a placebo or ADSC-EVs was administered, followed by RT-qPCR analysis. ADSC-EVs were isolated and identified. In vitro cell experiments were conducted using the mouse lung epithelial cell line MLE-12, mouse macrophage cell line RAW264.7, and mouse lung epithelial cell line (LEPC). ADSC-EVs were co-cultured with RAW264.7 and MLE-12/LEPC cells to study the regulatory mechanism of the lncRNA DLEU2. Cell viability, proliferation, and apoptosis of lung injury cells were assessed using CCK-8, EdU, and flow cytometry. ELISA was used to measure the levels of inflammatory cytokines in the sepsis mouse model, flow cytometry was performed to determine the number of M1 and M2 macrophages, lung tissue pathology was evaluated by H&E staining, and immunohistochemistry was conducted to examine the expression of proliferation- and apoptosis-related proteins. High-throughput sequencing and bioinformatics analysis revealed enrichment of the lncRNA DLEU2 in ADSC-EVs in sepsis lung tissue. Animal and in vitro cell experiments showed increased expression of the lncRNA DLEU2 in sepsis lung tissue after treatment with ADSC-EVs. Furthermore, ADSC-EVs were found to transfer the lncRNA DLEU2 to macrophages, promoting M2 polarization, reducing inflammation response in lung injury cells, and enhancing their viability, proliferation, and apoptosis inhibition. Further functional experiments indicated that lncRNA DLEU2 promotes M2 polarization of macrophages by regulating miR-106a-5p/LXN, thereby enhancing the viability and proliferation of lung injury cells and inhibiting apoptosis. Overexpression of miR-106a-5p could reverse the biological effects of ADSC-EVs-DLEU2 on MLE-12 and LEPC in vitro cell models. Lastly, in vivo animal experiments confirmed that ADSC-EVs-DLEU2 promotes high expression of LXN by inhibiting the expression of miR-106a-5p, further facilitating M2 macrophage polarization and reducing lung edema, thus alleviating sepsis-induced lung injury. lncRNA DLEU2 in ADSC-EVs may promote M2 polarization of macrophages and enhance the viability and proliferation of lung injury cells while inhibiting inflammation and apoptosis reactions, thus ameliorating sepsis-induced lung injury in a mechanism involving the regulation of the miR-106a-5p/LXN axis.

Pyrimethanil residue and dissipation in tomatoes and soil under field conditions.

A residue analytical method to detect pyrimethanil in tomatoes and soil was developed by using high-performance liquid chromatography with a diode array detector. The dissipation and residue level of pyrimethanil in tomatoes and soil were also investigated. Results showed that the average recoveries are in the range of 87.2 to 90.0 % with a relative standard difference of 2.22 to 7.61 % in tomatoes and soil. In Guangdong, Shandong, and Yunnan, the half-lives of pyrimethanil in tomatoes were 1.8, 3.6, and 4.2 days and those in soil were 4.0, 3.3, and 3.9 days, respectively. The dissipation rate of pyrimethanil in tomatoes and soil was affected by temperature, precipitation, and soil type. The terminal residue results showed that when pesticide pyrimethanil was used under the experiment design, all the results were far below the available maximum residue limits. Low residues in tomatoes and soil suggest that this pesticide is safe to use under the recommended dosage.

Novel Inhibitory Role of Fenofibric Acid by Targeting Cryptic Site on the RBD of SARS-CoV-2.

The emergence of the recent pandemic causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an alarming situation worldwide. It also prompted extensive research on drug repurposing to find a potential treatment for SARS-CoV-2 infection. An active metabolite of the hyperlipidemic drug fenofibrate (also called fenofibric acid or FA) was found to destabilize the receptor-binding domain (RBD) of the viral spike protein and therefore inhibit its binding to human angiotensin-converting enzyme 2 (hACE2) receptor. Despite being considered as a potential drug candidate for SARS-CoV-2, FA's inhibitory mechanism remains to be elucidated. We used molecular dynamics (MD) simulations to investigate the binding of FA to the RBD of the SARS-CoV-2 spike protein and revealed a potential cryptic FA binding site. Free energy calculations were performed for different FA-bound RBD complexes. The results suggest that the interaction of FA with the cryptic binding site of RBD alters the conformation of the binding loop of RBD and effectively reduces its binding affinity towards ACE2. Our study provides new insights for the design of SARS-CoV-2 inhibitors targeting cryptic sites on the RBD of SARS-CoV-2.

Immobilization enhancement of heavy metals in lightweight aggregate by component regulation of multi-source solid waste.

Integrated recycling of solid waste containing heavy metals is a critical environmental challenge. In this study, a green solution to reduce heavy metal leaching from solid waste is demonstrated by combining contaminated soil, industrial sludge and lithium slag in pairs to produce lightweight aggregates (LWAs). The physical properties and heavy metal leaching behavior of LWA samples were systematically investigated and characterized. The results showed that industrial sludge reduced the density and water absorption of LWA, while the high content of lithium slag was detrimental to the physical properties. LWA containing 80% contaminated soil and 20% lithium slag had the lowest particle density of 1.47 g/cm3 due to the hollow structure caused by the low viscosity and violent generation of SO2. LWAs with lithium slag leached excessive Cu and Cr relatively, while heavy metals were immobilized well in LWAs with contaminated soil and industrial sludge as the main components. Because the flux components of industrial sludge could enhance the encapsulation of heavy metals by glass phase. In addition, the co-immobilization of multiple heavy metals was observed in the spinel phase. This study provides an efficient and safe method for the synergistic recycling of solid waste.

Influence of Core Topologies on Poly-l-lysine Dendrimer Structures.

Poly-l-lysine (PLL) dendrimers have emerged as promising nanomaterials for gene/drug delivery, bioimaging, and biosensing due to their high efficacy and biocompatibility. In our previous works, we successfully synthesized two categories of PLL dendrimers with two different cores: the planar-shaped perylenediimide and the cubic-shaped polyhedral oligomeric silsesquioxanes. However, the effect of these two topologies on the PLL dendrimer structures is not clearly understood. In this work, we carried out in-depth investigations on the influence of core topologies on the PLL dendrimer structures using molecular dynamics simulations. We show that, even at high generations, the core topology affects the shape and branch distribution of the PLL dendrimer, which may further determine their performance. Moreover, our findings suggest that the core topology on the PLL dendrimer structures can be further designed and improved to fully exploit and utilize their potential in biomedical applications.

Immune checkpoint inhibitors increase the risk of kidney transplant rejection: a real-world pharmacovigilance study.

BACKGROUND: Kidney transplant recipients with cancer are at higher risk of kidney transplant rejection (KTR), and the safety of immune checkpoint inhibitors (ICIs) is unclear. The present study investigates the relationship between ICIs and KTR using data from the Food and Drug Administration Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS: Case reports of KTR inducted by ICIs in FAERS from 1 January 2011, to 30 June 2021, were collected, and a disproportionate analysis was performed to assess the correlation between ICIs and KTR. RESULTS: A total of 99 cases of ICI-related KTR were reported in the FAERS database. Most of them were male patients (n = 63, 84.0%), and more than half of patients suffered from malignant melanoma (n = 46, 52.9%). The median onset time after the medication was 22 days, the withdrawal rates of ICIs were 78.0%, and the overall death rate was 29.3%. In general, there was a significant relevance between ICIs and KTR (ROR = 3.92[3.21-4.79] IC025 = 1.56), of which PD-1 was the most prominent (n = 81 ROR = 5.26[4.22-6.57] IC025 = 1.86). CONCLUSIONS: ICIs may increase the risk of KTR in organ transplant recipients with cancer.

Direct Visualization of the Dynamic Process of Epsilon Toxin on Hemolysis.

Hemolysis is the process of rupturing erythrocytes (red blood cells) by forming nanopores on their membranes using hemolysins, which then impede membrane permeability. However, the self-assembly process before the state of transmembrane pores and underlying mechanisms of conformational change are not fully understood. In this work, theoretical and experimental evidence of the pre-pore morphology of Clostridium perfringens epsilon toxin (ETX), a typical hemolysin, is provided using in situ atomic force microscopy (AFM) complemented by molecular dynamics (MD) simulations to detect the conformational distribution of different states in Mica. The AFM suggests that the ETX pore is formed in two stages: ETX monomers first attach to the membrane and form a pre-pore in no special conditions required, which then undergo a conformational change to form a transmembrane pore at temperatures above the critical point in the presence of receptors. The authors' MD simulations reveal that initial nucleation occurs when specific amino acids adsorb to negatively charged mica cavities. This work fills the knowledge gap in understanding the early stage of hemolysis and the oligomerization of hemolysins. Moreover, the newly identified pre-pore of ETX holds promise as a candidate for nanopore applications.