Phosphorothioate DNA modification by BREX Type 4 systems in the human gut microbiome.

Among dozens of microbial DNA modifications regulating gene expression and host defense, phosphorothioation (PT) is the only known backbone modification, with sulfur inserted at a non-bridging oxygen by dnd and ssp gene families. Here we explored the distribution of PT genes in 13,663 human gut microbiome genomes, finding that 6.3% possessed dnd or ssp genes predominantly in Bacillota, Bacteroidota, and Pseudomonadota. This analysis uncovered several putative new PT synthesis systems, including Type 4 Bacteriophage Exclusion (BREX) brx genes, which were genetically validated in Bacteroides salyersiae. Mass spectrometric analysis of DNA from 226 gut microbiome isolates possessing dnd, ssp, and brx genes revealed 8 PT dinucleotide settings confirmed in 6 consensus sequences by PT-specific DNA sequencing. Genomic analysis showed PT enrichment in rRNA genes and depletion at gene boundaries. These results illustrate the power of the microbiome for discovering prokaryotic epigenetics and the widespread distribution of oxidation-sensitive PTs in gut microbes.

PT-seq: A method for metagenomic analysis of phosphorothioate epigenetics in complex microbial communities.

Among dozens of known epigenetic marks, naturally occurring phosphorothioate (PT) DNA modifications are unique in replacing a non-bridging phosphate oxygen with redox-active sulfur and function in prokaryotic restriction-modification and transcriptional regulation. Interest in PTs has grown due to the widespread distribution of the dnd, ssp, and brx genes among bacteria and archaea, as well as the discovery of PTs in 5-10% of gut microbes. Efforts to map PTs in complex microbiomes using existing next-generation and direct sequencing technologies have failed due to poor sensitivity. Here we developed PT-seq as a high-sensitivity method to quantitatively map PTs across genomes and metagenomically identify PT-containing microbes in complex genomic mixtures. Like other methods for mapping PTs in individual genomes, PT-seq exploits targeted DNA strand cleavage at PTs by iodine, followed by sequencing library construction using ligation or template switching approaches. However, PT-specific sequencing reads are dramatically increased by adding steps to heat denature the DNA, block pre-existing 3'-ends, fragment DNA after T-tailing, and enrich iodine-induced breaks using biotin-labeling and streptavidin beads capture. Iterative optimization of the sensitivity and specificity of PT-seq is demonstrated with individual bacteria and human fecal DNA.

New-QiangGuYin-Containing Serum Inhibits Osteoclast-Derived Exosome Secretion and Down-Regulates Notum to Promote Osteoblast Differentiation.

New-QiangGuYin (N-QGY), the addition of sea buckthorn on the basis of QGY formula, is herbal formula widely used clinically in China for the treatment of osteoporosis (OP), but its mechanism warrants further exploration. The mechanisms of QGY and N-QGY in the treatment of OP are probed from the perspective of osteoclast-osteoblast balance. Thirty Sprague-Dawley rats are randomly divided into N-QGY group, QGY group, and Control group. Beyond control rats that orally took normal saline, other rats are orally administered with isometric N-QGY or QGY twice every day for 3 days. The drug-containing serum and control serum are prepared and their effects on osteoclast-derived exosome secretion are determined by bicinchoninic acid assay (BCA), nanoparticle tracking analysis, and Western blot. GW4869 and Interleukin-1ß (IL-1ß) are adopted as the exosome inhibitor and inducer, respectively. Exosome uptake, cell counting kit-8, alkaline phosphatase (ALP) staining, alizarin red staining, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and Western blot are performed to examine the effects of altered osteoclast exosome content on osteogenic differentiation of mesenchymal stem cells (MSCs). N-QGY, QGY, and GW4869 inhibit osteoclast-derived exosome secretion and exosome uptake by MSCs, whereas IL-1ß exerted the opposite effects (p < 0.05). Different from IL-1ß, N-QGY, QGY, and GW4869 partially elevated MSC viability, osteocalcin secretion, ALP, RUNX Family Transcription Factor 2 (RUNX2) and Osteopontin (OPN) expressions, and calcium deposition in the osteoclast-MSCs coculture system (p < 0.05). Mechanically, osteoclasts increased Notum protein level but decreased ß-catenin level, which is enhanced by IL-1ß but is reversed by GW4869, QGY, and N-QGY (p < 0.05). And the effect of N-QGY is more conspicuous than that of QGY (P<0.05). N-QGY-containing serum inhibits exosome levels in osteoclasts, thereby enhancing osteogenic differentiation of MSCs via inhibition of Notum protein and promotion of ß-catenin protein.

Temporal dynamics and metagenomics of phosphorothioate epigenomes in the human gut microbiome.

Background: Epigenetic regulation of gene expression and host defense is well established in microbial communities, with dozens of DNA modifications comprising the epigenomes of prokaryotes and bacteriophage. Phosphorothioation (PT) of DNA, in which a chemically-reactive sulfur atom replaces a non-bridging oxygen in the sugar-phosphate backbone, is catalyzed by dnd and ssp gene families widespread in bacteria and archaea. However, little is known about the role of PTs or other microbial epigenetic modifications in the human microbiome. Here we optimized and applied fecal DNA extraction, mass spectrometric, and metagenomics technologies to characterize the landscape and temporal dynamics of gut microbes possessing PT modifications. Results: Exploiting the nuclease-resistance of PTs, mass spectrometric analysis of limit digests of PT-containing DNA reveals PT dinucleotides as part of genomic consensus sequences, with 16 possible dinucleotide combinations. Analysis of mouse fecal DNA revealed a highly uniform spectrum of 11 PT dinucleotides in all littermates, with PTs estimated to occur in 5-10% of gut microbes. Though at similar levels, PT dinucleotides in fecal DNA from 11 healthy humans possessed signature combinations and levels of individual PTs. Comparison with a widely distributed microbial epigenetic mark, m6dA, suggested temporal dynamics consistent with expectations for gut microbial communities based on Taylor's Power Law. Application of PT-seq for site-specific metagenomic analysis of PT-containing bacteria in one fecal donor revealed the larger consensus sequences for the PT dinucleotides in Bacteroidota, Firmicutes, Actinobacteria, and Proteobacteria, which differed from unbiased metagenomics and suggested that the abundance of PT-containing bacteria did not simply mirror the spectrum of gut bacteria. PT-seq further revealed low abundance PT sites not detected as dinucleotides by mass spectrometry, attesting to the complementarity of the technologies. Conclusions: The results of our studies provide a benchmark for understanding the behavior of an abundant and chemically-reactive epigenetic mark in the human gut microbiome, with implications for inflammatory conditions of the gut.

Deciphering the Diversity in Bacterial Transporters That Salvage Queuosine Precursors.

Queuosine (Q) is a modification of the wobble base of tRNA harboring GUN anticodons with roles in decoding accuracy and efficiency. Its synthesis is complex with multiple enzymatic steps, and several pathway intermediates can be salvaged. The only two transporter families known to salvage Q precursors are QPTR/COG1738 and QrtT/QueT. Analyses of the distribution of known Q synthesis and salvage genes in human gut and oral microbiota genomes have suggested that more transporter families remain to be found and that Q precursor exchanges must occur within the structured microenvironments of the mammalian host. Using physical clustering and fusion-based association with Q salvage genes, candidate genes for missing transporters were identified and five were tested experimentally by complementation assays in Escherichia coli. Three genes encoding transporters from three different Pfam families, a ureide permease (PF07168) from Acidobacteriota bacterium, a hemolysin III family protein (PF03006) from Bifidobacterium breve, and a Major Facilitator Superfamily protein (PF07690) from Bartonella henselae, were found to allow the transport of both preQ0 and preQ1 in this heterologous system. This work suggests that many transporter families can evolve to transport Q precursors, reinforcing the concept of transporter plasticity.

PELI1 overexpression contributes to pancreatic cancer progression through upregulating ubiquitination-mediated INPP5J degradation.

Inositol Polyphosphate-5-Phosphatase J (INPP5J), a 5-phosphatase, has been identified as a tumor suppressor in several types of cancer. However, its role in pancreatic cancer (PC) is unknown. We found that the INPP5J expression was markedly lower in PC tissues (n = 50) compared to paired adjacent non-tumor tissues, and the lower INPP5J expression was relevant to a worse prognosis of PC patients. We thus proposed that INPP5J might inhibit PC progression and conducted gain-of- and loss-of-function experiments to test our hypothesis. Our results showed that overexpression of INPP5J inhibited cell proliferation, invasion, migration, and xenografted tumor of PC cells. INPP5J silencing showed the opposite effect. Pellino E3 Ubiquitin Protein Ligase 1 (PELI1) is one of the ubiquitin ligases known to promote ubiquitination of its downstream targets. We found that PELI1 could interact with INPP5J and promote the ubiquitination and degradation of INPP5J. PELI1 overexpression enhanced malignant behaviors of PC cells. However, INPP5J overexpression restored the alterations caused by PELI1 overexpression. In conclusion, the results suggest that the decreased INPP5J expression, caused by PELI1 through ubiquitination, may promote PC progression. The PELI1-INPP5J axis represents a potential therapeutic targetable node for PC.

Biosynthesis and function of 7-deazaguanine derivatives in bacteria and phages.

SUMMARYDeazaguanine modifications play multifaceted roles in the molecular biology of DNA and tRNA, shaping diverse yet essential biological processes, including the nuanced fine-tuning of translation efficiency and the intricate modulation of codon-anticodon interactions. Beyond their roles in translation, deazaguanine modifications contribute to cellular stress resistance, self-nonself discrimination mechanisms, and host evasion defenses, directly modulating the adaptability of living organisms. Deazaguanine moieties extend beyond nucleic acid modifications, manifesting in the structural diversity of biologically active natural products. Their roles in fundamental cellular processes and their presence in biologically active natural products underscore their versatility and pivotal contributions to the intricate web of molecular interactions within living organisms. Here, we discuss the current understanding of the biosynthesis and multifaceted functions of deazaguanines, shedding light on their diverse and dynamic roles in the molecular landscape of life.

The Evolution and Future Trends of Stromal Vascular Fraction: A Bibliometric Analysis.

The heterogeneous population of cells obtained from processed adipose tissue, known as stromal vascular fraction (SVF), exhibits immunomodulatory and angiogenic properties. The therapeutic efficacy of SVF has been substantiated in numerous diseases, instilling hope for its clinical application as a cellular therapy. This study aims to provide a comprehensive analysis of the scholarly literature on SVF, including its worldwide progression, highlighting significant literatures, temporal development, research clusters, current active topics, and emerging trends. The combination of CiteSpace, HistCite Pro, and VOS Viewer tools was used to analyze the SVF literature. The overall panorama of the field is elucidated in terms of publication count, timeline, institutional distribution, journal coverage, and authors' contributions. In addition, this analysis explores the literature and keywords through the lens of co-occurrence, citation, and co-citation frequencies. Clustering algorithms are used to track the trajectory of the literature further, providing insight into its development. The findings offer a comprehensive overview of the progress made in the SVF field, highlighting distinct phases of development: the "Seedling period" from 1980 to 2010, the "Panicle period" from 2011 to 2016, and the "Flowering period" from 2017 to 2023. Within these periods, the evolution of 10 clusters is unraveled, encompassing topics such as vascular disease, CD34 expression, adipose tissue macrophage in 2013, cell-assisted lipotransfer, and knee osteoarthritis. In summary, this bibliometric study, conducting a quantitative analysis of publications in SVF research, encompasses a global overview of research, an analysis of pivotal literature in the field, research hotspots, and emerging frontiers.

Queuosine Salvage in Bartonella henselae Houston 1: A Unique Evolutionary Path.

Queuosine (Q) stands out as the sole tRNA modification that can be synthesized via salvage pathways. Comparative genomic analyses identified specific bacteria that showed a discrepancy between the projected Q salvage route and the predicted substrate specificities of the two identified salvage proteins: 1) the distinctive enzyme tRNA guanine-34 transglycosylase (bacterial TGT, or bTGT), responsible for inserting precursor bases into target tRNAs; and 2) Queuosine Precursor Transporter (QPTR), a transporter protein that imports Q precursors. Organisms like the facultative intracellular pathogen Bartonella henselae, which possess only bTGT and QPTR but lack predicted enzymes for converting preQ1 to Q, would be expected to salvage the queuine (q) base, mirroring the scenario for the obligate intracellular pathogen Chlamydia trachomatis. However, sequence analyses indicate that the substrate-specificity residues of their bTGTs resemble those of enzymes inserting preQ1 rather than q. Intriguingly, mass spectrometry analyses of tRNA modification profiles in B. henselae reveal trace amounts of preQ1, previously not observed in a natural context. Complementation analysis demonstrates that B. henselae bTGT and QPTR not only utilize preQ1, akin to their Escherichia coli counterparts, but can also process q when provided at elevated concentrations. The experimental and phylogenomic analyses suggest that the Q pathway in B. henselae could represent an evolutionary transition among intracellular pathogens-from ancestors that synthesized Q de novo to a state prioritizing the salvage of q. Another possibility that will require further investigations is that the insertion of preQ1 has fitness advantages when B. henselae is growing outside a mammalian host.

FTO Knockdown-Mediated Maturation of miR-383-5p Inhibits Malignant Advancement of Pancreatic Cancer by Targeting ITGA3.

m6A demethylase FTO is confirmed to be involved in pancreatic cancer progression. FTO regulates miRNA processing. To investigate the regulatory effect of FTO on miR-383-5p and its role in pancreatic cancer. The expression of miR-383-5p, ITGA3, and FTO was predicted using bioinformatic analysis in tissues and was measured using qPCR in cells. Cell biological functions were investigated using MTT assay, Transwell assay, sphere formation assay, and qPCR. The targeting relationship between miR-383-5p and ITGA3 was evaluated using the dual-luciferase reporter assay. The effect of FTO on miR-383-5p processing was evaluated using RIP and MeRIP assay. FTO expression was upregulated in pancreatic cancer and silencing of FTO promoted the processing of miR-383-5p in an m6A-dependent manner. m6A-modified miRNA processing was recognized by IGF2BP1. Downregulation of miR-383-5p reversed FTO knockdown-induced inhibition of cellular processes. The FTO/miR-383-5p/ITGA3 axis facilitated cell viability, metastasis, and stemness in pancreatic cancer.

Sequential embryo transfer versus double cleavage-stage embryo or double blastocyst transfer in patients with recurrent implantation failure with frozen-thawed embryo transfer cycles: a cohort study.

Background: Recurrent implantation failure (RIF) is more common among patients receiving assisted reproductive treatment. Many efforts have been made to increase the incidence of clinical pregnancy among patients with RIF. The effect of the sequential transfer procedure, a two-step interval transfer of a cleavage-stage embryo followed by a blastocyst in one transfer cycle, on the clinical outcomes of RIF patients remains controversial. Methods: In total, 1774 frozen-thawed embryo transfer (FET) cycles in RIF patients were included. Of these cycles, 302 were sequential embryo transfer (ET) cycles, 979 were double day 3 cleavage-stage ET cycles, and 493 were double blastocyst ET cycles. The primary outcomes were the rates of implantation, clinical pregnancy and multiple pregnancy, and the secondary outcomes were the rates of hCG positive, early miscarriage and ectopic pregnancy. Results: The implantation, hCG positive, and clinical pregnancy rates in the sequential ET group (32.1%, 58.9%, 50.7%) were significantly higher than those in the day 3 cleavage-stage ET group (24.9%, 46.5%, 40.4%) and were similar to those in the blastocyst transfer group (30.1%, 56.4%, 47.1%). The early miscarriage rate in the blastocyst transfer group was significantly higher than that in the cleavage-stage ET group (17.2% vs. 8.1%, P <0.05), while the ectopic pregnancy rate in the blastocyst transfer group was significantly lower than that in the cleavage-stage ET group (0.4% vs. 3.0%, P <0.05). The multiple pregnancy rate in the sequential ET group was significantly lower than that in the cleavage-stage ET group (17.0% vs. 25.5%, P <0.05) and the blastocyst transfer group (17.0% vs. 27.6%, P <0.05). When cycles of blastocyst culture failure were excluded, the clinical pregnancy rate was significantly higher (55.7% vs. 47.1%, P <0.05), and the early miscarriage rate and multiple pregnancy rate were significantly lower (8.5% vs. 17.2%, 17.7% vs. 27.6%; P <0.05, respectively) in the sequential ET group than in the double blastocyst ET group. Conclusions: Sequential embryo transfer in FET cycles could improve the clinical outcomes of patients with RIF.

PSMD12 interacts with CDKN3 and facilitates pancreatic cancer progression.

Proteasome 26S subunit, non-ATPase 12 (PSMD12) genes have been implicated in several types of malignancies but the role of PSMD12 in pancreatic cancer (PC) remains elusive. Bioinformatics analysis showed that PSMD12 was highly expressed in PC patients and was associated with shorter overall survival. PSMD12 was also shown to be highly expressed in PC tissues and cell lines. Upregulated PSMD12 showed enhanced cell viability, increased colony formation rate and upregulated levels of PCNA and c-Myc, while the inhibition of PSMD12 abated these levels. PSMD12 knockdown promoted cell apoptosis. The results of xenografts in nude mice confirmed that PSMD12 promoted PC tumor growth in vivo. Protein‒protein interaction network and functional enrichment analyses implied that PSMD12 may have a connection with cyclin-dependent kinase inhibitor 3 (CDKN3). Co­immunoprecipitation and western blot results confirmed that PSMD12 could interact with and abate the ubiquitination level of CDKN3, thus stabilizing the CDKN3 protein. Rescue assays showed that PSMD12 overexpression caused cell proliferation and that knockdown-induced cell apoptosis could be reversed by CDKN3 regulation. This work reveals the essential roles of PSMD12 in the proliferation and apoptosis of PC development. PSMD12 may regulate CDKN3 expression by interacting with and abating the ubiquitination level of CDKN3, thereby participating in the malignant behavior of PC.

GID2 Interacts With CDKN3 and Regulates Pancreatic Cancer Growth and Apoptosis.

Dysregulation of deubiquitinase or ubiquitinase-mediated protein expression contributes to various diseases, including cancer. In the present study, we identified GID2, a subunit of the glucose-induced degradation-deficient (GID) complex that functions as an E3 ubiquitin ligase, as a potential key candidate gene in pancreatic cancer (PC) progression. The functional role and potential mechanism of GID2 in PC progression were investigated. Integrated bioinformatics analysis was performed to identify differentially expressed genes in PC based on the Gene Expression Profiling Interactive Analysis data sets. We found that GID2 was upregulated in PC tissues and that a high level of GID2 expression in clinical PC samples was positively associated with tumor stage and poor survival. Functional assays elucidated that GID2 expression promoted cell growth in vitro and accelerated tumor growth in vivo. GID2 knockdown effectively attenuated the malignant behaviors of PC cells and tumor formation. Furthermore, the protein network that interacted with the GID2 protein was constructed based on the GeneMANIA website. Cyclin-dependent kinase inhibitor 3 (CDKN3), a cell cycle regulator, was identified as a potential target of the GID2 protein. We revealed that GID2 positively regulated CDKN3 expression and inhibited CDKN3 ubiquitination. Furthermore, CDKN3 downregulation reversed the promoting effects of GID2 on PC progression. Therefore, the present study demonstrated that GID2 might regulate PC progression by maintaining the stability of the CDKN3 protein. These findings highlight the potential roles of the GID2/CDKN3 axis as a potential therapeutic target in PC.

Exploratory study of sea buckthorn enhancing QiangGuYin efficacy by inhibiting CKIP-1 and Notum activating the Wnt/ß-catenin signaling pathway and analysis of active ingredients by molecular docking.

Background: Sea buckthorn (SBT) is a traditional Chinese medicine (TCM), rich in calcium, phosphorus, and vitamins, which can potentially prevent and treat osteoporosis. However, no research has been conducted to confirm these hypotheses. QiangGuYin (QGY) is a TCM compound used to treat osteoporosis. There is a need to investigate whether SBT enhances QGY efficacy. Objectives: The aim of this study was to explore whether SBT enhances QGY efficacy by inhibiting CKIP-1 and Notum expression through the Wnt/ß-catenin pathway. The study also aimed to explore the active components of SBT. Methods: Experimental animals were divided into control, model, QGY, SBT, SBT + Eucommia ulmoides (EU), and SBT + QGY groups. After treatment, bone morphometric parameters, such as estrogen, PINP, and S-CTX levels, and Notum, CKIP-1, and ß-catenin expression were examined. Screening of SBT active components was conducted by molecular docking to obtain small molecules that bind Notum and CKIP-1. Results: The results showed that all the drug groups could elevate the estrogen, PINP, and S-CTX levels, improve femoral bone morphometric parameters, inhibit Notum and CKIP-1 expression, and promote ß-catenin expression. The effect of SBT + EU and SBT + QGY was superior to the others. Molecular docking identified that SBT contains seven small molecules (folic acid, rhein, quercetin, kaempferol, mandenol, isorhamnetin, and ent-epicatechin) with potential effects on CKIP-1 and Notum. Conclusion: SBT improves bone morphometric performance in PMOP rats by inhibiting CKIP-1 and Notum expression, increasing estrogen levels, and activating the Wnt/ß-catenin signaling pathway. Furthermore, SBT enhances the properties of QGY. Folic acid, rhein, quercetin, kaempferol, mandenol, isorhamnetin, and ent-epicatechin are the most likely active ingredients of SBT. These results provide insight into the pharmacological mechanisms of SBT in treating osteoporosis.

The absence of the queuosine tRNA modification leads to pleiotropic phenotypes revealing perturbations of metal and oxidative stress homeostasis in Escherichia coli K12.

Queuosine (Q) is a conserved hypermodification of the wobble base of tRNA containing GUN anticodons but the physiological consequences of Q deficiency are poorly understood in bacteria. This work combines transcriptomic, proteomic and physiological studies to characterize a Q-deficient Escherichia coli K12 MG1655 mutant. The absence of Q led to an increased resistance to nickel and cobalt, and to an increased sensitivity to cadmium, compared to the wild-type (WT) strain. Transcriptomic analysis of the WT and Q-deficient strains, grown in the presence and absence of nickel, revealed that the nickel transporter genes (nikABCDE) are downregulated in the Q- mutant, even when nickel is not added. This mutant is therefore primed to resist to high nickel levels. Downstream analysis of the transcriptomic data suggested that the absence of Q triggers an atypical oxidative stress response, confirmed by the detection of slightly elevated reactive oxygen species (ROS) levels in the mutant, increased sensitivity to hydrogen peroxide and paraquat, and a subtle growth phenotype in a strain prone to accumulation of ROS.

Antiosteoporosis effect of tanshinol in osteoporosis animal models: A systematic review and meta-analysis.

Background: Osteoporosis (OP) is an age-related bone disease that has emerged as a worldwide public health concern due to its increasing incidence and high disability rate. Tanshinol [D (+) ß-3,4-dihydroxyphenyl lactic acid, TS], a water-soluble component extracted from Salvia miltiorrhiza, has proven to be effective in attenuating OP in vitro and in vivo. However, there is insufficient evidence to support its clinical application. Objective: This meta-analysis aimed to investigate available OP animal model studies to demonstrate the antiosteoporosis effects of TS in a systematic manner. Methods: Electronic searches of related studies were conducted in the following databases: EMBASE, PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese VIP Database, Chinese Biomedical Literature Database, and Wanfang. The retrieval date was January 2022, and there were no time or language restrictions. The CAMARADES 10-item quality checklist was utilized to test the risk of potential bias for each study, and modifications were performed accordingly. The primary outcome was bone mineral density (BMD, which included the femur and lumbar spine); and secondary outcomes were parameters for trabecular bone such as bone volume over total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), conditions of the femur (including bone maximum load and bone elastic load), and markers of bone metabolism (serum osteocalcin, S-OCN). Results: A total of nine studies including 176 rats were chosen for this analysis. Egger's test revealed the presence of publication bias in various studies regarding the primary outcome. According to this systematic review, TS significantly increased the BMD of the femur (BMD-femur) (SMD = 4.40; 95% CI = 1.61 to 7.19; p = 0.002, I 2 = 94.6%), BMD of the lumbar spine (BMD-lumbar) (SMD = 6.390; 95% CI = 2.036 to 10.744; p = 0.004, I2 = 95.9%), BV/TV (SMD = 0.790; 95% CI = 0.376 to 1.204; p = 0.000, I2 = 10.8), Tb.N (SMD = 0.690; 95% CI = 0.309 to 1.071; p = 0.000, I2 = 12%), Tb.Th (SMD = 0.772; 95% CI = 0.410 to 1.134; p = 0.000, I2 = 32.2%), and S-OCN (SMD = 3.13; 95% CI = 0.617 to 5.65; p = 0.015, I2 = 92.3%), while the Tb.Sp level was markedly decreased in OP models in comparison to the controls (SMD = -0.822; 95% CI = -1.207 to -0.437; p = 0.000, I2 = 0%). Moreover, TS treatment was associated with a significant improvement of the bone biomechanical indicators, including bone maximum load (SMD = 0.912; 95% CI = 0.370 to 1.455; p = 0.001, I2 = 40%) and elasticity load (SMD = 0.821; 95% CI = 0.290 to 1.351; p = 0.002, I 2 = 0%). Conclusion: Collectively, our findings suggest that TS can improve BMD, bone microarchitecture, bone biomechanics, and S-OCN expression in rats, implying that it could be used clinically in the future. Systematic Review Registration: https://inplasy.com/inplasy-2022-3-0053/, identifier [INPLASY202230053].

Injectable and Self-Healing Polysaccharide Hydrogel Loading Molybdenum Disulfide Nanoflakes for Synergistic Photothermal-Photodynamic Therapy of Breast Cancer.

In order to overcome the limitation of traditional therapies for cancer and improve the accuracy of treatment, more advantageous cancer treatment methods need to be explored and studied. As a result, photothermal photodynamic therapy of breast cancer using bovine serum albumin (BSA) modifies molybdenum disulfide nanoflakes. Then the well-dispersed BSA-MoS2 NFs are loaded in the injectable and self-healing polysaccharide hydrogel which is prepared by the reaction of oxidized sodium alginate (OSA) and hydroxypropyl chitosan (HPCS) through the formation of Schiff base bonds. The injection and self-healing properties of the nanocomposite hydrogel are investigated. In vitro photothermal and photodynamic investigations demonstrate that BSA-MoS2 NFs possess obvious photothermal conversion and production of reactive oxygen species (ROS) under the irradiation of near infrared (NIR) laser (808 nm). In vivo anticancer investigation indicates that the nanocomposite hydrogel can be directly injected and remain in the tumor sites and achieve the synergistic photothermal-photodynamic therapy of cancer.

GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer.

PURPOSE: GAS41 is a YEATS domain protein that binds to acetylated histone H3 to promote the chromatin deposition of H2A.Z in non-small cell lung cancer. The role of GAS41 in pancreatic cancer is still unknown. Here, we aimed to reveal this role. METHODS: GAS41 expression in pancreatic cancer tissues and cell lines was examined using qRT-PCR, Western blotting and immunohistochemistry. MTT, colony formation, spheroid formation and in vivo tumorigenesis assays were performed to assess the proliferation, tumorigenesis, stemness and gemcitabine (GEM) resistance of pancreatic cancer cells. Mechanistically, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assays were used to evaluate the roles of GAS41, H2A.Z.2 and Notch1 in pancreatic cancer. RESULTS: We found that GAS41 is overexpressed in human pancreatic cancer tissues and cell lines, and that its expression increases following the acquisition of GEM resistance. We also found that GAS41 up-regulates Notch, as well as pancreatic cancer cell stemness and GEM resistance in vitro and in vivo. We show that GAS41 binds to H2A.Z.2 and activates Notch and its downstream mediators, thereby regulating stemness and drug resistance. Depletion of GAS41 or H2A.Z.2 was found to down-regulate Notch and to sensitize pancreatic cancer cells to GEM. CONCLUSION: Our data indicate that GAS41 mediates proliferation and GEM resistance in pancreatic cancer cells via H2A.Z.2 and Notch1.

The Effect of Online Health Information Seeking on Physician-Patient Relationships: Systematic Review.

BACKGROUND: The internet has now become part of human life and is constantly changing people's way of life. With the increasing popularity of online health information (OHI), it has been found that OHI can affect the physician-patient relationship by influencing patient behaviors. OBJECTIVE: This study aims to systematically investigate the impact of OHI-seeking behavior on the physician-patient relationship. METHODS: Literature retrieval was conducted on 4 databases (Web of Science, PubMed, China National Knowledge Infrastructure, SinoMed), and the time limit for literature publication was before August 1, 2021. RESULTS: We selected 53 target papers (42 [79%] English papers and 11 [21%] Chinese papers) that met the inclusion criteria. Of these, 31 (58%) papers believe that patients' OHI behavior can enable them to participate in their own medical care, improve patient compliance, and improve the physician-patient relationship. In addition, 14 (26%) papers maintain a neutral attitude, some believing that OHI behavior has no significant effect on doctors and patients and others believing that due to changes in the factors affecting OHI behavior, they will have a negative or a positive impact. Furthermore, 8 (15%) papers believe that OHI search behavior has a negative impact on doctors and patients, while 6 (11%) papers show that OHI reduces Chinese patients' trust in doctors. CONCLUSIONS: Our main findings showed that (1) OHI-seeking behavior has an impact on patients' psychology, behavior, and evaluation of doctors; (2) whether patients choose to discuss OHI with doctors has different effects on the physician-patient relationship; and (3) the negative impact of OHI on China's internet users is worthy of attention. Due to the low quality of OHI, poor health information literacy, short physician-patient communication time, and various types of negative news, patients' trust in doctors has declined, thus affecting the physician-patient relationship. Improvement of people's health information literacy and the quality of OHI are important factors that promote the positive impact of OHI on the physician-patient relationship.