Single-Domain Antibody-Based Protein Degrader for Synucleinopathies.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic ligand enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

High blood pressure is associated with increased risk of future fracture, but not vice versa.

The association between high blood pressure and fracture showed obvious discrepancies and were mostly between hypertension with future fracture, but rarely between fracture and incident hypertension. The present study aims to investigate the associations of hypertension with future fracture, and fracture with incident hypertension. We included adult participants from the China Health and Nutrition Survey (CHNS) prospective cohort in 1997-2015 (N = 10,227), 2000-2015 (N = 10,547), 2004-2015 (N = 10,909), and 2006-2015 (N = 11,121) (baseline in 1997, 2000, 2004, 2006 respectively and outcome in 2015). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. In the analysis of the association between hypertension and future fracture, the adjusted HRs (95% CIs) were 1.34 (0.95-1.90) in 1997-2015, 1.40 (1.04-1.88) in 2000-2015, 1.32 (0.98-1.78) in 2004-2015, and 1.38 (1.01-1.88) in 2006-2015. In the analysis of the association between fracture and incident hypertension, the adjusted HRs (95% CIs) were 1.28 (0.96-1.72) in 1997-2015, 1.18 (0.94-1.49) in 2000-2015, 1.12 (0.89-1.40) in 2004-2015, and 1.09 (0.85-1.38) in 2006-2015. The present study showed that hypertension history was associated with increased risk of future fracture, but not vice versa.

Transmembrane domain-driven PD-1 dimers mediate T cell inhibition.

Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.

Integrated small RNA, transcriptome and physiological approaches provide insight into Taxodium hybrid 'Zhongshanshan' roots in acclimation to prolonged flooding.

Although Taxodium hybrid 'Zhongshanshan' 406 (Taxodium mucronatum Tenore × Taxodium distichum; Taxodium 406) is an extremely flooding-tolerant woody plant, the physiological and molecular mechanisms underlying acclimation of its roots to long-term flooding remain largely unknown. Thus, we exposed saplings of Taxodium 406 to either non-flooding (control) or flooding for 2 months. Flooding resulted in reduced root biomass, which is in line with lower concentrations of citrate, α-ketoglutaric acid, fumaric acid, malic acid and adenosine triphosphate (ATP) in Taxodium 406 roots. Flooding led to elevated activities of pyruvate decarboxylase, alcohol dehydrogenase and lactate dehydrogenase, which is consistent with higher lactate concentration in the roots of Taxodium 406. Flooding brought about stimulated activities of superoxide dismutase and catalase and elevated reduced glutathione (GSH) concentration and GSH/oxidized glutathione, which is in agreement with reduced concentrations of O2- and H2O2 in Taxodium 406 roots. The levels of starch, soluble protein, indole-3-acetic acid, gibberellin A4 and jasmonate were decreased, whereas the concentrations of glucose, total non-structural carbohydrates, most amino acids and 1-aminocyclopropane-1-carboxylate (ACC) were improved in the roots of flooding-treated Taxodium 406. Underlying these changes in growth and physiological characteristics, 12,420 mRNAs and 42 miRNAs were significantly differentially expressed, and 886 miRNA-mRNA pairs were identified in the roots of flooding-exposed Taxodium 406. For instance, 1-aminocyclopropane-1-carboxylate synthase 8 (ACS8) was a target of Th-miR162-3p and 1-aminocyclopropane-1-carboxylate oxidase 4 (ACO4) was a target of Th-miR166i, and the downregulation of Th-miR162-3p and Th-miR166i results in the upregulation of ACS8 and ACO4, probably bringing about higher ACC content in flooding-treated roots. Overall, these results indicate that differentially expressed mRNA and miRNAs are involved in regulating tricarboxylic acid cycle, ATP production, fermentation, and metabolism of carbohydrates, amino acids and phytohormones, as well as reactive oxygen species detoxification of Taxodium 406 roots. These processes play pivotal roles in acclimation to flooding stress. These results will improve our understanding of the molecular and physiological bases underlying woody plant flooding acclimation and provide valuable insights into breeding-flooding tolerant trees.

COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways.

BACKGROUND: Pancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. METHODS: ELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. RESULTS: ELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-ß1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. CONCLUSION: In conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.

Thermo-sensitive PLGA-PEG-PLGA hydrogel for sustained release of EGF to inhibit cervical cancer recurrence.

Overexpression of epidermal growth factor receptor (EGFR) in cancer is a key cause of recurrence of cervical cancer (CC). Although the EGF-EGFR pathway has been studied for decades, preventing tumor growth and recurrence caused by peripheral EGF remains a great challenge. In this work, a strategy is proposed to reduce the stimulation of high concentration EGF on tumor growth by using a thermo-sensitive hydrogel. The hydrogel is a triblock copolymer composed of polyethylene glycol (PEG) and poly (lactide glycolide) (PLGA). Based on the excellent temperature sensitivity, carrier capacity, swelling property and biocompatibility, the hydrogel can absorb the liquid around the tumor by injection and release EGF continuously at low concentration. The inhibitory effect of hydrogel on tumor growth is fully confirmed by an implanted tumor mouse model with human cervical cancer cell lines (HeLa) using triple-immunodeficient NCG mice. Compared with free EGF, the EGF-loaded hydrogel can hardly induce surface plasmon resonance (SPR) response, which proves that hydrogel can effectively weaken cytoskeleton rearrangement and inhibit cell migration by continuously releasing low concentration EGF. In addition, the EGF-loaded hydrogel can reduce cell proliferation by delaying the progress of cell cycle progression. Taken together, the hydrogel can effectively protect tumor microenvironment from the stimulation of high concentration EGF, delay cancer cellular processes and tumor growth, and thus providing an approach for inhibiting tumor recurrence of CC.

Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.

Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.

Inducing mitochondriopathy-like damages by transformable nucleopeptide nanoparticles for targeted therapy of bladder cancer.

Mitochondriopathy inspired adenosine triphosphate (ATP) depletions have been recognized as a powerful way for controlling tumor growth. Nevertheless, selective sequestration or exhaustion of ATP under complex biological environments remains a prodigious challenge. Harnessing the advantages of in vivo self-assembled nanomaterials, we designed an Intracellular ATP Sequestration (IAS) system to specifically construct nanofibrous nanostructures on the surface of tumor nuclei with exposed ATP binding sites, leading to highly efficient suppression of bladder cancer by induction of mitochondriopathy-like damages. Briefly, the reported transformable nucleopeptide (NLS-FF-T) self-assembled into nuclear-targeted nanoparticles with ATP binding sites encapsulated inside under aqueous conditions. By interaction with KPNA2, the NLS-FF-T transformed into a nanofibrous-based ATP trapper on the surface of tumor nuclei, which prevented the production of intracellular energy. As a result, multiple bladder tumor cell lines (T24, EJ and RT-112) revealed that the half-maximal inhibitory concentration (IC50) of NLS-FF-T was reduced by approximately 4-fold when compared to NLS-T. Following intravenous administration, NLS-FF-T was found to be dose-dependently accumulated at the tumor site of T24 xenograft mice. More significantly, this IAS system exhibited an extremely antitumor efficacy according to the deterioration of T24 tumors and simultaneously prolonged the overall survival of T24 orthotopic xenograft mice. Together, our findings clearly demonstrated the therapeutic advantages of intracellular ATP sequestration-induced mitochondriopathy-like damages, which provides a potential treatment strategy for malignancies.

Critical factors driving spatiotemporal variability in the phytoplankton community structure of the coral habitat in Dongshan Bay, China.

This study investigated the spatiotemporal distribution of the phytoplankton in the coral habitat of Dongshan Bay (China), along with critical factors affecting the distribution, during June, August, and December 2022. Phytoplankton abundance in Dongshan Bay exhibited considerably temporal variation, peaking in June 2022, gradually decreasing thereafter, and reaching its lowest point in December 2022. The abundance of bottom-layer phytoplankton consistently exceeded that of the surface layer throughout all seasons. The average phytoplankton abundance in the coral habitat of Dongshan Bay was lower than that in non-coral habitat areas. Fluctuations in the Zhangjiang River and coastal upwelling influenced the diversity and community structure of the phytoplankton. Critical factors causing spatiotemporal variability in phytoplankton community structure included nutrient concentrations and seawater temperature. Nutrients played key roles in influencing various phytoplankton groups. Dominant diatom species, such as Thalassionema nitzschioides and Thalassiosira diporocyclus, were positively correlated with ammonia nitrogen, seawater salinity, coral cover, and the number of coral species present. In winter, Calanus sinicus exhibited a negative correlation with harmful algal bloom species. Additionally, it was found that both in the coral habitat and surrounding open sea, currents, nutrients, and zooplankton may play crucial roles in determining the spatiotemporal variability in the phytoplankton community structure.

Supramolecular complexation of C60 with branched polyethylene.

Fullerene C60 is a ubiquitous material for application in organic electronics and nanotechnology, due to its desirable optoelectronic properties including good molecular orbital alignment with electron-rich donor materials, as well as high and isotropic charge carrier mobility. However, C60 possesses two limitations that hinder its integration into large-scale devices: (1) poor solubility in common organic solvents leading to expensive device processing, and (2) poor optical absorbance in the visible portion of the spectrum. Covalent functionalization has long been the standard for introducing structural tunability into molecular design, but non-covalent interactions have emerged as an alternative strategy to tailor C60-based materials, offering a versatile and tuneable alternative to novel functional materials and applications. In this work, we report a straightforward non-covalent functionalization of C60 with a branched polyethylene (BPE), which occurs spontaneously in dilute chloroform solution under ambient conditions. A detailed characterization strategy, based on UV-vis spectroscopy and size-exclusion chromatography was performed to verify and investigate the structure of the C60+BPE complex. Among others, our work reveals that the supramolecular complex has an order of magnitude higher molecular weight than its C60 and BPE constituents and points towards oxidation as the driving force behind complexation. The C60+BPE complex also possesses significantly broadened optical absorbance compared to unfunctionalized C60, extending further into the visible portion of the spectrum. This non-covalent approach presents an inexpensive route to address the shortcomings of C60 for electronic applications, situating the C60+BPE complex as a promising candidate for further investigation in organic electronic devices.

Is there any difference in urinary continence between bilateral and unilateral nerve sparing during radical prostatectomy? A systematic review and meta-analysis.

CONTEXT: In men with prostate cancer, urinary incontinence is one of the most common long-term side effects of radical prostatectomy (RP). The recovery of urinary continence in patients is positively influenced by preserving the integrity of the neurovascular bundles (NVBs). However, it is still unclear if bilateral nerve sparing (BNS) is superior to unilateral nerve sparing (UNS) in terms of post-RP urinary continence. The aim of this study is to systematically compare the differences in post-RP urinary continence outcomes between BNS and UNS. METHODS: The electronic databases of PubMed and Web of Science were comprehensively searched. The search period was up to May 31, 2023. English language articles comparing urinary continence outcomes of patients undergoing BNS and UNS radical prostatectomy were included. Meta-analyses were performed to calculate pooled relative risk (RR) estimates with 95% confidence intervals for urinary continence in BNS and UNS groups at selected follow-up intervals using a random-effects model. Sensitivity analyses were performed in prospective studies and robotic-assisted RP studies. RESULTS: A meta-analysis was conducted using data from 26,961 participants in fifty-seven studies. A meta-analysis demonstrated that BNS improved the urinary continence rate compared to UNS at all selected follow-up points. RRs were 1.36 (1.14-1.63; p = 0.0007) at ≤ 1.5 months (mo), 1.28 (1.08-1.51; p = 0.005) at 3-4 mo, 1.12 (1.03-1.22; p = 0.01) at 6 mo, 1.08 (1.05-1.12; p < 0.00001) at 12 mo, and 1.07 (1.00-1.13; p = 0.03) at ≥ 24 mo, respectively. With the extension of the follow-up time, RRs decreased from 1.36 to 1.07, showing a gradual downward trend. Pooled estimates were largely heterogeneous. Similar findings were obtained through sensitivity analyses of prospective studies and robotic-assisted RP studies. CONCLUSION: The findings of this meta-analysis demonstrate that BNS yields superior outcomes in terms of urinary continence compared to UNS, with these advantages being sustained for a minimum duration of 24 months. It may be due to the real effect of saving the nerves involved. Future high-quality studies are needed to confirm these findings.

Targeting Grancalcin Accelerates Wound Healing by Improving Angiogenesis in Diabetes.

Chronic diabetic wounds are a serious complication of diabetes and often result in limb amputations and confer high mortality rates. The proinflammatory secretome in the wound perpetuates defective neovascularization and contributes to dysregulated tissue repair. This study aims to design a gelatin methacrylamide (GelMA) hydrogel to sustained the release of grancalcin-neutralizing antibody (GCA-NAb) and evaluate it as a potential scaffold to promote diabetic wound healing. Results show that the expression of grancalcin(GCA), a protein secreted by bone marrow-derived immune cells, is elevated in the wound sites of individuals and animals with diabetic ulcers. Genetic inhibition of grancalcin expression accelerates vascularization and healing in an animal model. Mechanistic studies show that grancalcin binds to transient receptor potential melastatin 8(TRPM8) and partially inactivates its downstream signaling pathways, thereby impairing angiogenesis in vitro and ex vivo. Systemic or topical administration of a GCA-NAb accelerate wound repair in mice with diabetes. The data suggest that GCA is a potential therapeutic target for the treatment of diabetic ulcers.

Pirfenidone alleviates chronic pancreatitis via suppressing the activation of pancreatic stellate cells and the M1 polarization of macrophages.

In the realm of fibroinflammatory conditions, chronic pancreatitis (CP) stands out as a particularly challenging ailment, lacking a dedicated, approved treatment. The potential of Pirfenidone (PFD), a drug originally used for treating idiopathic pulmonary fibrosis (IPF), in addressing CP's fibrotic aspects has sparked new interest. This investigation focused on the role of PFD in diminishing fibrosis and immune response in CP, using a mouse model induced by caerulein. The research extended to in vitro studies examining the influence of PFD on pancreatic stellate cells' (PSCs) behavior and the polarization of macrophages into M1 and M2 types. Advanced techniques like RNA sequencing and comprehensive data analyses were employed to decode the molecular interactions of PFD with PSCs. Supplementary experiments using techniques such as quantitative real-time PCR, western blotting, and immunofluorescence were also implemented. Results showed a notable reduction in pancreatic damage in PFD-treated mice, manifested through decreased acinar cell atrophy, lower collagen deposition, and a reduction in macrophage presence. Further investigation revealed PFD's capacity to hinder PSCs' migration, growth, and activation, alongside a reduction in the production and secretion of extracellular matrix proteins. This effect is primarily achieved by interfering with signaling pathways such as TGF-ß/Smad, Wnt/ß-catenin, and JAK/STAT. Additionally, PFD selectively hampers M1 macrophage polarization through the STAT3 pathway, without impacting M2 polarization. These outcomes highlight PFD's dual mechanism in moderating PSC activity and M1 macrophage polarization, positioning it as a promising candidate for CP therapy.

Effect of Pleurotus eryngii mycelial fermentation on the composition and antioxidant properties of tartary buckwheat.

In this study, we investigated the effect of solid-state fermentation of Pleurotus eryngii on the composition and antioxidant activity of Tartary buckwheat (TB). Firstly, the solid-state fermentation of P. eryngii mycelium with buckwheat was carried out, and the fermentation process was explored. The results of the extraction process and method selection experiments showed that the percolation extraction method was superior to the other two methods. The results of extraction rate, active components and antioxidant activity measurements before and after fermentation of TB extract showed that the extraction rate increased about 1.7 times after fermentation. Total flavonoids, rutin and triterpene contents were increased after fermentation compared to control. Meanwhile, LC-MS results showed an increase in the content of the most important substances in the fermented TB extract and the incorporation of new components, such as oleanolic acid, ursolic acid, amino acids, and D-chiral inositol. The fermented TB extract showed stronger antioxidant activity, while the protein and amino acid contents increased by 1.93-fold and 1.94-fold, respectively. This research was the first to use P. eryngii to ferment TB and prepared a lyophilized powder that could be used directly using vacuum freeze-drying technology. Not only the use of solid-state fermentation technology advantages of edible fungi to achieve value-added buckwheat, but also to broaden the scope of TB applications. This study will provide ideas and directions for the development and application of edible mushroom fermentation technology and TB.

Creation of Interfacial S4 -Sn-N2 Electron Pathways for Efficient Light-Driven Hydrogen Evolution.

Establishing effective charge transfer channels between two semiconductors is key to improving photocatalytic activity. However, controlling hetero-structures in situ and designing binding modes pose significant challenges. Herein, hydrolytic SnCl2 ·2H2 O is selected as the metal source and loaded in situ onto a layered carbon nitriden supramolecular precursor. A composite photocatalyst, S4 -Sn-N2 , with electron pathways of SnS2 and tubular carbon nitriden (TCN) is prepared through pyrolysis and vulcanization processes. The contact interface of SnS2 -TCN is increased significantly, promoting the formation of S4 -Sn-N2 micro-structure in a Z-scheme charge transfer channel. This structure accelerates the separation and transport of photogenerated carriers, maintains the stronger redox ability, and improves the stability of SnS2 in this series of heterojunctions. Therefore, the catalyst demonstrated exceptional photocatalytic hydrogen production efficiency, achieving a reaction rate of 86.4 µmol h-1 , which is 3.15 times greater than that of bare TCN.

A green and environmentally benign route to synthesizing Z-scheme Bi2S3-TCN photocatalyst for efficient hydrogen production.

Designing and developing photocatalysts with excellent performance in order to achieve efficient hydrogen production is an important strategy for addressing future energy and environmental challenges. Traditional single-phase photocatalytic materials either have a large bandgap and low visible light response or experience rapid recombination of the photogenerated carriers with low quantum efficiency, seriously hindering their photocatalytic applications. To solve these issues, an important solution is to construct well-matched heterojunctions with highly efficient charge separation capabilities. To this end, an in situ sulfurization reaction was adopted after the deposition of Bi3+ supramolecular complex on a layered supramolecular precursor of tubular carbon nitride (TCN). X-ray diffraction (XRD) patterns confirmed that the as-prepared sample has a good crystalline structure without any other impurities, while high-resolution transmission electron microscopy (HR-TEM) revealed that the heterojunction possesses a 2D structure with a layer of nano-array on its surface. Combined Fourier-transform infrared (FT-IR) spectra and energy-dispersive X-ray spectroscopy (EDX) revealed the interfacial interactions. Owing to the formation of the Z-scheme heterojunction, the visible light adsorption and the separation efficiency of the photo-generated carriers are both obviously enhanced, leaving the high energy electrons and high oxidative holes to participate in the photocatalytic reactions. As a result, the photocatalytic hydrogen evolution rate of Bi2S3-TCN achieves 65.2 µmol g-1·h-1. This proposed green and environmentally benign route can also be applied to construct other sulfides with 2D TCN, providing some important information for the design and optimization of novel carbon-nitride-based semiconductors.

In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy.

Emerging evidence indicates that the activation of ferroptosis by glutathione peroxidase 4 (GPX4) inhibitors may be a prominent therapeutic strategy for tumor suppression. However, the wide application of GPX4 inhibitors in tumor therapy is hampered due to poor tumor delivery efficacy and the nonspecific activation of ferroptosis. Taking advantage of in vivo self-assembly, we develop a peptide-ferriporphyrin conjugate with tumor microenvironment specific activation to improve tumor penetration, endocytosis and GPX4 inhibition, ultimately enhancing its anticancer activity via ferroptosis. Briefly, a GPX4 inhibitory peptide is conjugated with an assembled peptide linker decorated with a pH-sensitive moiety and ferriporphyrin to produce the peptide-ferriporphyrin conjugate (Gi-F-CAA). Under the acidic microenvironment of the tumor, the Gi-F-CAA self-assembles into large nanoparticles (Gi-F) due to enhanced hydrophobic interaction after hydrolysis of CAA, improving tumor endocytosis efficiency. Importantly, Gi-F exhibits substantial inhibition of GPX4 activity by assembly enhanced binding (AEB) effect, augmenting the oxidative stress of ferriporphyrin-based Fenton reaction, ultimately enabling antitumor properties in multiple tumor models. Our findings suggest that this peptide-ferriporphyrin conjugate design with AEB effect can improve the therapeutic effect via induction of ferroptosis, providing an alternative strategy for overcoming chemoresistance.

HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralization by antibodies.

Bacteria dysbiosis has been associated with an increased risk of HIV-1 transmission and acquisition. The prevalent idea is that bacteria dysbiosis compromises mucosal integrity and promotes inflammatory conditions to cause recruitment and activation of immune cells that harbor or are targeted by HIV-1. However, it is also possible that HIV-1 directly binds bacteria or bacterial products to impact virus infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, which is part of the fimbriae shrouding the bacteria surface and recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. Conversely, N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to broadly neutralizing antibodies targeting different regions of Env. Hence, this study highlights the potential contribution of O-glycans in promoting HIV-1 infection through the exploitation of O-glycan-binding lectins from commensal bacteria at the mucosa.