Unraveling the role of ubiquitin-conjugating enzyme 5 (UBC5) in disease pathogenesis: A comprehensive review.

While certain members of ubiquitin-coupled enzymes (E2s) have garnered attention as potential therapeutic targets across diverse diseases, research progress on Ubiquitin-Conjugating Enzyme 5 (UBC5)-a pivotal member of the E2s family involved in crucial cellular processes such as apoptosis, DNA repair, and signal transduction-has been relatively sluggish. Previous findings suggest that UBC5 plays a vital role in the ubiquitination of various target proteins implicated in diseases and homeostasis, particularly in various cancer types. This review comprehensively introduces the structure and biological functions of UBC5, with a specific focus on its contributions to the onset and advancement of diverse diseases. It suggests that targeting UBC5 holds promise as a therapeutic approach for disease therapy. Recent discoveries highlighting the high homology between UBC5, UBC1, and UBC4 have provided insight into the mechanism of UBC5 in protein degradation and the regulation of cellular functions. As our comprehension of the structural distinctions among UBC5 and its homologues, namely UBC1 and UBC4, advances, our understanding of UBC5's functional significance also expands.

In situ implantable DNA hydrogel for diagnosis and therapy of postoperative rehemorrhage following intracerebral hemorrhage surgery.

Postoperative rehemorrhage following intracerebral hemorrhage surgery is intricately associated with a high mortality rate, yet there is now no effective clinical treatment. In this study, we developed a hemoglobin (Hb)-responsive in situ implantable DNA hydrogel comprising Hb aptamers cross-linked with two complementary chains and encapsulating deferoxamine mesylate (DFO). Functionally, the hydrogel generates signals upon postoperative rehemorrhage by capturing Hb, demonstrating a distinctive "self-diagnosis" capability. In addition, the ongoing capture of Hb mediates the gradual disintegration of the hydrogel, enabling the on-demand release of DFO without compromising physiological iron-dependent functions. This process achieves self-treatment by inhibiting the ferroptosis of neurocytes. In a collagenase and autologous blood injection model-induced mimic postoperative rehemorrhage model, the hydrogel exhibited a 5.58-fold increase in iron absorption efficiency, reducing hematoma size significantly (from 8.674 to 4.768 cubic millimeters). This innovative Hb-responsive DNA hydrogel not only offers a therapeutic intervention for postoperative rehemorrhage but also provides self-diagnosis feedback, holding notable promise for enhancing clinical outcomes.

Modified montmorillonite armed probiotics with enhanced on-site mucus-depleted intestinal colonization and H2S scavenging for colitis treatment.

Inflammatory bowel diseases (IBD) are often associated with dysregulated gut microbiota and excessive inflammatory microenvironment. Probiotic therapy combined with inflammation management is a promising approach to alleviate IBD, but the efficacy is hindered by the inferior colonization of probiotics in mucus-depleted inflammatory bowel segments. Here, we present modified montmorillonite armed probiotic Escherichia coli Nissle 1917 (MMT-Fe@EcN) with enhanced intestinal colonization and hydrogen sulfide (H2S) scavenging for synergistic alleviation of IBD. The montmorillonite layer that can protect EcN against environmental assaults in oral delivery and improve on-site colonization of EcN in the mucus-depleted intestinal segment due to its strong adhesive capability and electronegativity, with a 22.6-fold increase in colonization efficiency compared to EcN. Meanwhile, MMT-Fe@EcN can manage inflammation by scavenging H2S, which allows for enhancing probiotic viability and colonization for restoring the gut microbiota. As a result, MMT-Fe@EcN exhibits extraordinary therapeutic effects in the dextran sulfate sodium-induced mouse colitis models, including alleviating intestinal inflammation and restoring disrupted intestinal barrier function, and gut microbiota. These findings provide a promising strategy for clinical IBD treatment and potentially other mucus-depletion-related diseases.

Dendritic Cell-Hitchhiking In Vivo for Vaccine Delivery to Lymph Nodes.

Therapeutic cancer vaccines are among the first FDA-approved cancer immunotherapies. Among them, it remains a major challenge to achieve robust lymph-node (LN) accumulation. However, delivering cargo into LN is difficult owing to the unique structure of the lymphatics, and clinical responses have been largely disappointing. Herein, inspired by the Migrated-DCs homing from the periphery to the LNs, an injectable hydrogel-based polypeptide vaccine system is described for enhancing immunostimulatory efficacy, which could form a local niche of vaccine "hitchhiking" on DCs. The OVA peptide modified by lipophilic DSPE domains in the hydrogel is spontaneously inserted into the cell membrane to achieve "antigen anchoring" on DCs in vivo. Overall, OVA peptide achieves active access LNs through recruiting and "hitchhiking" subcutaneous Migrated-DCs. Remarkably, it is demonstrated that the composite hydrogel enhances LNs targeting efficacy by approximately six-fold compared to free OVA peptide. Then, OVA peptide can be removed from the cell surface under a typical acidic microenvironment within the LNs, further share them with LN-resident APCs via the "One-to-Many" strategy (One Migrated-DC corresponding to Many LN-resident APCs), thereby activating powerful immune stimulation. Moreover, the hydrogel vaccine exhibits significant tumor growth inhibition in melanoma and inhibits pulmonary metastatic nodule formation.

The State-of-the-Art Antibacterial Activities of Glycyrrhizin: A Comprehensive Review.

Licorice (Glycyrrhiza glabra) is a plant of the genus Glycyrrhiza in the family Fabaceae/Leguminosae and is a renowned natural herb with a long history of medicinal use dating back to ancient times. Glycyrrhizin (GLY), the main active component of licorice, serves as a widely utilized therapeutic agent in clinical practice. GLY exhibits diverse medicinal properties, including anti-inflammatory, antibacterial, antiviral, antitumor, immunomodulatory, intestinal environment maintenance, and liver protection effects. However, current research primarily emphasizes GLY's antiviral activity, while providing limited insight into its antibacterial properties. GLY demonstrates a broad spectrum of antibacterial activity via inhibiting the growth of bacteria by targeting bacterial enzymes, impacting cell membrane formation, and altering membrane permeability. Moreover, GLY can also bolster host immunity by activating pertinent immune pathways, thereby enhancing pathogen clearance. This paper reviews GLY's inhibitory mechanisms against various pathogenic bacteria-induced pathological changes, its role as a high-mobility group box 1 inhibitor in immune regulation, and its efficacy in combating diseases caused by pathogenic bacteria. Furthermore, combining GLY with other antibiotics reduces the minimum inhibitory concentration, potentially aiding in the clinical development of combination therapies against drug-resistant bacteria. Sources of information were searched using PubMed, Web of Science, Science Direct, and GreenMedical for the keywords "licorice", "Glycyrrhizin", "antibacterial", "anti-inflammatory", "HMGB1", and combinations thereof, mainly from articles published from 1979 to 2024, with no language restrictions. Screening was carried out by one author and supplemented by others. Papers with experimental flaws in their experimental design and papers that did not meet expectations (antifungal papers, etc.) were excluded.

The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

Theoretical study of the nitrogen reduction reaction catalyzed by a B-doped MoO2 six-membered ring.

In this study, two potential catalysts with double-B atom-doped atomic MoO2 (B2/MoO2) and single-B atom-doped atomic MoO2 (B/MoO2) were designed and constructed. The thermodynamics and selectivity of two catalysts in the nitrogen fixation reaction were analyzed by a DFT calculation method. The results show that B2/MoO2 shows better adsorption activation and reduction and can effectively activate nitrogen molecules by two adjacent boron atoms. It achieves an extremely low overpotential of -0.18 V and rapid NRR kinetics through an enzymatic mechanism. Therefore, B2/MoO2 is a very promising NRR candidate catalyst. This research shows that doping with diatomic B (as an active site) results in an excellent NRR catalytic activity, which provides a certain theoretical basis for the preparation of high-performance NRR catalysts.

The emerging role of deubiquitylating enzyme USP21 as a potential therapeutic target in cancer.

Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers.This reviewcomprehensively summarizes the structure and biological functions of USP21 with an emphasis on its role in tumorigenesis, and elucidates the advances on the discovery of tens of small-molecule inhibitors targeting USP21, which suggests that targeting USP21 may represent a potential strategy for cancer therapy.

Curriculum vitae of CUG binding protein 1 (CELF1) in homeostasis and diseases: a systematic review.

RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.

Biomimetic Nanovehicle-Enabled Targeted Depletion of Intratumoral Fusobacterium nucleatum Synergizes with PD-L1 Blockade against Breast Cancer.

Immune checkpoint blockade (ICB) therapy has been approved for breast cancer (BC), but clinical response rates are limited. Recent studies have shown that commensal microbes colonize a variety of tumors and are closely related to the host immune system response. Here, we demonstrated that Fusobacterium nucleatum (F.n), which is prevalent in BC, creates an immunosuppressive tumor microenvironment (ITME) characterized by a high-influx of myeloid cells that hinders ICB therapy. Administering the antibiotic metronidazole in BC can deplete F.n and remodel the ITME. To prevent an imbalance in the systemic microbiota caused by antibiotic administration, we designed a biomimetic nanovehicle for on-site antibiotic delivery inspired by F.n homing to BC. Additionally, ferritin-nanocaged doxorubicin was coloaded into this nanovehicle, as immunogenic chemotherapy has shown potential for synergy with ICB. It has been demonstrated that this biomimetic nanovehicle can be precisely homed to BC and efficiently eliminate intratumoral F.n without disrupting the diversity and abundance of systemic microbiota. This ultimately remodels the ITME, improving the therapeutic efficacy of the PD-L1 blocker with a tumor inhibition rate of over 90% and significantly extending the median survival of 4T1 tumor-bearing mice.

A Neutrophil Hijacking Nanoplatform Reprograming NETosis for Targeted Microglia Polarizing Mediated Ischemic Stroke Treatment.

Precise and efficient regulation of microglia is vital for ischemic stroke therapy and prognosis. The infiltration of neutrophils into the brain provides opportunities for regulatory drugs across the blood-brain barrier, while hindered by neutrophil extracellular traps (NETs) and targeted delivery of intracerebral drugs to microglia. This study reports an efficient neutrophil hijacking nanoplatform (referred to as APTS) for targeted A151 (a telomerase repeat sequence) delivery to microglia without the generation of NETs. In the middle cerebral artery occlusion (MCAO) mouse model, the delivery efficiency to ischemic stroke tissues increases by fourfold. APTS dramatically reduces the formation of NETs by 2.2-fold via reprogramming NETosis to apoptosis in neutrophils via a reactive oxygen species scavenging-mediated citrullinated histone 3 inhibition pathway. Noteworthy, A151 within neutrophils is repackaged into apoptotic bodies following the death pattern reprogramming, which, when engulfed by microglia, polarizes microglia to an anti-inflammatory M2 phenotype. After four times treatment, the cerebral infarction area in the APTS group decreases by 5.1-fold. Thus, APTS provides a feasible, efficient, and practical drug delivery approach for reshaping the immune microenvironment and treating brain disorders in the central nervous system.

Neutrophil hitchhiking nanoparticles enhance bacteria-mediated cancer therapy via NETosis reprogramming.

Bacteria have shown great potential in anti-tumor treatment, and an attenuated strain of Salmonella named VNP20009 has been shown to be safe in clinical trials. However, colonized bacteria recruit neutrophils into the tumor, which release NETs to capture and eliminate bacteria, compromising bacterial-based tumor treatment. In this study, we report a neutrophil hitchhiking nanoparticles (SPPS) that block the formation of NET to enhance bacteria-mediated tumor therapy. In the 4 T1 tumor-bearing mouse model, following 24 h of bacterial therapy, there was an approximately 3.0-fold increase in the number of neutrophils in the bloodstream, while the amount of SPPS homing to tumor tissue through neutrophil hitchhiking increased approximately 2.0-fold. It is worth noting that the NETs in tumors significantly decreased by approximately 2.0-fold through an intracellular ROS scavenging-mediated NETosis reprogramming, thereby increasing bacterial vitality by 1.9-fold in tumors. More importantly, the gene drug (siBcl-2) loaded in SPPS can be re-encapsulated in apoptotic bodies by reprogramming neutrophils from NETosis to apoptosis, and enable the redelivery of drugs to tumor cells, further boosting the antitumor efficacy with a synergistic effect, resulting in about 98% tumor inhibition rate and 90% survival rate.

Pharmacokinetics and bioequivalence evaluation of two oral formulations of cotrimoxazole tablets in healthy Chinese volunteers under fasting conditions.

This bioequivalence study was conducted to evaluate two oral formulations of cotrimoxazole tablets in healthy Chinese subjects. All 26 subjects recruited to this study were randomly and evenly classified into two groups and received a single dose (sulfamethoxazole: 400 mg and trimethoprim: 80 mg) of test cotrimoxazole tablets (generic drug) or reference cotrimoxazole tablets (branded drug). After a 7-day washout period, these subjects received one dose of reference drug or test drug. Blood samples were collected from participants before and up to 48 h after dosing to assess the concentration of sulfamethoxazole (SMX) and trimethoprim (TMP) in plasma and a plasma concentration-time curve was drawn. Then, the pharmacokinetics parameters were calculated accordingly. Our data revealed that there were no significant differences observed in the maximum plasma concentration (Cmax), area under the curve from time 0 to the last measurable concentration (AUC0-t), and area under the curve from time 0 to infinity (AUC0-∞) between the two formulations. For SMX, the 90% confidence intervals (CI) of the geometric mean ratio for Cmax, AUC0-t, and AUC0-∞ were 104.03-113.92%, 100.46-103.70%, and 100.41-103.81%, respectively. Similarly, for Trimethoprim (TMP), the 90% CI ranged from 98.54 to 106.95% for Cmax, from 99.31 to 107.68% for AUC0-t, and from 99.49 to 107.55% for AUC0-∞. Importantly, all these 90% CI values fell within the range of 80.00-125.00%, indicating that the test drug is bioequivalent to the reference drug. Furthermore, throughout the entire trial, no suspected serious adverse events were reported, indicating the safety profile of the newly developed generic cotrimoxazole. In summary, our study demonstrates that the newly developed generic formulation of cotrimoxazole is bioequivalent to the branded formulation under fasting conditions.

Ultrasensitive Optical Detection and Elimination of Residual Microtumors with a Postoperative Implantable Hydrogel Sensor for Preventing Cancer Recurrence.

In vivo optical imaging of trace biomarkers in residual microtumors holds significant promise for cancer prognosis but poses a formidable challenge. Here, a novel hydrogel sensor is designed for ultrasensitive and specific imaging of the elusive biomarker. This hydrogel sensor seamlessly integrates a molecular beacon nanoprobe with fibroblasts, offering both high tissue retention capability and an impressive signal-to-noise ratio for imaging. Signal amplification is accomplished through exonuclease I-mediated biomarker recycling. The resulting hydrogel sensor sensitively detects the biomarker carcinoembryonic antigen with a detection limit of 1.8 pg mL-1 in test tubes. Moreover, it successfully identifies residual cancer nodules with a median diameter of less than 2 mm in mice bearing partially removed primary triple-negative breast carcinomas (4T1). Notably, this hydrogel sensor is proven effective for the sensitive diagnosis of invasive tumors in post-surgical mice with infiltrating 4T1 cells, leveraging the role of fibroblasts in locally enriching tumor cells. Furthermore, the residual microtumor is rapidly photothermal ablation by polydopamine-based nanoprobe under the guidance of visualization, achieving ≈100% suppression of tumor recurrence and lung metastasis. This work offers a promising alternative strategy for visually detecting residual microtumors, potentially enhancing the prognosis of cancer patients following surgical interventions.

Nanoenabled Intracellular Metal Ion Homeostasis Regulation for Tumor Therapy.

Endogenous essential metal ions play an important role in many life processes, especially in tumor development and immune response. The approval of various metallodrugs for tumor therapy brings more attention to the antitumor effect of metal ions. With the deepening understanding of the regulation mechanisms of metal ion homeostasis in vivo, breaking intracellular metal ion homeostasis becomes a new means to inhibit the proliferation of tumor cells and activate antitumor immune response. Diverse nanomedicines with the loading of small molecular ion regulators or metal ions have been developed to disrupt metal ion homeostasis in tumor cells, with higher safety and efficiency than free small molecular ion regulators or metal compounds. This comprehensive review focuses on the latest progress of various intracellular metal ion homeostasis regulation-based nanomedicines in tumor therapy including calcium ion (Ca2+ ), ferrous ion (Fe2+ ), cuprous ion (Cu+ ), managanese ion (Mn2+ ), and zinc ion (Zn2+ ). The physiological functions and homeostasis regulation processes of ions are summarized to guide the design of metal ion regulation-based nanomedicines. Then the antitumor mechanisms of various ions-based nanomedicines and some efficient synergistic therapies are highlighted. Finally, the challenges and future developments of ion regulation-based antitumor therapy are also discussed, hoping to provide a reference for finding more effective metal ions and synergistic therapies.

Liposomal Antibiotic Booster Potentiates Carbapenems for Combating NDMs-Producing Escherichia coli.

Infections caused by Enterobacterales producing New Delhi Metallo-ß-lactamases (NDMs), Zn(II)-dependent enzymes hydrolyzing carbapenems, are difficult to treat. Depriving Zn(II) to inactivate NDMs is an effective solution to reverse carbapenems resistance in NDMs-producing bacteria. However, specific Zn(II) deprivation and better bacterial outer membrane penetrability in vivo are challenges. Herein, authors present a pathogen-primed liposomal antibiotic booster (M-MFL@MB), facilitating drugs transportation into bacteria and removing Zn(II) from NDMs. M-MFL@MB introduces bismuth nanoclusters (BiNCs) as a storage tank of Bi(III) for achieving ROS-initiated Zn(II) removal. Inspired by bacteria-specific maltodextrin transport pathway, meropenem-loaded BiNCs are camouflaged by maltodextrin-cloaked membrane fusion liposome to cross the bacterial envelope barrier via selectively targeting bacteria and directly outer membrane fusion. This fusion disturbs bacterial membrane homeostasis, then triggers intracellular ROS amplification, which activates Bi(III)-mediated Zn(II) replacement and meropenem release, realizing more precise and efficient NDMs producer treatment. Benefiting from specific bacteria-targeting, adequate drugs intracellular accumulation and self-activation Zn(II) replacement, M-MFL@MB rescues all mice infected by NDM producer without systemic side effects. Additionally, M-MFL@MB decreases the bacterial outer membrane vesicles secretion, slowing down NDMs producer's transmission by over 35 times. Taken together, liposomal antibiotic booster as an efficient and safe tool provides new strategy for tackling NDMs producer-induced infections.

Urease-Powered Micromotors with Spatially Selective Distribution of Enzymes for Capturing and Sensing Exosomes.

Enzyme-catalyzed micro/nanomotors (MNMs) exhibit tremendous potential for biological isolation and sensing, because of their biocompatibility, versatility, and ready access to biofuel. However, flow field generated by enzyme-catalyzed reactions might significantly hinder performance of surface-linked functional moieties, e.g., the binding interaction between MNMs and target cargos. Herein, we develop enzymatic micromotors with spatially selective distribution of urease to enable the independent operation of various modules and facilitate the capture and sensing of exosomes. When urease is modified into the motors' cavity, the flow field from enzyme catalysis has little effect on the exterior surface of the motors. The active motion and encapsulating urease internally result in enhancement of ∼35% and 18% in binding efficiency of target cargos, e.g., exosomes as an example here, compared to their static counterparts and moving micromotors with urease modified externally, respectively. Once exosomes are trapped, they can be transferred to a clean environment by the motors for Raman signal detection and/or identification using the surface Raman enhancement scattering (SERS) effect of coated gold nanoshell. The biocatalytic micromotors, achieving spatial separation between driving module and function module, offer considerable promise for future design of multifunctional MNMs in biomedicine and diagnostics.