Distinct Neural Circuits for the Formation and Retrieval of Episodic Memories.

The formation and retrieval of a memory is thought to be accomplished by activation and reactivation, respectively, of the memory-holding cells (engram cells) by a common set of neural circuits, but this hypothesis has not been established. The medial temporal-lobe system is essential for the formation and retrieval of episodic memory for which individual hippocampal subfields and entorhinal cortex layers contribute by carrying out specific functions. One subfield whose function is poorly known is the subiculum. Here, we show that dorsal subiculum and the circuit, CA1 to dorsal subiculum to medial entorhinal cortex layer 5, play a crucial role selectively in the retrieval of episodic memories. Conversely, the direct CA1 to medial entorhinal cortex layer 5 circuit is essential specifically for memory formation. Our data suggest that the subiculum-containing detour loop is dedicated to meet the requirements associated with recall such as rapid memory updating and retrieval-driven instinctive fear responses.

Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer.

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.

RABC: Rheumatoid Arthritis Bioinformatics Center.

Advances in sequencing technologies have led to the rapid growth of multi-omics data on rheumatoid arthritis (RA). However, a comprehensive database that systematically collects and classifies the scattered data is still lacking. Here, we developed the Rheumatoid Arthritis Bioinformatics Center (RABC, http://www.onethird-lab.com/RABC/), the first multi-omics data resource platform (data hub) for RA. There are four categories of data in RABC: (i) 175 multi-omics sample sets covering transcriptome, epigenome, genome, and proteome; (ii) 175 209 differentially expressed genes (DEGs), 105 differentially expressed microRNAs (DEMs), 18 464 differentially DNA methylated (DNAm) genes, 1 764 KEGG pathways, 30 488 GO terms, 74 334 SNPs, 242 779 eQTLs, 105 m6A-SNPs and 18 491 669 meta-mQTLs; (iii) prior knowledge on seven types of RA molecular markers from nine public and credible databases; (iv) 127 073 literature information from PubMed (from 1972 to March 2022). RABC provides a user-friendly interface for browsing, searching and downloading these data. In addition, a visualization module also supports users to generate graphs of analysis results by inputting personalized parameters. We believe that RABC will become a valuable resource and make a significant contribution to the study of RA.

Interrogation of 3d Transition Bimetallic Nanocrystal Nucleation and Growth Using In Situ Electron Microscope and Synchrotron X-ray Techniques.

Understanding the nucleation and growth mechanism of 3d transition bimetallic nanocrystals (NCs) is crucial to developing NCs with tailored nanostructures and properties. However, it remains a significant challenge due to the complexity of 3d bimetallic NCs formation and their sensitivity to oxygen. Here, by combining in situ electron microscopy and synchrotron X-ray techniques, we elucidate the nucleation and growth pathways of Fe-Ni NCs. Interestingly, the formation of Fe-Ni NCs emerges from the assimilation of Fe into Ni clusters together with the reduction of Fe-Ni oxides. Subsequently, these NCs undergo solid-state phase transitions, resulting in two distinct solid solutions, ultimately dominated by γ-Fe3Ni2. Furthermore, we deconvolve the interplays between local coordination and electronic state concerning the growth temperature. We directly visualize the oxidation-state distributions of Fe and Ni at the nanoscale and investigate their changes. This work may reshape and enhance the understanding of nucleation and growth in atomic crystallization.

Effects of genetic variation on the structure of RNA and protein.

Changes in the structure of RNA and protein, have an important impact on biological functions and are even important determinants of disease pathogenesis and treatment. Some genetic variations, including copy number variation, single nucleotide variation, and so on, can lead to changes in biological function and increased susceptibility to certain diseases by changing the structure of RNA or protein. With the development of structural biology and sequencing technology, a large amount of RNA and protein structure data and genetic variation data resources has emerged to be used to explain biological processes. Here, we reviewed the effects of genetic variation on the structure of RNAs and proteins, and investigated their impact on several diseases. An online resource (http://www.onethird-lab.com/gems/) to support convenient retrieval of common tools is also built. Finally, the challenges and future development of the effects of genetic variation on RNA and protein were discussed.

A review of disease risk prediction methods and applications in the omics era.

Risk prediction and disease prevention are the innovative care challenges of the 21st century. Apart from freeing the individual from the pain of disease, it will lead to low medical costs for society. Until very recently, risk assessments have ushered in a new era with the emergence of omics technologies, including genomics, transcriptomics, epigenomics, proteomics, and so on, which potentially advance the ability of biomarkers to aid prediction models. While risk prediction has achieved great success, there are still some challenges and limitations. We reviewed the general process of omics-based disease risk model construction and the applications in four typical diseases. Meanwhile, we highlighted the problems in current studies and explored the potential opportunities and challenges for future clinical practice.

Phosphatidylinositol (3,5)-bisphosphate machinery regulates neurite thickness through neuron-specific endosomal protein NSG1/NEEP21.

Phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] is a critical signaling phospholipid involved in endolysosome homeostasis. It is synthesized by a protein complex composed of PIKfyve, Vac14, and Fig4. Defects in PtdIns(3,5)P2 synthesis underlie a number of human neurological disorders, including Charcot-Marie-Tooth disease, child onset progressive dystonia, and others. However, neuron-specific functions of PtdIns(3,5)P2 remain less understood. Here, we show that PtdIns(3,5)P2 pathway is required to maintain neurite thickness. Suppression of PIKfyve activities using either pharmacological inhibitors or RNA silencing resulted in decreased neurite thickness. We further find that the regulation of neurite thickness by PtdIns(3,5)P2 is mediated by NSG1/NEEP21, a neuron-specific endosomal protein. Knockdown of NSG1 expression also led to thinner neurites. mCherry-tagged NSG1 colocalized and interacted with proteins in the PtdIns(3,5)P2 machinery. Perturbation of PtdIns(3,5)P2 dynamics by overexpressing Fig4 or a PtdIns(3,5)P2-binding domain resulted in mislocalization of NSG1 to nonendosomal locations, and suppressing PtdIns(3,5)P2 synthesis resulted in an accumulation of NSG1 in EEA1-positive early endosomes. Importantly, overexpression of NSG1 rescued neurite thinning in PtdIns(3,5)P2-deficient CAD neurons and primary cortical neurons. Our study uncovered the role of PtdIns(3,5)P2 in the morphogenesis of neurons, which revealed a novel aspect of the pathogenesis of PtdIns(3,5)P2-related neuropathies. We also identified NSG1 as an important downstream protein of PtdIns(3,5)P2, which may provide a novel therapeutic target in neurological diseases.

Construction of Chiral-Magnetic-Dielectric Trinity Structures with Different Magnetic Systems for Efficient Low-Frequency Microwave Absorption.

The fabrication of carbon nanocoil (CNC)-based chiral-dielectric-magnetic trinity composites holds great significance in low-frequency microwave absorption fields. However, it is not clear that how the different magnetic systems affect the magnetic and frequency responses of the composites. Herein, four types of magnetic metals, FeCo, CoNi, FeNi, and FeCoNi, are selected to be combined with the chiral templates respectively, resulting in four types of chiral-dielectric-magnetic composites with similar morphology. The CNC templates endow all the composites with excellent dielectric loss. Further permeability analysis and the micro-magnetic simulation confirm that the frequency response region can be well adjusted by changing the magnetic systems with specific magnetic resonance modes and magnetic domain motion. Due to the synergistic effect between magnetism, chirality, and dielectricity, the FeNi-based composites exhibit the best low-frequency microwave absorption performance. The minimum RL of -60.7 dB is achieved at 6.7 GHz with an ultra-low filling ratio of 10%, and the EAB value in low-frequency region is extended to 3.7 GHz. This study provides further guidelines for the design of the chiral-dielectric-magnetic trinity composites in low-frequency microwave absorption.

(+)-3,6-Epoxymaaliane: A Novel Derivative of (+)-Bicyclogermacrene Oxidation Catalyzed by CYP450 BM3-139-3 and Its Variants.

(+)-Bicyclogermacrene is a sesquiterpene compound found in various plant essential oils and serves as a crucial precursor for multiple biologically active compounds. Many derivatives of (+)-bicyclogermacrene have been shown to exhibit valuable bioactivities. Cytochrome P450 BM3 from Bacillus megaterium can catalyze a variety of substrates and different types of oxidation reactions, making it become a powerful tool for oxidizing terpenes. In this study, we employed P450 BM3-139-3 variant for in vitro enzymatic oxidation of (+)-bicyclogermacrene, identifying a novel oxidized derivative of (+)-bicyclogermacrene, named (+)-3,6-epoxymaaliane, and an unknown sesquiterpenoid in a ratio of 70 : 30 (by GC peak area). (+)-3,6-Epoxymaaliane showed demonstrated antibacterial activities toward Escherichia coli and Staphylococcus aureus. To obtain a better variant of the monooxygenase with a high selectivity to form (+)-3,6-epoxymaaliane, we combined alanine scanning with the "Focused Rational Iterative Site-Specific Mutagenesis" (FRISM) strategy to modify the closest residues within 5 Šradius surrounding the substrate to create a small-but-smart library of mutants. Consequently, it gave an optimal variant with 1.6-fold improvement, in a turnover number (TON) of up to 964 toward (+)-3,6-epoxymaaliane production with a higher product selectivity.

Persulfidation of transcription factor MYB10 inhibits anthocyanin synthesis in red-skinned pear.

Hydrogen sulfide (H2S) is a gaseous signaling molecule that delays color change during fruit ripening. Whether H2S affects anthocyanin biosynthesis in red-skinned pears (Pyrus L.) remains unclear. Here, we found that H2S substantially inhibits anthocyanin accumulation in red-skinned pears and the expression of several genes encoding transcription factors is affected in response to H2S signaling. For example, PyMYB10 and PyMYB73 were down-regulated, whereas PyMYB114 and PyMYB6 were up-regulated. Bioinformatics analysis showed that PyMYB73 and PyMYB6, each containing an EAR motif, may negatively regulate anthocyanin accumulation. Transient expression analysis showed that PyMYB73 substantially promotes anthocyanin biosynthesis by co-transforming with PyMYB10/PyMYB114 + PybHLH3; however, PyMYB6 inhibited anthocyanin biosynthesis in strawberry (Fragaria vesca) receptacles and pear fruits, and PyMYB73 interacted with PyMYB10 and PyMYB6 but not PyMYB114 or PybHLH3. Further investigation showed that Cys194 and Cys218 of PyMYB10 were modified by persulfidation and that PyMYB10Cys218Ala substantially increased anthocyanin accumulation by a transient transformation system. Co-transformation of PyMYB10Cys218Ala + PyMYB73/PyMYB6 also promoted anthocyanin accumulation in pear fruits. Yeast two-hybrid assays showed that the mutation of PyMYB10 did not affect the interaction between PyMYB10 and PyMYB73, but it inhibited interaction with PyMYB6. Moreover, H2S weakened the interaction between PyMYB10 and PyMYB73 but enhanced the interaction with PyMYB6. Thus, we provided a model in which PyMYB10 undergoes persulfidation at Cys218, enhancing the interaction with PyMYB6 and reducing the interaction with PyMYB73. These subsequently results in lower expression of the anthocyanin biosynthesis-related genes Pyrus dihydroflavonol 4-reductase (PyDFR), Pyrus anthocyanidin synthase (PyANS), Pyrus UDP-glucose: flavonoid 3-glucosyl transferase (PyUFGT) and Pyrus glutathione S-transferase (PyGST), thereby inhibiting anthocyanin accumulation in red-skinned pears. Our findings provided a molecular mechanism for H2S-mediated anthocyanin biosynthesis in red-skinned pears.

E3 ligase BRG3 persulfidation delays tomato ripening by reducing ubiquitination of the repressor WRKY71.

Hydrogen sulfide (H2S) is a gaseous signaling molecule reported to play multiple roles in fruit ripening. However, the molecular mechanisms underlying H2S-mediated delay in fruit ripening remain to be established. Here, the gene encoding a WRKY transcription factor, WRKY71, was identified as substantially upregulated in H2S-treated tomato (Solanum lycopersicum) via transcriptome profiling. The expression of WRKY71 was negatively associated with that of CYANOALANINE SYNTHASE1 (CAS1). Transient and stable genetic modification experiments disclosed that WRKY71 acts as a repressor of the tomato ripening process. CAS1 appears to play an opposite role, based on the finding that the ripening process was delayed in the cas1 mutant and accelerated in CAS1-OE tomatoes. Dual-luciferase reporter assay, yeast one-hybrid, electrophoretic mobility shift assay, and transient transformation experiments showed that WRKY71 bound to the CAS1 promoter and suppressed its activation. Moreover, the persulfidation of WRKY71 enhanced its binding ability to the CAS1 promoter. Data from luciferase complementation and Y2H assays confirmed that WRKY71 interacts with a BOI-related E3 ubiquitin-protein ligase 3 (BRG3) and is ubiquitinated in vitro. Further experiments showed that modification of BRG3 via persulfidation at Cys206 and Cys212 led to reduced ubiquitination activity. Our findings support a model whereby BRG3 undergoes persulfidation at Cys206 and Cys212, leading to reduced ubiquitination activity and decreased interactions with the WRKY71 transcript, with a subsequent increase in binding activity of the persulfidated WRKY71 to the CAS1 promoter, resulting in its transcriptional inhibition and thereby delayed ripening of tomatoes. Our collective findings provide insights into a mechanism of H2S-mediated regulation of tomato fruit ripening.

Organolead Halide-Based Coordination Polymers: Intrinsic Stability and Photophysical Applications.

ConspectusOrganolead halide-based photovoltaics are one of the state-of-the-art solar cell systems with efficiencies increasing to 25% over the past decade, ascribed to their high light-absorption coefficient, broad wavelength coverage, tunable band structure, and excellent carrier mobility. Indeed, these optical characteristics are highly demanding in photocatalysis and photoluminescence (PL), which also involve the solar energy utilization and charge transport. However, the vast majority of organolead halides are ionically bonded structures and susceptible to degradation upon high-polarity protic molecules (e.g., water (vapor) and alcohol), which are often inevitable in many photochemical applications. Encapsulation is a commonly used stabilization approach by coating protective layers, avoiding the direct contact between organolead halides and polar molecules. However, this may partially hinder the light penetration to the inner hybrid halide materials, and introduce new interface problems that are important in photocatalysis and luminescent sensing. Therefore, developing intrinsically stable organometal halide hybrids is a major target for their applications in optoelectronic applications.In this Account, recent research progress on the synthesis of organolead halide-based coordination polymers for a variety of photoactive applications is described. Herein, we propose a general strategy to advance the intrinsic stability of organometal halide crystalline materials by using coordinating anionic organic linkers, which occupy the excellent photophysical features analogous to those of perovskites. Unlike the organoammonium cations as for ionically bonded structures, the anionic structure-directing agents (e.g., organocarboxylates) render well-defined metal-carboxylate coordination motifs in extended architectures spanning from low-dimensional (0D, 1D) to high-dimensional cationic inorganic Pb-X-Pb (X = F-/Cl-/Br-/I-) sublattices. This family of organolead halide coordination polymers can endure chemically reactive environments over a wide range of pH and aqueous boiling condition, which have been systematically investigated by experimental studies and theoretical calculations. Many chloride/bromide-based coordination polymers show air-stable, broadband self-trapped emission with large Stokes shift and high color rendition, exhibiting the absolute quantum yields of 35-72%. Among them, the porous frameworks with low-dimensional (0D, 1D) inorganic blocks are recognized as a rare class of porous metal-organic frameworks (MOFs) constructed by lead halides as secondary building units (SBUs). They not only occupy substantially higher light-harvesting and carrier-transport properties than conventional metal oxide-based MOFs, but also allow for isoreticular modification to regulate the PL characteristics by guest molecules. More importantly, combining the high stability with excellent carrier characteristics, a layered organolead iodide coordination polymer shows the overall photocatalytic water splitting without the use of any sacrificial agent under simulated sunlight illumination. Given the wide choice of structurally diverse organocarboxylate linkers, we hope this Account provides deep insights on the importance of coordination chemistry in the discovery of a wide family of intrinsically stable organolead halides to expand their photophysical applications.

A serum panel of three microRNAs may serve as possible biomarkers for kidney renal clear cell carcinoma.

BACKGROUND: Although non-invasive radiological techniques are widely applied in kidney renal clear cell carcinoma (KIRC) diagnosis, more than 50% of KIRCs are detected incidentally during the diagnostic procedures to identify renal cell carcinoma (RCC). Thus, sensitive and accurate KIRC diagnostic methods are required. Therefore, in this study, we aimed to identify KIRC-associated microRNAs (miRNAs). METHODS: This three-phase study included 224 participants (112 each of patients with KIRC and healthy controls (NCs)). RT-qPCR was used to evaluate miRNA expression in KIRC and NC samples. Receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were used to predict the usefulness of serum miRNAs in KIRC diagnosis. In addition, we performed survival and bioinformatics analyses. RESULTS: We found that miR-1-3p, miR-129-5p, miR-146b-5p, miR-187-3p, and miR-200a-3p were significantly differentially expressed in patients with KIRC. A panel consisting of three miRNAs (miR-1-3p, miR-129-5p, and miR-146b-5p) had an AUC of 0.895, ranging from 0.848 to 0.942. In addition, using the GEPIA database, we found that the miRNAs were associated with CREB5. According to the survival analysis, miR-146b-5p overexpression was indicative of a poorer prognosis in patients with KIRC. CONCLUSIONS: The identified three-miRNA panel could serve as a non-invasive indicator for KIRC and CREB5 as a potential target gene for KIRC treatment.

Deep learning-aided respiratory motion compensation in PET/CT: addressing motion induced resolution loss, attenuation correction artifacts and PET-CT misalignment.

PURPOSE: Respiratory motion (RM) significantly impacts image quality in thoracoabdominal PET/CT imaging. This study introduces a unified data-driven respiratory motion correction (uRMC) method, utilizing deep learning neural networks, to solve all the major issues caused by RM, i.e., PET resolution loss, attenuation correction artifacts, and PET-CT misalignment. METHODS: In a retrospective study, 737 patients underwent [18F]FDG PET/CT scans using the uMI Panorama PET/CT scanner. Ninety-nine patients, who also had respiration monitoring device (VSM), formed the validation set. The remaining data of the 638 patients were used to train neural networks used in the uRMC. The uRMC primarily consists of three key components: (1) data-driven respiratory signal extraction, (2) attenuation map generation, and (3) PET-CT alignment. SUV metrics were calculated within 906 lesions for three approaches, i.e., data-driven uRMC (proposed), VSM-based uRMC, and OSEM without motion correction (NMC). RM magnitude of major organs were estimated. RESULTS: uRMC enhanced diagnostic capabilities by revealing previously undetected lesions, sharpening lesion contours, increasing SUV values, and improving PET-CT alignment. Compared to NMC, uRMC showed increases of 10% and 17% in SUVmax and SUVmean across 906 lesions. Sub-group analysis showed significant SUV increases in small and medium-sized lesions with uRMC. Minor differences were found between VSM-based and data-driven uRMC methods, with the SUVmax was found statistically marginal significant or insignificant between the two methods. The study observed varied motion amplitudes in major organs, typically ranging from 10 to 20 mm. CONCLUSION: A data-driven solution for respiratory motion in PET/CT has been developed, validated and evaluated. To the best of our knowledge, this is the first unified solution that compensates for the motion blur within PET, the attenuation mismatch artifacts caused by PET-CT misalignment, and the misalignment between PET and CT.

Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo.

Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.

Testing the accuracy of a four serum microRNA panel for the detection of primary bladder cancer: a discovery and validation study.

BACKGROUND: Bladder cancer (BC) is one of the ten most common cancers worldwide with late detection and early age of diagnosis. There is abundant evidence that early detection and timely intervention can lead to a better prognosis of BC. Substantial evidence has indicated that microRNAs (miRNAs) are specific to different tumour types and are remarkably stable, indicating that serum miRNAs may serve as potential cancer diagnostic markers. This study aimed to identify suitable serum miRNAs to create a panel that can be used to diagnose primary BC. METHODS: In this study, 18 miRNAs that were differentially expressed in BC were obtained from the PubMed or Gene Expression Omnibus database. Then, 18 BC-related-miRNAs were verified in screening and validation sets created using 56 (28 primary BC vs. 28 NCs) and 168 (84 primary BC vs. 84 NCs) serum samples, respectively. Quantitative reverse transcription-PCR (qRT-PCR) was performed to verify the identity of the differential miRNAs. A multi-miRNA panel with superior diagnostic performance was constructed. TCGA and KEGG databases were used to conduct the survival analysis and bioinformatics analysis, respectively. RESULTS: Six serum miRNAs (miR-221-5p, miR-181a-5p, miR-98-5p, miR-15a-5p, miR-222-3p, and miR-197-3p) were significantly aberrantly expressed in the BC patients, while four miRNAs from among them (miR-221-5p, miR-181a-5p, miR-15a-5p, miR-222-3p) were assembled into a panel that showed high diagnostic value (AUC = 0.875, 95% CI: 0.815 - 0.921; sensitivity: 82.14%; and specificity: 85.71%) based on the logistic regression analysis. The survival analysis showed that miR-181a-5p was closely associated with BC prognosis (Log-rank p-value < 0.05). CONCLUSION: The combination of the four miRNAs (miR-221-5p, miR-181a-5p, miR-15a-5p and miR-222-3p) may be a novel non-invasive serological biomarker for BC screening.

Early detection and timely intervention can lead to a better prognosis of bladder cancer.This study aimed to identify suitable serum miRNAs to create a panel that can be used to diagnose primary bladder cancer.

Bacteria-responsive drug release platform for the local treatment of bacterial vaginosis.

Bacterial vaginosis (BV) is a common vaginal infection affecting millions of women. Vaginal anaerobic dysbiosis occurs whenLactobacillusspp., the dominant flora in healthy vagina is replaced by certain overgrown anaerobes, resulting in unpleasant symptoms such as vaginal discharge and odor. With a high recurrence rate, BV also severely impacts the overall quality of life of childbearing women by inducing preterm delivery and increasing the risks of pelvic inflammatory disease and sexually transmitted infections. Among various BV-associated bacteria,Gardnerella vaginalis(G. vaginalis) has been identified as a primary pathogen since it has been isolated from almost all women carrying BV and exhibits higher virulence potential over other bacteria. When dealing with BV relapse, intravaginal drug delivery systems are superior to conventional oral antibiotic therapies in improving therapeutic efficacy owing to more effective drug dose, reduced drug resistance and minimized side effects such as stomach irritation. Traditional intravaginal drug administration generally involves solids, semi-solids and delivery devices inserted into the vaginal lumen to achieve sustained drug release. However, they are mostly designed for continuous drug release and are not preventative therapies, resulting in severe side effects caused by excess dosing. Stimuli-responsive systems that can release drug only when needed ('on-demand') can help diminish these negative side effects. Hence, we developed a bacteria-responsive liposomal platform for the prevention and treatment of BV. This platform demonstrated sustained drug release in the presence of vaginolysin, a toxin secreted specifically byG. vaginalis. We prepared four liposome formulations and evaluated their responsiveness toG. vaginalis. The results demonstrated that the liposome formulations could achieve cumulative drug release ranging from 46.7% to 51.8% over a 3-5 d period in response toG. vaginalisand hardly any drug release in the presence ofLactobacillus crispatus(L. crispatus), indicating the high specificity of the system. Overall, the bacteria-responsive drug release platform has great potential, since it will be the first time to realize sustained drug release stimulated by a specific pathogen for BV prevention and treatment. This on-demand therapy can potentially provide relief to the millions of women affected by BV.

Regulation of Keap1-Nrf2 signaling in health and diseases.

Nuclear factor erythroid 2-related factor 2 (Nrf2) functions as a central regulator in modulating the activities of diverse antioxidant enzymes, maintaining cellular redox balance, and responding to oxidative stress (OS). Kelch-like ECH-associated protein 1 (Keap1) serves as a principal negative modulator in controlling the expression of detoxification and antioxidant genes. It is widely accepted that OS plays a pivotal role in the pathogenesis of various diseases. When OS occurs, leading to inflammatory infiltration of neutrophils, increased secretion of proteases, and the generation of large quantities of reactive oxygen radicals (ROS). These ROS can oxidize or disrupt DNA, lipids, and proteins either directly or indirectly. They also cause gene mutations, lipid peroxidation, and protein denaturation, all of which can result in disease. The Keap1-Nrf2 signaling pathway regulates the balance between oxidants and antioxidants in vivo, maintains the stability of the intracellular environment, and promotes cell growth and repair. However, the antioxidant properties of the Keap1-Nrf2 signaling pathway are reduced in disease. This review overviews the mechanisms of OS generation, the biological properties of Keap1-Nrf2, and the regulatory role of its pathway in health and disease, to explore therapeutic strategies for the Keap1-Nrf2 signaling pathway in different diseases.

Salivary and serum biomarkers to evaluate psychological disorders in burning mouth syndrome: A systematic review and meta-analysis.

BACKGROUND: Burning mouth syndrome is a chronic pain syndrome mainly characterized by an intensive burning sensation of tongue. Previous studies have suggested that saliva/serum biomarkers in burning mouth syndrome might be associated with psychological disorders. The aim of systematic review was to observe whether the biomarkers in serum/saliva could be an alternative method to evaluate the psychological disorders in patients with burning mouth syndrome. MATERIALS AND METHODS: The PubMed, Embase, and Cochrane Library databases were searched for papers published up to March 15, 2023. Risk of bias was measured by using the Newcastle-Ottawa Scale. RevMan was used for meta-analysis. RESULTS: A total of 467 articles were screened, which of 12 studies were included. These studies collected 43 different biomarkers in saliva and 35 in serum. Of these biomarkers, only three (cortisol, α-amylase, and IL-6) were analyzed in two or more studies. Only salivary cortisol levels were significantly higher in the patient group compared to the controls (Mean Difference = 1.39; 95% CI [0.80-1.97]; p < 0.001). Moreover, cortisol might be relevant to psychological scores, especially anxiety. CONCLUSION: Different papers have investigated salivary and serum biomarkers in burning mouth syndrome patients with controversial results. This meta-analysis showed that cortisol levels in saliva may be a potential biomarker to assess the psychological disorders in burning mouth syndrome patients.

Novel sulfonyl-substituted tetrandrine derivatives for colon cancer treatment by inducing mitochondrial apoptosis and inhibiting PI3K/AKT/mTOR pathway.

Tetrandrine (TET) possesses multiple pharmacological activities and could suppress tumor proliferation via PI3K pathway inhibition. However, inferior antitumor activity and potential toxicity limit its clinical application. In the present study, a series of 14-sulfonamide and sulfonate TET derivatives were designed, synthesized, and evaluated for biological activities. Through structural-activity relationship studies, compound 3c with α, ß-unsaturated carbonyl group exhibited the most potent activity against all tested tumor cell lines (including Hela, HCT116, HepG2, MCF-7, and SHSY5Y), as well as negligible toxicity against normal cell lines LO2 and HEK293. Additionally, compound 3c effectively inhibited HCT116 and CT26 cell proliferation in vitro with increased cell proportion in the G2/M phase, activated the mitochondrial apoptosis pathway, and induced colon cancer cell apoptosis by suppressing the PI3K/AKT/mTOR pathway. The further molecular docking results confirmed that compound 3c is potentially bound to multiple residues in PI3K with a stronger binding affinity than TET. Ultimately, compound 3c dramatically suppressed tumor growth in the CT26 xenograft tumor model, without noticeable visceral toxicity detected in the high-dose group. In summary, compound 3c might present new insights for designing new PI3K inhibitors and be a potential candidate for colon cancer treatment.