[Effect of Xuming Decoction in Records of Proved Prescriptions, Ancient a nd Modern on cerebral ischemic injury and angiogenesis in rat model of acute cerebral infarction].

This paper aims to explore the effect of Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern on cerebral ischemic injury and angiogenesis in the rat model of acute cerebral infarction. SD rats were randomized into 6 groups: sham group, model group, low-, medium-, and high-dose(5.13, 10.26, and 20.52 g·kg~(-1), respectively) Xuming Decoction groups, and butylphthalide(0.06 g·kg~(-1)) group. After the successful establishment of the rat model by middle cerebral artery occlusion(MCAO), rats in the sham and model groups were administrated with distilled water and those in other groups with corresponding drugs for 7 consecutive days. After the neurological function was scored, all the rats were sacrificed, and the brain tissue samples were collected. The degree of cerebral ischemic injury was assessed by the neurological deficit score and staining with 2,3,5-triphenyltetrazolium chloride. Hematoxylin-eosin staining was performed to observe the pathological changes in the brain. Transmission electron microscopy was employed to observe the ultrastructures of neurons and microvascular endothelial cells(ECs) on the ischemic side of the brain tissue. Immunofluorescence assay was employed to detect the expression of von Willebrand factor(vWF) and hematopoietic progenitor cell antigen CD34(CD34) in the ischemic brain tissue. Real-time PCR and Western blot were employed to determine the mRNA and protein levels, respectively, of Runt-related transcription factor 1(RUNX1), vascular endothelial growth factor(VEGF), angiopoietin-1(Ang-1), angiopoietin-2(Ang-2), and VEGF receptor 2(VEGFR2) in the ischemic brain tissue. The results showed that compared with the sham group, the model group showed increased neurological deficit score and cerebral infarction area(P<0.01), pathological changes, and damaged ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Furthermore, the modeling up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.05 or P<0.01). Compared with the model group, high-dose Xuming Decoction and butylphthalide decreased the neurological deficit score and cerebral infarction area(P<0.01) and alleviated the pathological changes and damage of the ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Moreover, they up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01). The results suggest that Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern can promote the angiogenesis and collateral circulation establishment to alleviate neurological dysfunction of the ischemic brain tissue in MCAO rats by regulating the RUNX1/VEGF pathway.

Photoinduced Site-Selective Aryl C-H Borylation with Electron-Donor-Acceptor Complex Derived from B2Pin2 and Isoquinoline.

Due to boron's metalloid properties, aromatic boron reagents are prevalent synthetic intermediates. The direct borylation of aryl C-H bonds for producing aromatic boron compounds offers an appealing, one-step solution. Despite significant advances in this field, achieving regioselective aryl C-H bond borylation using simple and readily available starting materials still remains a challenge. In this work, we attempted to enhance the reactivity of the electron-donor-acceptor (EDA) complex by selecting different bases to replace the organic base (NEt3) used in our previous research. To our delight, when using NH4HCO3 as the base, we have achieved a mild visible-light-mediated aromatic C-H bond borylation reaction with exceptional regioselectivity (rr > 40:1 to single isomers). Compared with our previous borylation methodologies, this protocol provides a more efficient and broader scope for aryl C-H bond borylation through the use of N-Bromosuccinimide. The protocol's good functional-group tolerance and excellent regioselectivity enable the functionalization of a variety of biologically relevant compounds and novel cascade transformations. Mechanistic experiments and theoretical calculations conducted in this study have indicated that, for certain arenes, the aryl C-H bond borylation might proceed through a new reaction mechanism, which involves the formation of a novel transient EDA complex.

Sialic Acid Conjugate-Modified Cationic Liposomal Paclitaxel for Targeted Therapy of Lung Metastasis in Breast Cancer: What a Difference the Cation Content Makes.

Cationic lipids play a pivotal role in developing novel drug delivery systems for diverse biomedical applications, owing to the success of mRNA vaccines against COVID-19 and the Phase III antitumor agent EndoTAG-1. However, the therapeutic potential of these positively charged liposomes is limited by dose-dependent toxicity. While an increased content of cationic lipids in the formulation can enhance the uptake and cytotoxicity toward tumor-associated cells, it is crucial to balance these advantages with the associated toxic side effects. In this work, we synthesized the cationic lipid HC-Y-2 and incorporated it into sialic acid (SA)-modified cationic liposomes loaded with paclitaxel to target tumor-associated immune cells efficiently. The SA-modified cationic liposomes exhibited enhanced binding affinity toward both RAW264.7 cells and 4T1 tumor cells in vitro due to the increased ratios of cationic HC-Y-2 content while effectively inhibiting 4T1 cell lung metastasis in vivo. By leveraging electrostatic forces and ligand-receptor interactions, the SA-modified cationic liposomes specifically target malignant tumor-associated immune cells such as tumor-associated macrophages (TAMs), reduce the proportion of cationic lipids in the formulation, and achieve dual objectives: high cellular uptake and potent antitumor efficacy. These findings highlight the potential advantages of this innovative approach utilizing cationic liposomes.

Durable protective efficiency provide by mRNA vaccines require robust immune memory to antigens and weak immune memory to lipid nanoparticles.

The Pegylated lipids in lipid nanoparticle (LNPs) vaccines have been found to cause acute hypersensitivity reactions in recipients, and generate anti-LNPs immunity after repeated administration, thereby reducing vaccine effectiveness. To overcome these challenges, we developed a new type of LNPs vaccine (SAPC-LNPs) which was co-modified with sialic acid (SA) - lipid derivative and cleavable PEG - lipid derivative. This kind of mRNA vaccine can target dendritic cells (DCs) and rapidly escape from early endosomes (EE) and lysosomes with a total endosomal escape rate up to 98 %. Additionally, the PEG component in SAPC-LNPs was designed to detach from the LNPs under the catalysis of carboxylesterase in vivo, which reduced the probability of PEG being attached to LNPs entering antigen-presenting cells. Compared with commercially formulated vaccines (1.5PD-LNPs), mice treated with SAPC-LNPs generated a more robust immune memory to tumor antigens and a weaker immune memory response to LNPs, and showed lower side effects and long-lasting protective efficiency. We also discovered that the anti-tumor immune memory formed by SAPC-LNPs mRNA vaccine was directly involved in the immune cycle to rattack tumor. This immune memory continued to strengthen with multiple cycles, supporting that the immune memory should be incorporated into the theory of tumor immune cycle.

Phenotypic characterisation of regulatory T cells in patients with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a common complication that occurs during pregnancy. Emerging evidence suggests that immune abnormalities play a pivotal role in the development of GDM. Specifically, regulatory T cells (Tregs) are considered a critical factor in controlling maternal-fetal immune tolerance. However, the specific characteristics and alterations of Tregs during the pathogenesis of GDM remain poorly elucidated. Therefore, this study aimed to investigate the changes in Tregs among pregnant women diagnosed with GDM compared to healthy pregnant women. A prospective study was conducted, enrolling 23 healthy pregnant women in the third trimester and 21 third-trimester women diagnosed with GDM. Participants were followed up until the postpartum period. The proportions of various Treg, including Tregs, mTregs, and nTregs, were detected in the peripheral blood of pregnant women from both groups. Additionally, the expression levels of PD-1, HLA-G, and HLA-DR on these Tregs were examined. The results revealed no significant differences in the proportions of Tregs, mTregs, and nTregs between the two groups during the third trimester and postpartum period. However, GDM patients exhibited significantly reduced levels of PD-1+ Tregs (P < 0.01) and HLA-G+ Tregs (P < 0.05) in the third trimester compared to healthy pregnant women in the third trimester. Furthermore, GDM patients demonstrated significantly lower levels of PD-1+ mTregs (P < 0.01) and HLA-G+ (P < 0.05) mTregs compared to healthy pregnant women in the third trimester. Overall, the proportion of Tregs did not exhibit significant changes during the third trimester in GDM patients compared to healthy pregnant women. Nevertheless, the observed dysregulation of immune regulation function in Tregs and mTregs may be associated with the development of GDM in pregnant women.

Rational design of super reductive EDA photocatalyst for challenging reactions: a theoretical and experimental study.

We reported a novel electron-donor-acceptor (EDA) photocatalyst formed in situ from isoquinoline, a diboron reagent, and a weak base. To further optimize the efficiency of this photocatalyst, Density Functional Theory (DFT) calculations were conducted to investigate the substituent effects on the properties of vertical excitation energy and redox potential. Subsequently, we experimentally validated these effects using a broader range of substituents and varying substitution positions. Notably, the 4-NH2 EDA complex derived from 4-NH2-isoquinoline exhibits the highest photocatalytic efficiency, enabling feasible metal free borylation of aromatic C-H bond and detosylaion of Ts-anilines under green and super mild conditions. These experimental results demonstrate the effectiveness of our strategy for photocatalyst optimization.

Sialic acid-modified doxorubicin liposomes target tumor-related immune cells to relieve multiple inhibitions of CD8+ T cells.

In different types of cancer treatments, cancer-specific T cells are required for effective anticancer immunity, which has a central role in cancer immunotherapy. However, due to the multiple inhibitions of CD8+ T cells by tumor-related immune cells, CD8+ T-cell mediated antitumor immunotherapy has not achieved breakthrough progress in the treatment of solid tumors. Receptors for sialic acid (SA) are highly expressed in tumor-associated immune cells, so SA-modified nanoparticles are a drug delivery nanoplatform using tumor-associated immune cells as vehicles. To relieve the multiple inhibitions of CD8+ T cells by tumor-associated immune cells, we prepared SA-modified doxorubicin liposomes (SL-DOX, Scheme 1A). In our study, free SA decreased the toxicity of SL-DOX to tumor-associated immune cells. Compared with common liposomes, SL-DOX could inhibit tumor growth more effectively. It is worth noting that SL-DOX could not only kill tumor-related neutrophils and monocytes to relieve the multiple inhibitions of CD8+ T cells but also induce immunogenic death of tumor cells to promote the infiltration and differentiation of CD8+ T cells (Scheme 1B). Therefore, SL-DOX has potential value for the clinical therapeutic effect of CD8+ T cells mediating anti-tumor immunotherapy.

The selection of animal models influences the assessment of anti-tumor efficacy: promising sialic acid-conjugate modified liposomes demonstrate remarkable therapeutic effects in diverse mouse strains.

Mice as a crucial tool for preclinical assessment of antineoplastic agents. The impact of physiological differences among mouse strains on the in vivo efficacy of antitumor drugs, however, has been significantly overlooked. Mononuclear phagocyte system (MPS) is the major player in clearance in vivo, and differences in MPS among different strains may potentially impact the effectiveness of antitumor preparations. Therefore, in this study, we employed conventional liposomes (CL-EPI) and SA-ODA modified liposomes (SAL-EPI) as model preparations to investigate the comprehensive tumor therapeutic effects of CL-EPI and SAL-EPI in KM, BALB/c, and C57BL/6 tumor-bearing mice. The results demonstrated significant variability in the efficacy of CL-EPI for tumor treatment across different mouse strains. Therefore, we should pay attention to the selection of animal models in the study of antitumor agents. SAL-EPI effectively targeted tumor sites by binding to Siglec-1 on the surface of peripheral blood monocytes (PBMs), and achieved good therapeutic effect in different mouse strains with little difference in treatment. The SA modified preparation is therefore expected to achieve a favorable therapeutic effect in tumor patients with different immune states through PBMs delivery (Siglec-1 was expressed in both mice and humans), thereby possessing clinical translational value and promising development prospects.

Simultaneous dendritic cells targeting and effective endosomal escape enhance sialic acid-modified mRNA vaccine efficacy and reduce side effects.

mRNA vaccines are attractive prospects for the development of DC-targeted vaccines; however, no clinical success has been realized because, currently, it is difficult to simultaneously achieve DC targeting and efficient endosomal/lysosomal escape. Herein, we developed a sialic acid (SA)-modified mRNA vaccine that simultaneously achieved both. The SA modification promoted DCs uptake of lipid nanoparticles (LNPs) by 2 times, >90% of SA-modified LNPs rapidly escaped from early endosomes (EEs), avoided entering lysosomes, achieved mRNA simultaneously translated in ribosomes distributed in the cytoplasm and endoplasmic reticulum (ER), significantly improved the transfection efficiency of mRNA LNPs in DCs. Additionally, we applied cleavable PEG-lipids in mRNA vaccines for the first time and found this conducive to cellular uptake and DC targeting. In summary, SA-modified mRNA vaccines targeted DCs efficiently, and showed significantly higher EEs/lysosomal escape efficiency (90% vs 50%), superior tumor treatment effect, and lower side effects than commercially formulated mRNA vaccines.

PSMC5 regulates microglial polarization and activation in LPS-induced cognitive deficits and motor impairments by interacting with TLR4.

Luteolin is a flavonoid found in high concentrations in celery and green pepper, and acts as a neuroprotectant. PSMC5 (proteasome 26S subunit, ATPase 5) protein levels were reduced after luteolin stimulation in activated microglia. We aimed to determine whether regulating PSMC5 expression could inhibit neuroinflammation, and investigate the underlying mechanisms.BV2 microglia were transfected with siRNA PSMC5 before the addition of LPS (lipopolysaccharide, 1.0 µg/ml) for 24 h in serum free DMEM. A mouse model of LPS-induced cognitive and motor impairment was established to evaluate the neuroprotective effects of shRNA PSMC5. Intracerebroventricular administration of shRNA PSMC5 was commenced 7 days prior to i.p. injection of LPS (750 µg/kg). Treatments and behavioral experiments were performed once daily for 7 consecutive days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced hippocampal damage. Molecular dynamics simulation was used to confirm the interaction between PSMC5 and TLR4 (Toll-like receptor 4) in LPS-stimulated BV2 microglia. SiRNA PSMC5 inhibited BV2 microglial activation, and suppressed the release of inflammatory factors (IL-1ß, COX-2, PGE2, TNF-α, and iNOS) upon after LPS stimulation in BV2 microglia. LPS increased IκB-α and p65 phosphorylation, which was attenuated by siRNA PSMC5. Behavioral tests and pathological/biochemical assays showed that shRNA PSMC5 attenuated LPS-induced cognitive and motor impairments, and restored synaptic ultrastructure and protein levels in mice. ShRNA PSMC5 reduced pro-inflammatory cytokine (TNF-α, IL-1ß, PGE2, and NO) levels in the serum and brain, and relevant protein factors (iNOS and COX-2) in the brain. Furthermore, shRNA PSMC5 upregulated the anti-inflammatory mediators interleukin IL-4 and IL-10 in the serum and brain, and promoted a pro-inflammation-to-anti-inflammation phenotype shift in microglial polarization. Mechanistically, shRNA PSMC5 significantly alleviated LPS-induced TLR4 expression. The polarization of LPS-induced microglial pro-inflammation phenotype was abolished by TLR4 inhibitor and in the TLR-4-/- mouse, as in shRNA PSMC5 treatment. PSMC5 interacted with TLR4 via the amino sites Glu284, Met139, Leu127, and Phe283. PSMC5 site mutations attenuated neuroinflammation and reduced pro-inflammatory factors by reducing TLR4-related effects, thereby reducing TLR4-mediated MyD88 (myeloid differentiation factor 88)-dependent activation of NF-κB. PSMC5 could be an important therapeutic target for treatment of neurodegenerative diseases involving neuroinflammation-associated cognitive deficits and motor impairments induced by microglial activation.

Potent gene delivery from fluorinated poly(ß-amino ester) in adhesive and suspension difficult-to-transfect cells for apoptosis and ferroptosis.

Tremendous efforts have been made to improve polymeric property in gene delivery performances, especially when obstacle of transferring gene construct into difficult-to-transfect cells occurs. Innovations in the area of fluorination and fluorinated compounds with biomedical potential in medicinal chemistry are believed to assist in the development of new therapeutics. Fluorine modified polymers have shown to navigate the gene transfection cellular barriers and promoted the transfection outcomes. Gene transfer into some liver cancer cells and human leukemia cells has always been a challenge. Here, by facile incorporation of a fluorine containing amine monomer, 1H,1H-undecafluorohexylamine, fluorinated poly(ß-amino ester) (FPAE) was synthesized to significantly improve the transfection performance, achieving high transfection efficiency of 87% and 55% in two representative difficult-to-transfect cells, HepG2 and Molt-4, which were cultured in adhesive and suspension condition, respectively. However, the potency of Lipofectamine 3000 was very limited. More importantly, functional studies revealed that FPAE can dramatically outperform Lipofectamine 3000 in delivering Bcl-xL and PKCßII to either provide the protection against apoptosis or promote the ferroptosis in HepG2 cells. This work facilitates gene therapies by overcoming biological barriers for targeting difficult-to-transfect cells and disease models when medically necessary.

Efferocytosis: An Emerging Therapeutic Strategy for Type 2 Diabetes Mellitus and Diabetes Complications.

Increasing evidence indicates that chronic, low-grade inflammation is a significant contributor to the fundamental pathogenesis of type 2 diabetes mellitus (T2DM). Efferocytosis, an effective way to eliminate apoptotic cells (ACs), plays a critical role in inflammation resolution. Massive accumulation of ACs and the proliferation of persistent inflammation caused by defective efferocytosis have been proven to be closely associated with pancreatic islet ß cell destruction, adipose tissue inflammation, skeletal muscle dysfunction, and liver metabolism abnormalities, which together are considered the most fundamental pathological mechanism underlying T2DM. Therefore, here we outline the association between the molecular mechanisms of efferocytosis in glucose homeostasis, T2DM, and its complications, and we analyzed the present constraints and potential future prospects for therapeutic targets in T2DM and its complications.

Cleavable-Branched Polymer-Modified Liposomes Reduce Accelerated Blood Clearance and Enhance Photothermal Therapy.

In recent years, cationic liposomes have been successfully used as delivery platforms for mRNA vaccines. Poly(ethylene glycol) (PEG)-lipid derivatives are widely used to enhance the stability and reduce the toxicity of cationic liposomes. However, these derivatives are often immunogenic, triggering the rise of anti-PEG antibodies. Understanding the role and impact of PEG-lipid derivatives on PEGylated cationic liposomes is key to solving the PEG dilemma. In this study, we designed linear, branched, and cleavable-branched cationic liposomes modified with PEG-lipid derivatives and investigated the effect of the liposome-induced accelerated blood clearance (ABC) phenomenon on photothermal therapy. Our study indicated that the linear PEG-lipid derivatives mediated the effect of photothermal therapy by stimulating splenic marginal zone (MZ) B cells to secrete anti-PEG antibodies and increasing the level of IgM expression in the follicular region of the spleen. However, the cleavable-branched and branched PEG-lipid derivatives did not activate the complement system and avoided the ABC phenomenon by inducing noticeably lower levels of anti-PEG antibodies. The cleavable-branched PEGylated cationic liposomes improved the effect of photothermal therapy by reversing the charge on the liposome surface. This detailed study of PEG-lipid derivatives contributes to the further development and clinical application of PEGylated cationic liposomes.

Knowledge mapping of nano drug delivery systems across blood - Brain barrier from 1996 to 2022: A bibliometric analysis.

Background: The blood-brain barrier (BBB) is a natural physiological barrier that protects the central nervous system from foreign substances and limits the delivery of drugs to the brain. Nanotechnology has opened up new possibilities for drug delivery in the brain. Over several decades, various Nanoparticle Drug Delivery Systems (NDDS) that can cross the BBB have been developed for targeted delivery in the brain. To gain a comprehensive understanding of the current research hotspots and trends of NDDS across the BBB, this paper employs bibliometric analysis of articles published in the core database of Web of Science (WOS) from 1996 to 2022. Method: A search for relevant research literature on NDDS that can cross the BBB was conducted in the Web of Science database, covering the period from 1996 to 2022. The Bibliometrix R-4.0 software package was used to analyze data related to the countries of publication, research institutions, journals, citations, and keywords. The analysis aimed to identify the co-occurrence of keywords in the documents, including their titles and abstracts. Additionally, cooperative network analyses of authors, institutions, and countries of publication were conducted. Results: A total of 436 articles were analyzed, originating from 174 journals and 13 books, with the majority published in Q1 and Q2 journals. Contributors from 53 countries or regions participated in the publication of these articles, with China, the United States, and India having the highest number of articles by correspondent authors, and China, the United States, and Germany being the most cited countries. Fudan University, Hacettepe University, and Sichuan University were the top three institutions with the most publications. Among the 436 articles analyzed, 1337 keywords and 1450 keywords plus were identified. Factor analysis grouped the keywords plus into two categories: drug delivery systems, polymeric nanoparticles, gold nanoparticles, transferrin, and others, and drug, delivery, efficiency, expression, and mechanism. Conclusion: The research on NDDS that can cross the BBB is gradually receiving attention, and the recognition and cooperation in this field have increased.

[CiteSpace knowledge map of gut microbiota research involving traditional Chinese medicine in recent twenty years].

We employed bibliometrics to comprehensively study the hotspots and frontiers of gut microbiota research involving traditional Chinese medicine(TCM), aiming to provide new ideas for the subsequent research in this field. The studies of gut microbiota with TCM published from January 1, 2002 to December 31, 2021 were retrieved from CNKI, Wanfang, VIP and Web of Science(WoS). After data screening and cleaning, CiteSpace 5.8.R3 was used to visualize and analyze the authors, journals, and keywords. A total of 1 119 Chinese articles and 815 English articles were included in the study. The period of 2019-2021 witnessed the surge in the number of articles published in this field, being the peak research period. TAN Zhou-jin and DUAN Jin-ao were the authors publishing the most articles in Chinese and English, respectively. The two authors ranked top in both Chinese and English articles, playing a central role in this research field. The top five Chinese and English journals in this field had a large influence in the international research field. High-frequency keywords and keyword clustering showed that the research hotspots in this field were concentrated in four areas: trial and clinical research on the regulation of gut microbiota in disease treatment by TCM, metabolic transformation of Chinese medicines by gut microbiota, and the effect of TCM added to feed on the gut microbiota and growth performance of animals. The study of gut microbiota structure in patients with different TCM syndromes, as well as that of TCM combined with probiotics/flora transplantation in the treatment of diseases, can provide new ideas for clinical diagnosis and traditional drug treatment of diseases and has great research space and research value in the future.

A novel micellar carrier to reverse multidrug resistance of tumours: TPGS derivatives with end-grafted cholesterol.

D-α-tocopherol polyethylene glycol succinate (TPGS) has good biocompatibility, low immunogenicity, prolonged circulation time, and it can reverse multidrug resistance of tumours. However, the micelle concentration (CMC) of TPGS is too high (0.2 mg/mL) to develop the formulation of the micelle. In this study, TPGS was modified with cholesterol to obtain a new carrier material, TPGS-CHMC. The CMC of TPGS-CHMC was 2 µg/mL, which was extremely lower than that of TPGS. Docetaxel (DTX)-loaded TPGS-CHMC micelles (TPGS-CHMC/DTX) exhibited an average size of approximately 13 nm, a zeta potential of approximately -4.66 mV, and high encapsulation efficiency (99.2 ± 0.6%). TPGS-CHMC reduced mitochondrial membrane potential and cell membrane fluidity in paclitaxel-resistant ovarian cancer cells (A2780/T). In vivo, DiR-loaded TPGS-CHMC micelles were selectively distributed in A2780/T tumour-bearing nude mice. In A2780/T tumour-bearing nude mice, TPGS-CHMC/DTX micelles displayed significantly higher anti-tumour activity and less toxicity than the free DTX solution. In summary, TPGS-CHMC has various advantages and provides a new option for developing functional polymeric micelles.

Meta-analysis of the relations between gut microbiota and pathogens and Parkinson's disease.

BACKGROUND: The motor symptoms in patients with Parkinson's disease (PD) are commonly preceded by gastrointestinal (GI) symptoms. The enteric nervous system (ENS) has also been reported to exhibit neuropathological characteristics of PD. OBJECTIVES: To evaluate the relationship between the incidence of parkinsonism and alteration in gut microbiota and pathogens. MATERIAL AND METHODS: Studies in different languages that evaluate the relationship between gut microorganisms and PD were included into this meta-analysis. The outcomes of these studies were analyzed using a random effects model; it was also used to calculate the mean difference (MD) with 95% confidence interval (95% CI) in order to quantify the impact of different rehabilitation techniques on clinical parameters. Dichotomous and continuous models were used for the analysis of extracted data. RESULTS: A total of 28 studies were included in our analysis. The analysis of small intestinal bacterial overgrowth showed a significant correlation with Parkinson's subjects compared with controls (p < 0.001). In addition, the presence of Helicobacter pylori (HP) infection was significantly related to the Parkinson's group (p < 0.001). On the other hand, there was a significantly higher abundance level of Bifidobacteriaceae (p = 0.008), Verrucomicrobiaceae (p < 0.001) and Christensenellaceae (p = 0.003) in Parkinson's subjects. In contrast, a significantly lower abundance levels in Parkinson's subjects were found in Faecalibacterium (p = 0.03), Lachnospiraceae (p = 0.005) and Prevotellaceae (p = 0.005). No significant difference was related to Ruminococcaceae. CONCLUSION: Parkinson's subjects showed a higher degree of alteration of gut microbiota and pathogens compared with normal human subjects. Future multicenter randomized trials are needed.

Blockade of neutrophil recruitment to tumor sites based on sialic acid-modified nanoplatforms enhances the efficacy of checkpoint blockade immunotherapy.

Checkpoint inhibitors are designed to rejuvenate depleted or suppressed T cells in the tumor microenvironment, relying on the immune system to control and kill tumors. However, accumulating evidence indicates that tumor-infiltrating neutrophils impede the proliferation and activation of T cells and determine the resistance to checkpoint blockade and chemotherapy. In this study, sialic acid ligand-modified colchicine derivative phospholipid complexes specifically targeted tumor-associated neutrophils in the peripheral blood, blocked neutrophil accumulation in tumors, and attenuated the inhibitory effect of infiltrating neutrophils on T cells. Neutrophil blocking therapy enhanced the immunotherapy effect of the PD-L1 antibody in S180 advanced tumors and 4T1 breast cancer. Our study found that PD-L1 antibody monotherapy increased the tumor infiltration of immunosuppressive neutrophils. Combination therapy with neutrophil blocking can greatly reduce tumor-infiltrating neutrophils and increase the proliferation of cytotoxic CD8+ T lymphocytes in the tumor. The combination therapy significantly improved the survival rate of mice with advanced S180 tumors and increased the sensitivity of immune checkpoint inhibitors to 4T1 cold tumors.

Liposomal Doxorubicin: the Sphingomyelin/Cholesterol System Significantly Enhances the Antitumor Efficacy of Doxorubicin.

Doxorubicin (DOX) has a cytotoxic effect on many tumor cells; however, its clinical application is limited owing to its strong side effects. Although Doxil® reduces the cardiotoxicity of free DOX, it has also introduced a new dose-limiting toxicity. In a previous study, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified onto the surface of DOX-loaded liposomes to target tumor-associated macrophages (TAMs), further improving the efficacy of DOX-loaded liposomes over that of Doxil®. Meanwhile, the good retention characteristics and promising antitumor ability of sphingomyelin/cholesterol (SM/CH) system for water-soluble drugs have attracted wide attention. Therefore, we aimed to use SA-CH as the target and hydrogenated soybean phosphatidylcholine (HSPC) or egg sphingomyelin (ESM) as the membrane material to develop a more stable DOX-loaded liposome with stronger antitumor activity. The liposomes were evaluated for particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release, long-term storage, cytotoxicity, cellular uptake, pharmacokinetics, tumor targetability, and in vivo antitumor activity. In the liposomes prepared using HSPC/CH, sialic acid (SA) modification considerably increased the accumulation of DOX-loaded liposomes in the tumor, thus exerting a better antitumor effect. However, SA modification in DOX-ESL (SA-CH-modified DOX-loaded liposomes prepared by ESM/CH) destroyed the strong retention effect of the ESM/CH system on DOX, resulting in a reduced antitumor effect. Notably, DOX-ECL (DOX-loaded liposome prepared by ESM/CH) had the optimal storage stability, lowest toxicity, and optimal antitumor effect due to better drug retention properties. Thus, the ESM/CH liposome of DOX is a potential drug delivery system. Sketch of the effect of two DOX-loaded liposomes with hydrogenated soybean phospholipid (HSPC) and egg sphingomyelin (ESM) as lipid membrane material and surface-modified SA derivative on tumor growth inhibition.

A potential platform of combining sialic acid derivative-modified paclitaxel cationic liposomes with antibody-drug conjugates inspires robust tumor-specific immunological memory in solid tumors.

The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in the past few years have fueled the ongoing development of this class of drug. However, the limitation of ADCs is selectivity toward cancer cells especially overexpressing the antigen of interest. To broaden the anti-cancer spectrum of ADCs, combinatorial strategies of ADCs with chemotherapy have become a central focus of the current preclinical and clinical research. Here, we used the microtubule stabilizer paclitaxel and enfortumab vedotin-ejfv (EV), an ADC carrying the microtubule inhibitor payload monomethyl auristatin E (MMAE), for co-administration under the consideration of their mechanism of action associated with microtubules. We designed a sialic acid-cholesterol (SA-CH) conjugate-modified cationic liposome platform loaded with PTX (PTX-SAL) for efficiently targeting tumor-associated immune cells. Compared with monotherapy, PTX-SAL-mediated combination therapy with ADCs significantly inhibited S180 tumor growth in mice, with complete tumor regression occurring. The formation of a durable tumor-specific immunological memory response in mice that experienced complete tumor regression was assessed by secondary tumor cell rechallenge, and the production of memory T cells in the spleen was detected as related to the increased CD4+T memory cells and the enhanced serum IFN-γ. All our preliminary results throw light on the tremendous application potential for the application of this combination therapy regimen capable of mounting a durable immune response and stimulating a robust T cell-mediated tumor-specific immunological memory.