Probiotic Lactobacillus rhamnosus GG improves insulin sensitivity and offspring survival via modulation of gut microbiota and serum metabolite in a sow model.

BACKGROUND: Sows commonly experience insulin resistance in late gestation and lactation, causing lower feed intake and milk production, which can lead to higher mortality rates in newborn piglets. The probiotic Lactobacillus rhamnosus GG (LGG) is known to improve insulin resistance. However, whether supplementing LGG can improve insulin sensitivity in sows and enhance lactation performance, particularly the early survival of offspring remains unclear. Hence, we explored the effects and mechanisms of supplementing LGG during late gestation and lactation on sow insulin sensitivity, lactation performance, and offspring survival. In total, 20 sows were randomly allocated to an LGG (n = 10) and control group (n = 10). RESULTS: In sows, LGG supplementation significantly improved insulin sensitivity during late gestation and lactation, increased feed intake, milk production and colostrum lactose levels in early lactation, and enhanced newborn piglet survival. Moreover, LGG treatment significantly reshaped the gut microbiota in sows, notably increasing microbiota diversity and enriching the relative abundance of insulin sensitivity-associated probiotics such as Lactobacillus, Bifidobacterium, and Bacteroides. Serum metabolite and amino acid profiling in late-gestation sows also revealed decreased branched-chain amino acid and kynurenine serum levels following LGG supplementation. Further analyses highlighted a correlation between mitigated insulin resistance in late pregnancy and lactation by LGG and gut microbiota reshaping and changes in serum amino acid metabolism. Furthermore, maternal LGG enhanced immunity in newborn piglets, reduced inflammation, and facilitated the establishment of a gut microbiota. CONCLUSIONS: We provide the first evidence that LGG mitigates insulin resistance in sows and enhances offspring survival by modulating the gut microbiota and amino acid metabolism.

Construction of a novel disulfidptosis-related lncRNAs signature for prognosis prediction and anti-tumor immunity in laryngeal squamous cell carcinoma.

Disulfidptosis, an innovative type of controlled cellular death linked to metabolic dysfunction, has garnered attention. However, there is limited knowledge regarding the involvement of disulfidptosisrelated lnRNAs (DRlncRNAs) in laryngeal squamous cell carcinoma (LSCC). The objective of our team in this study seeks to establish a DRlncRNAs signature, investigate their prognostic value in LSCC, and explore their associations with immune cell subpopulations, biological signaling pathways, and exploring implications for drug sensitivity. We accessed LSCC patients' RNA-seq data and pertinent clinical data for subsequent further analysis from The Cancer Genome Atlas (TCGA) portal. A literature search was conducted focusing on disulfidptosis-related genes. Pearson correlation coefficients were calculated to identify DRlncRNAs. Differential expression analysis of lncRNAs was performed. Utilizing univariate Cox regression analysis, we identified disulfidptosis-associated prognostic lncRNAs. The LASSO-Cox regression analysis was employed to refine this set of lncRNAs and construct a disulfidptosis-related lncRNAs signature. Various statistical techniques were employed to appraise model predictive performance. Subsequently, risk groups were stratified based on the risk score derived from the DRlncRNAs signature. The superiority of the risk score in prognostication over traditional clinicopathological features in LSCC patients was demonstrated. Evident distinctions emerged between risk groups, particularly in immune cell subpopulations like activated mast cells, eosinophils, and activated NK cells. Finally, the low-risk group demonstrated reduced IC50 values for specific chemotherapeutics like cisplatin and gemcitabine. The in vitro experiments indicated differential behavior of our DRlncRNAs. The DRlncRNAs signature can serve as a robust biomarker with the ability to predict both prognosis and therapeutic responses among patients with LSCC.

Genetic fusion of CCL11 to antigens enhances antigenicity in nucleic acid vaccines and eradicates tumor mass through optimizing T-cell response.

Nucleic acid vaccines have shown promising potency and efficacy for cancer treatment with robust and specific T-cell responses. Improving the immunogenicity of delivered antigens helps to extend therapeutic efficacy and reduce dose-dependent toxicity. Here, we systematically evaluated chemokine-fused HPV16 E6/E7 antigen to improve the cellular and humoral immune responses induced by nucleotide vaccines in vivo. We found that fusion with different chemokines shifted the nature of the immune response against the antigens. Although a number of chemokines were able to amplify specific CD8 + T-cell or humoral response alone or simultaneously. CCL11 was identified as the most potent chemokine in improving immunogenicity, promoting specific CD8 + T-cell stemness and generating tumor rejection. Fusing CCL11 with E6/E7 antigen as a therapeutic DNA vaccine significantly improved treatment effectiveness and caused eradication of established large tumors in 92% tumor-bearing mice (n = 25). Fusion antigens with CCL11 expanded the TCR diversity of specific T cells and induced the infiltration of activated specific T cells, neutrophils, macrophages and dendritic cells (DCs) into the tumor, which created a comprehensive immune microenvironment lethal to tumor. Combination of the DNA vaccine with anti-CTLA4 treatment further enhanced the therapeutic effect. In addition, CCL11 could also be used for mRNA vaccine design. To summarize, CCL11 might be a potent T cell enhancer against cancer.

Alleviation of allergic asthma by rosmarinic acid via gut-lung axis.

BACKGROUND: Asthma affects 3% of the global population, leading to over 0.25 million deaths. Due to its complexity, asthma is difficult to cure or prevent, and current therapies have limitations. This has led to a growing demand for alternative asthma treatments. We found rosmarinic acid (RosA) as a potential new drug candidate from natural medicine. However, RosA has poor bioavailability and remains mainly in the gastrointestinal tract after oral administration, suggesting the involvement of gut microbiota in its bioactivity. PURPOSE: To investigate the mechanism of RosA in alleviating allergic asthma by gut-lung axis. METHODS: We used 16S rRNA gene sequencing and metabolites analysis to investigate RosA's modulation of gut microbiota. Techniques of molecular biology and metabolomics were employed to study the pharmacological mechanism of RosA. Cohousing was used to confirm the involvement of gut microbiota in RosA-induced improvement of allergic asthma. RESULTS: RosA decreased cholate levels from spore-forming bacteria, leading to reduced 5-hydroxytryptamine (5-HT) synthesis, bronchoconstriction, vasodilation, and inflammatory cell infiltration. It also increased short-chain fatty acids (SCFAs) levels, facilitating the expression of intestinal tight junction proteins to promote intestinal integrity. SCFAs upregulated intestinal monocarboxylate transporters (MCTs), thereby improving their systemic delivery to reduce Th2/ILC2 mediated inflammatory response and suppress eosinophil influx and mucus production in lung. Additionally, RosA inhibited lipopolysaccharide (LPS) production and translocation, leading to reduced TLR4-NFκB mediated pulmonary inflammation and oxidative stress. CONCLUSIONS: The anti-asthmatic mechanism of oral RosA is primarily driven by modulation of gut microbiota-derived 5-HT, SCFAs, and LPS, achieving a combined synergistic effect. RosA is a safe, effective, and reliable drug candidate that could potentially replace glucocorticoids for asthma treatment.

Maternal folic acid and vitamin B12 supplementation during medium to late gestation promotes fetal development via improving placental antioxidant capacity, angiogenesis and amino acid transport.

BACKGROUND: Folic acid and vitamin B12 (FV), being B vitamins, not only facilitate the remethylation of homocysteine (Hcy) but also contribute to embryonic development. This study aimed to assess the impact of FV supplementation during late pregnancy on sows' reproductive performance, amino acid metabolism, placental angiogenesis, and related parameters. Twenty primiparous sows at day 60 of gestation were randomly allocated to two groups: a basal diet (CON) group and a group receiving a basal diet supplemented with folic acid at 20 ppm and vitamin B12 at 125 ppb. RESULTS: The findings revealed that dietary FV supplementation significantly reduced the incidence of intrauterine growth retardation compared to the CON group (P < 0.05). Furthermore, it led to a decrease in the Hcy levels in umbilical cord serum (P < 0.05) and activation of the placental mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway (P < 0.05). Additionally, FV supplementation lowered placental malondialdehyde levels (P < 0.05) and increased the expression of placental thioredoxin (P = 0.05). Moreover, maternal FV supplementation notably elevated placental vascular density (P < 0.05) and the expression of sodium-coupled neutral amino acid transporter 2 (SNAT2) (P < 0.05), as well as amino acid concentrations in umbilical cord blood (P < 0.05). CONCLUSION: Maternal FV supplementation during medium to late gestation reduced Hcy levels in umbilical cord blood and positively impacted fetal development. This improvement was closely associated with increased placental antioxidant capacity and vascular density, as well as activation of the placental mTORC1-SNAT2 signaling pathway. © 2023 Society of Chemical Industry.

Bacterial butyrate mediates the anti-atherosclerotic effect of silybin.

Silybin (SIL) is a versatile bioactive compound used for improving liver damage and lipid disorders and is also thought to be beneficial for atherosclerosis (AS). The goal of this study was to investigate the efficacy of SIL in the treatment of AS in ApoE-/-mice fed a high-fat diet and explore the mechanism underlying treatment outcomes. We found that SIL significantly alleviated AS-related parameters, including the extent of aortic plaque formation, hyperlipidemia, and adhesion molecule secretion in the vascular endothelium. 16 S rRNA gene sequencing analysis, together with the application of antibiotics, showed that intestinal butyrate-producing bacteria mediated the ameliorative effect of SIL on AS. Further analysis revealed that SIL facilitated butyrate production by increasing the level of butyryl-CoA: acetate CoA-transferase (BUT). The increased expression of monocarboxylic acid transporter-1 (MCT1) induced by butyrate and MCT4 induced by SIL in the apical and basolateral membranes of colonocytes, respectively, resulted in enhanced absorption of intestinal butyrate into the circulation, leading to the alleviation of arterial endothelium dysfunction. Moreover, the SIL-mediated increase in intestinal butyrate levels restored gut integrity by upregulating the expression of tight junction proteins and promoting gut immunity, thus inhibiting the AS-induced inflammatory response. This is the first study to show that SIL can alleviate AS by modulating the production of bacterial butyrate and its subsequent absorption.

The common neurological basis and targeted therapeutic approaches for chronic pain and opioid addiction.

Chronic pain and drug addiction seriously threaten human health and generate a large loss of labor. Most highly addictive drugs are derived from opioids, which have severe side effects and are difficult to quit completely. On the other hand, opioid analgesics are widely used in detoxification for opioid addiction. These opioids are effective for controlling acute withdrawal symptoms, but can be problematic under long-term usage as maintenance therapy. Both chronic pain and opioid abuse are related to neurotransmitters and central reward pathways in the brain. As to provide new weapons for defending human health, this article summarized the similarities and differences between chronic pain and opioid addiction, based on their common neurobiological basis, and discussed the breakthroughs in targeted therapeutic approaches. Furthermore, we have brought out an innovative and integrative therapeutic scheme by combining drugs, medical devices, and phycological / behavioral therapies, according to the patient's individual situation, aiming at achieving better effects against these two types of diseases.

Antinociceptive effects of cefadroxil and ceftriaxone in experimental animal models of pain.

BACKGROUND: As an "off-target" effect, cephalosporins can enhance glutamate transporter-1 expression in astrocytes to recycle glutamate from synaptic cleft, and exhibited analgesic properties in animals and humans with chronic pain. METHODS: In the present study, we focused on making a side-by-side comparison of the analgesic potentials of cefadroxil and ceftriaxone, using rodent models of peripheral neuropathic pain, inflammatory pain and incisional pain. Microdialysis technique was adopted to validate the in vivo glutamate regulatory properties of these two drugs in central nervous system. RESULTS: We have shown that cefadroxil and ceftriaxone are beneficial in a variety of pain scenarios, without inducing observable side effects. The two cephalosporins worked better on neuropathic pain, rather than inflammatory pain or incisional pain, suggesting nociceptive system was differentially affected. Further, microdialysis has confirmed that cephalosporins can effectively reverse the elevated levels of glutamate in brain of animals with neuropathic pain. CONCLUSIONS: The outcome of this study may guide us to identify a molecular skeleton derived from cefadroxil, based on which we could possibly develop new non-antibiotic analgesic compounds with glutamate recycling properties.

Construction of a novel MPT-driven necrosis-related lncRNAs signature for prognosis prediction in laryngeal squamous cell carcinoma.

Mitochondrial permeability transition (MPT)-driven necrosis, a type of programmed cell death, has recently gained much attention in a variety of tumor types. Few studies have been performed to explore the role of MPT-driven necrosis-related lncRNAs (MPTDNRlncRNAs) in laryngeal squamous cell carcinoma (LSCC). The purpose of our study is to screen MPTDNRlncRNAs with prognostic value and to explore their potential roles in LSCC. The RNA-sequencing data and the corresponding clinical data of LSCC patients were obtained from the TCGA database, and those MPT-driven necrosis-related genes were extracted from the Gene Set Enrichment Analysis (GSEA) database. We identified MPTDNRlncRNAs differentially expressed in LSCC. Also, we gained MPT-driven necrosis-related prognostic lncRNAs by univariate cox regression analysis. A novel MPTDNRlncRNAs signature was constructed by LASSO-COX. The accuracy and utility of the MPTDNRlncRNAs signature were evaluated via a variety of statistical methods. Multiple bioinformatics tools were used to explore the underlying difference in biological functions and signaling pathways between the different risk groups. The expressions levels of MPTDNRlncRNAs were analyzed using RT-qPCR in LSCC cell line. Finally, we identified A 5 MPTDNRlncRNAs signature in LSCC. Our prognostic model demonstrated an efficient ability to predict outcomes. The proportion difference of immune cells in the subgroups were significant, such as M0 macrophage and T follicular helper cells. The in vitro experiments suggested that our MPTDNRlncRNAs were significantly different. This 5 MPTDNRlncRNAs signature is a prognostic biomarker for LSCC. More importantly, the novel biologic prognostic model can be utilized for personalized immunotherapy in LSCC patients.

Berberine is a potential alternative for metformin with good regulatory effect on lipids in treating metabolic diseases.

Metformin (MTF) and berberine (BBR) share several therapeutic benefits in treating metabolic-related disorders. However, as the two agents have very different chemical structure and bioavailability in oral route, the goal of this study is to learn their characteristics in treating metabolic disorders. The therapeutic efficacy of BBR and MTF was systemically investigated in the high fat diet feeding hamsters and/or ApoE(-/-) mice; in parallel, gut microbiota related mechanisms were studied for both agents. We discovered that, although both two drugs had almost identical effects on reducing fatty liver, inflammation and atherosclerosis, BBR appeared to be superior over MTF in alleviating hyperlipidemia and obesity, but MTF was more effective than BBR for the control of blood glucose. Association analysis revealed that the modulation of intestinal microenvironment played a crucial role in the pharmacodynamics of both drugs, in which their respective superiority on the regulation of gut microbiota composition and intestinal bile acids might contribute to their own merits on lowering glucose or lipids. This study shows that BBR may be a good alternative for MTF in treating diabetic patients, especially for those complicated with dyslipidemia and obesity.

Microbiota-derived short-chain fatty acids mediate the effects of dengzhan shengmai in ameliorating cerebral ischemia via the gut-brain axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Dengzhan shengmai (DZSM) formula, composed of four herbal medicines (Erigeron breviscapus, Panax ginseng, Schisandra chinensis, and Ophiopogon japonicus), is widely used in the recovery period of ischemic cerebrovascular diseases; however, the associated molecular mechanism remains unclear. AIM OF THE STUDY: The purpose of this study was to uncover the links between the microbiota-gut-brain axis and the efficacy of DZSM in ameliorating cerebral ischemic diseases. MATERIALS AND METHODS: The effects of DZSM on the gut microbiota community and bacteria-derived short-chain fatty acid (SCFA) production were evaluated in vivo using a rat model of cerebral ischemia and in vitro through the anaerobic incubation with fresh feces derived from model animals. Subsequently, the mechanism underlying the role of SCFAs in the DZSM-mediated treatment of cerebral ischemia was explored. RESULTS: We found that DZSM treatment significantly altered the composition of the gut microbiota and markedly enhanced SCFA production. The consequent increase in SCFA levels led to the upregulation of the expression of monocarboxylate transporters and facilitated the transportation of intestinal SCFAs into the brain, thereby inhibiting the apoptosis of neurocytes via the regulation of the PI3K/AKT/caspase-3 pathway. The increased intestinal SCFA levels also contributed to the repair of the 2VO-induced disruption of gut barrier integrity and inhibited the translocation of lipopolysaccharide from the intestine to the brain, thus attenuating neuroinflammation. Consequently, cerebral neuropathy and oxidative stress were significantly improved in 2VO model rats, leading to the amelioration of cerebral ischemia-induced cognitive dysfunction. Finally, fecal microbiota transplantation could reproduce the beneficial effects of DZSM on SCFA production and cerebral ischemia. CONCLUSIONS: Our findings suggested that SCFAs mediate the effects of DZSM in ameliorating cerebral ischemia via the gut microbiota-gut-brain axis.

Cuproptosis-related LncRNA signatures as a prognostic model for head and neck squamous cell carcinoma.

Cuproptosis is a novel, distinct form of regulated cell death. However, little is known about the role of cuproptosis-related lncRNAs (CRlncRNAs) in head and neck squamous cell carcinoma (HNSCC). This study aimed to identify a CRlncRNAs signature, explore its prognostic value in HNSCC. RNA-seq data and relevant clinical data were downloaded from The Cancer Genome Atlas (TCGA) database, and cuproptosis-related genes were identified from a search of the relevant candidate-gene literature. Analysis of differentially expressed lncRNAs (DElncRNAs) was performed using the R package "edgeR". The intersection of the lncRNAs between DElncRNAs and CRlncRNAs was obtained using the R package "Venn Diagram". Univariate Cox regression was used to identify cuproptosis-related prognostic lncRNAs. LASSO-Cox method was used to narrow these cuproptosis-related prognostic lncRNAs and construct a prognostic model. Multiple statistical methods were used to evaluate the predictive ability of the model. Moreover, the relationships between the model and immune cell subpopulations, related functions and pathways and drug sensitivity were explored. Then, two risk groups were established according to the risk score calculated by the CRlncRNAs signature included three lncRNAs. In HNSCC patients, the risk score was a better predictor of survival than traditional clinicopathological features. In addition, significant differences in immune cells such as B cells, T cells and macrophages were observed between the two groups. Finally, the high-risk group had a lower IC50 for certain chemotherapeutic agents, such as cisplatin and cetuximab. This 3 CRlncRNAs signature is a powerful prognostic biomarker for predicting clinical outcomes and therapeutic responses in HNSCC patients.

Multidimensional Control of Repeating Unit/Sequence/Topology for One-Step Synthesis of Block Polymers from Monomer Mixtures.

Synchronously and thoroughly adjusting the chemical structure difference between two blocks of the diblock copolymer is very useful for designing materials but difficult to achieve via self-switchable alternating copolymerization. Here, we report self-switchable alternating copolymerization from a mixture of two different cyclic anhydrides, epoxides, and oxetanes, where a simple alkali metal carboxylate catalyst switches between ring-opening alternating copolymerization (ROCOP) of cyclic anhydrides/epoxides and ROCOP of cyclic anhydrides/oxetanes, resulting in the formation of a perfect block tetrapolymer. By investigating the reactivity ratio of these comonomers, a reactivity gradient was established, enabling the precise synthesis of block copolymers with synchronous adjustment of each unit's chemical structure/sequence/topology. Consequently, a diblock tetrapolymer with two glass transition temperatures (Tg) can be easily produced by adjusting the difference in chemical structures between the two blocks.

Analgesic Alkaloids Derived From Traditional Chinese Medicine in Pain Management.

Chronic pain is one of the most prevalent health problems. The establishment of chronic pain is complex. Current medication for chronic pain mainly dependent on anticonvulsants, tricyclic antidepressants and opioidergic drugs. However, they have limited therapeutic efficacy, and some even with severe side effects. We turned our interest into alkaloids separated from traditional Chinese medicine (TCM), that usually act on multiple drug targets. In this article, we introduced the best-studied analgesic alkaloids derived from TCM, including tetrahydropalmatine, aloperine, oxysophocarpine, matrine, sinomenine, ligustrazine, evodiamine, brucine, tetrandrine, Stopholidine, and lappaconitine, focusing on their mechanisms and potential clinical applications. To better describe the mechanism of these alkaloids, we adopted the concept of drug-cloud (dCloud) theory. dCloud illustrated the full therapeutic spectrum of multitarget analgesics with two dimensions, which are "direct efficacy", including inhibition of ion channels, activating γ-Aminobutyric Acid/opioid receptors, to suppress pain signal directly; and "background efficacy", including reducing neuronal inflammation/oxidative stress, inhibition of glial cell activation, restoring the balance between excitatory and inhibitory neurotransmission, to cure the root causes of chronic pain. Empirical evidence showed drug combination is beneficial to 30-50% chronic pain patients. To promote the discovery of effective analgesic combinations, we introduced an ancient Chinese therapeutic regimen that combines herbal drugs with "Jun", "Chen", "Zuo", and "Shi" properties. In dCloud, "Jun" drug acts directly on the major symptom of the disease; "Chen" drug generates major background effects; "Zuo" drug has salutary and supportive functions; and "Shi" drug facilitates drug delivery to the targeted tissue. Subsequently, using this concept, we interpreted the therapeutic effect of established analgesic compositions containing TCM derived analgesic alkaloids, which may contribute to the establishment of an alternative drug discovery model.

SPINK5 is a Prognostic Biomarker Associated With the Progression and Prognosis of Laryngeal Squamous Cell Carcinoma Identified by Weighted Gene Co-Expression Network Analysis.

Laryngeal squamous cell carcinoma (LSCC) is one of the most common types of head and neck squamous cell carcinomas (HNSCC) and is the second most prevalent malignancy occurring in the head and neck or respiratory tract, with a high incidence and mortality rate. Survival is limited for patients with LSCC. To identify more biomarkers associated with the prognosis of patients with LSCC, using bioinformatics analysis, this study used The Cancer Genome Atlas (TCGA) LSCC dataset and gene expression profiles of GSE59102 from the Gene Expression Omnibus (GEO). Eighty-one differentially co-expressed genes were identified by weighted gene co-expression network analysis (WGCNA). Next, 10 hub genes (PPL, KRT78, CRNN, PTK7, SCEL, AGRN, SPINK5, AIF1L, EMP1, and PPP1R3C) were screened from a protein-protein interaction (PPI) network. Based on survival analysis, SPINK5 was significantly correlated with survival time in LSCC patients. After verification in the TCGA and HPA databases, SPINK5 was selected as a prognostic biomarker. Finally, the GSEA results showed that downregulation of SPINK5 gene expression may promote tumorigenesis and the development of cancers by the "BASAL CELL CARCINOMA" pathway, and it has been implicated in disrupting DNA damage and repair pathways. Collectively, SPINK5 may serve as a potential prognostic biomarker in LSCC.

Early death in supraglottic laryngeal squamous cell carcinoma: A population-based study.

BACKGROUND: Supraglottic laryngeal squamous cell carcinoma (LSCC) is the second most common type of laryngeal cancer with a poor prognosis. Current population-based estimates of the early death rate and associated factors for early death of supraglottic LSCC are lacking. The purpose of this study was to assess the early death rate and related factors for early death in patients with supraglottic LSCC. METHODS: We identified 3733 adult patients diagnosed with supraglottic LSCC between 2010 and 2017 for whom the vital status at 3 months was known from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were staged according to the seventh edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system. The early death (survival time ≤ 3 months) rate was calculated. Univariate and multivariate logistic regression analyses were performed to identify the risk factors associated with the early death rate. RESULTS: 313 (8.38%) of the 3733 patients died within 3 months of diagnosis of supraglottic LSCC. Of these, 225 patients died from cancer-specific causes. Multivariate logistic regression analyses confirmed that advanced age, male sex, advanced T stage, advanced N stage, advanced M stage, and not undergoing treatment (surgery, radiotherapy, and chemotherapy) had significant correlations with all-cause early death in supraglottic LSCC. In addition, advanced age, advanced T stage, advanced N stage, advanced M stage, and not undergoing treatment (surgery, radiotherapy, and chemotherapy) were significantly correlated with cancer specificity in supraglottic LSCC. CONCLUSION: When a tumor is newly diagnosed, we should pay close attention to sex, age, unmarried status and AJCC TNM staging to quickly detect supraglottic LSCC patients with a tendency toward early death. These findings have implications for precise prognosis prediction and individualized and personalized patient counseling and therapy.

One-step synthesis of sequence-controlled multiblock polymers with up to 11 segments from monomer mixture.

Switchable polymerization holds considerable potential for the synthesis of highly sequence-controlled multiblock. To date, this method has been limited to three-component systems, which enables the straightforward synthesis of multiblock polymers with less than five blocks. Herein, we report a self-switchable polymerization enabled by simple alkali metal carboxylate catalysts that directly polymerize six-component mixtures into multiblock polymers consisting of up to 11 blocks. Without an external trigger, the catalyst polymerization spontaneously connects five catalytic cycles in an orderly manner, involving four anhydride/epoxide ring-opening copolymerizations and one L-lactide ring-opening polymerization, creating a one-step synthetic pathway. Following this autotandem catalysis, reasonable combinations of different catalytic cycles allow the direct preparation of diverse, sequence-controlled, multiblock copolymers even containing various hyperbranched architectures. This method shows considerable promise in the synthesis of sequentially and architecturally complex polymers, with high monomer sequence control that provides the potential for designing materials.

Engineered ε-decalactone lipomers bypass the liver to selectively in vivo deliver mRNA to the lungs without targeting ligands.

RNA drugs hold real potential for tackling devastating diseases that are currently resistant to small molecule drugs or monoclonal antibodies. However, since these drugs are unstable in vivo and unable to pass through cellular membranes their clinical realization is limited by their successful delivery to target sites. Herein we report on the design of a combinatorial library of polyester lipomers based on the renewable monomer, ε-decalactone (ε-DL), via organocatalytic ring-opening polymerization for mRNA delivery. The ε-DL lipomers showed a surprisingly efficient ability to target the lungs upon intravenous administration. Interestingly, most of the lipomers achieved functional EGFP expression in the lungs, while minimally transfecting hepatocytes and splenic cells. This simple approach for the design of biodegradable materials has the potential for the clinical translation of genetic medicines for the treatment of lung diseases.

Risk factors for postoperative bleeding after endoscopic sinus surgery to treat chronic rhinosinusitis.

BACKGROUND: Although there has been progress in improving endoscopic sinus surgery (ESS), patients undergoing ESS are still at risk of postoperative bleeding. Little attention has been given to identifying specific risk factors for postoperative bleeding after ESS to treat chronic rhinosinusitis (CRS). OBJECTIVES: The aim of this study was to identify the incidence and risk factors associated with postoperative bleeding in patients who underwent ESS to treat CRS. MATERIALS AND METHODS: Six hundred and five patients with CRS who underwent ESS between 2017 and 2020 were included in this retrospective analysis. Univariate and multivariate analysis was performed to assess the association between the incidence of postoperative bleeding and the background characteristics. RESULTS: Out of 605 ESSs, 36 (6.0%) patients developed postoperative bleeding. Multiple logistic regression revealed that the use of antiplatelet and/or anticoagulant drugs, the presence of hypertension and the Lund-Mackay CT score were significantly correlated with the occurrence of postoperative bleeding. CONCLUSION: Postoperative bleeding is a common complication following ESS. The risk factors for postoperative bleeding were as follows: the use of antiplatelet and/or anticoagulant drugs, hypertension and the Lund-Mackay CT score.

Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson's disease by regulating gut microbiota.

The phenylalanine-tyrosine-dopa-dopamine pathway provides dopamine to the brain. In this process, tyrosine hydroxylase (TH) is the rate-limiting enzyme that hydroxylates tyrosine and generates levodopa (L-dopa) with tetrahydrobiopterin (BH4) as a coenzyme. Here, we show that oral berberine (BBR) might supply H• through dihydroberberine (reduced BBR produced by bacterial nitroreductase) and promote the production of BH4 from dihydrobiopterin; the increased BH4 enhances TH activity, which accelerates the production of L-dopa by the gut bacteria. Oral BBR acts in a way similar to vitamins. The L-dopa produced by the intestinal bacteria enters the brain through the circulation and is transformed to dopamine. To verify the gut-brain dialog activated by BBR's effect, Enterococcus faecalis or Enterococcus faecium was transplanted into Parkinson's disease (PD) mice. The bacteria significantly increased brain dopamine and ameliorated PD manifestation in mice; additionally, combination of BBR with bacteria showed better therapeutic effect than that with bacteria alone. Moreover, 2,4,6-trimethyl-pyranylium tetrafluoroborate (TMP-TFB)-derivatized matrix-assisted laser desorption mass spectrometry (MALDI-MS) imaging of dopamine identified elevated striatal dopamine levels in mouse brains with oral Enterococcus, and BBR strengthened the imaging intensity of brain dopamine. These results demonstrated that BBR was an agonist of TH in Enterococcus and could lead to the production of L-dopa in the gut. Furthermore, a study of 28 patients with hyperlipidemia confirmed that oral BBR increased blood/fecal L-dopa by the intestinal bacteria. Hence, BBR might improve the brain function by upregulating the biosynthesis of L-dopa in the gut microbiota through a vitamin-like effect.