Transient inhibition of type I interferon enhances CD8 + T cell stemness and vaccine protection.

Developing vaccines that promote CD8 + T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1 + stem cell-like memory T (T SCM ) cells are important determinants of long-lived memory. Yet, the developmental requirements for T SCM formation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive T SCM cell generation. T SCM cells were transcriptionally distinct and emerged from a transitional precursor of exhausted (T PEX ) cellular state concomitant with viral clearance. T SCM differentiation correlated with T cell retention within the lymph node paracortex, due to increased CXCR3 chemokine abundance which disrupted gradient formation. These affects were due a counterintuitive increase in IFNψ, which controlled cell location. Combining IFNAR inhibition with mRNA-LNP vaccination promoted specific T SCM differentiation and enhanced protection against chronic infection. These finding propose a new approach to vaccine design whereby modulation of inflammation promotes memory formation and function. HIGHLIGHTS: Early, transient inhibition of the type I interferon (IFN) receptor (IFNAR) during acute viral infection promotes stem cell-like memory T (T SCM ) cell differentiation without establishing chronic infection. T SCM and precursor of exhausted (T PEX ) cellular states are distinguished transcriptionally and by cell surface markers. Developmentally, T SCM cell differentiation occurs via a transition from a T PEX state coinciding with viral clearance. Transient IFNAR blockade increases IFNψ production to modulate the ligands of CXCR3 and couple T SCM differentiation to cell retention within the T cell paracortex of the lymph node. Specific promotion of T SCM cell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge.

PRRX1-OLR1 axis supports CAFs-mediated lung cancer progression and immune suppression.

OBJECTIVE: To investigate the mechanism by which cancer-associated fibroblasts (CAFs) affect the growth and immune evasion of lung cancer cells. METHODS: Initially, datasets comparing CAFs with normal fibroblasts were downloaded from the GEO dataset GSE48397. Genes with the most significant differential expression were selected and validated using clinical data. Subsequently, CAFs were isolated, and the selected genes were knocked down in CAFs. Co-culture experiments were conducted with H1299 or A549 cells to analyze changes in lung cancer cell growth, migration, and immune evasion in vitro and in vivo. To further elucidate the upstream regulatory mechanism, relevant ChIP-seq data were downloaded from the GEO database, and the regulatory relationships were validated through ChIP-qPCR and luciferase reporter assays. RESULTS: OLR1 was significantly overexpressed in CAFs and strongly correlated with adverse prognosis in lung cancer patients. Knockdown of OLR1 markedly inhibited CAFs' support for the growth and immune evasion of lung cancer cells in vitro and in vivo. ChIP-seq results demonstrated that PRRX1 can promote OLR1 expression by recruiting H3K27ac and H3K4me3, thereby activating CAFs. Knockdown of PRRX1 significantly inhibited CAFs' function, while further overexpression of OLR1 restored CAFs' support for lung cancer cell growth, migration, and immune evasion. CONCLUSION: PRRX1 promotes OLR1 expression by recruiting H3K27ac and H3K4me3, activating CAFs, and thereby promoting the growth, migration, and immune evasion of lung cancer cells.

Targeting dendritic cell activation: the therapeutic impact of paeoniflorin in cortosteroid-dependent dermatitis management.

This study investigates the mechanism through which paeoniflorin inhibits TSLP expression to regulate dendritic cell activation in corticosteroid-dependent dermatitis treatment. Utilizing databases like TCMSP, we identified paeoniflorin's components, targets, and constructed networks. Molecular docking and gene enrichment analysis helped pinpoint key targets and pathways affected by paeoniflorin. In vitro and in vivo models were used to study CD80, CD86, cytokines, T-cell activation, skin lesions, histopathological changes, TSLP, CD80, and CD86 expression. Our study revealed paeoniflorin's active constituent targeting IL-6 in corticosteroid-dependent dermatitis. In vitro experiments demonstrated reduced TSLP expression, CD80, CD86, and cytokine secretion post-paeoniflorin treatment. In vivo, paeoniflorin significantly decreased skin lesion severity, cytokine levels, TSLP, CD80, and CD86 expression. The study highlights paeoniflorin's efficacy in inhibiting TSLP expression and suppressing dendritic cell activation in corticosteroid-dependent dermatitis, suggesting its potential as a therapeutic intervention. Additionally, it offers insights into the complex molecular mechanisms underlying paeoniflorin's anti-inflammatory properties in treating corticosteroid-dependent dermatitis.

EP300 regulates the SLC16A1-AS1-AS1/TCF3 axis to promote lung cancer malignancies through the Wnt signaling pathway.

Objective: To investigate the regulatory mechanism of EP300 in the interaction between SLC16A1-AS1 and TCF3 to activate the Wnt pathway, thereby promoting malignant progression in lung cancer. Methods: In lung cancer cell lines, SLC16A1-AS1 was knocked down, and the impact of this knockdown on the malignant progression of lung cancer cells was assessed through clonogenic assays, Transwell assays, and apoptosis experiments. The regulatory relationship between EP300 and SLC16A1-AS1 was investigated through bioinformatic analysis and ChIP experiments. The expression of SLC16A1-AS1 and TCF3 in 56 paired lung cancer tissues was examined using RT-qPCR, and their correlation was analyzed. The interaction between TCF3 and SLC16A1-AS1 was explored through bioinformatic analysis and CoIP experiments. Activation of the Wnt/ß-catenin pathway was assessed by detecting the accumulation of ß-catenin in the nucleus through Western blotting. The role of EP300 in regulating the effect of SLC16A1-AS1/TCF3-mediated Wnt/ß-catenin signaling on lung cancer malignant progression was validated through in vitro and in vivo experiments. Results: SLC16A1-AS1 is highly expressed in lung cancer and regulates its malignant progression. EP300 mediates histone modifications on the SLC16A1-AS1 promoter, thus controlling its expression. SLC16A1-AS1 exhibits specific interactions with TCF3, and the SLC16A1-AS1/TCF3 complex activates the Wnt/ß-catenin pathway. EP300 plays a critical role in regulating the impact of SLC16A1-AS1/TCF3-mediated Wnt/ß-catenin signaling on lung cancer malignant progression. Conclusion: EP300 regulates the SLC16A1-AS1/TCF3-mediated Wnt/ß-catenin signaling pathway, influencing the malignant progression of lung cancer.

In situ single-cell profiling sheds light on IFI27 localisation during SARS-CoV-2 infection.

The utilization of single-cell resolved spatial transcriptomics to delineate immune responses during SARS-CoV-2 infection was able to identify M1 macrophages to have elevated expression of IFI27 in areas of infection.

Delivery of mRNA Vaccine with 1, 2-Diesters-Derived Lipids Elicits Fast Liver Clearance for Safe and Effective Cancer Immunotherapy.

Messenger RNA (mRNA) vaccine is explored as a promising strategy for cancer immunotherapy, but the side effects, especially the liver-related damage caused by LNP, raise concerns about its safety. In this study, a novel library of 248 ionizable lipids comprising 1,2-diesters is designed via a two-step process involving the epoxide ring-opening reaction with carboxyl group-containing alkyl chains followed by an esterification reaction with the tertiary amines. Owing to the special chemical structure of 1,2-diesters, the top-performing lipids and formulations exhibit a faster clearance rate in the liver, contributing to increased stability and higher safety compared with DLin-MC3-DMA. Moreover, the LNP shows superior intramuscular mRNA delivery and elicits robust antigen-specific immune activation. The vaccinations delivered by the LNP system suppress tumor growth and prolong survival in both model human papillomavirus E7 and ovalbumin antigen-expressing tumor models. Finally, the structure of lipids which enhances the protein expression in the spleen and draining lymph nodes compared with ALC-0315 lipid in Comirnaty is further optimized. In conclusion, the 1, 2-diester-derived lipids exhibit rapid liver clearance and effective anticancer efficiency to different types of antigens-expressing tumor models, which may be a safe and universal platform for mRNA vaccines.

Prognostic significance of lactate dehydrogenase and its impact on the outcomes of gastric cancer: a systematic review and meta-analysis.

Background: The prognostic significance of lactate dehydrogenase (LDH) and its impact on the outcomes of gastric cancer (GC) is still unclear. We assessed the link between the levels of LDH and the overall survival (OS) and disease-free survival (DFS) in GC patients. Methods: A comprehensive search (both electronic and manual) was carried out in PubMed via MEDLINE, Web of Science (WoS), Experta Medical Database (Embase), and CENTRAL (Cochrane Library) databases for citations that evaluated the strength of association between LDH cut-off levels and OS and/or DFS in GC. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model, and heterogeneity was assessed. Results: Eighteen studies with 5328 patients were included in our review. The overall pooled HR for OS was 1.48 (95% CI: 1.22-1.80) with high heterogeneity (I2 = 86%). Subgroup analyses showed that the link between LDH and OS was more prominent in Caucasian (HR 1.50 95% CI [0.80, 2.81], p=0.21) than in Asian cohorts (HR, 1.51 95% CI [1.21, 1.87], p=0.002). No significant overall association between LDH and OS (HR = 1.12, 95% CI: 0.76-1.65, p = 0.58) was found. Similar subgroup analyses results were reported for the association between LDH and DFS. Conclusion: In patients with GC, elevated LDH levels may correlate with worse OS and DFS, but the association is not significant. LDH is a significant predictor of OS but not of DFS. Further studies with larger sample sizes and more standardized criteria for defining elevated LDH levels are needed to confirm our findings. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023412449.

Nutrition-associated health levels in persons with cancer: item response modelling based on the International Classification of Functioning, Disability and Health.

BACKGROUND: The nutritional status of individuals with cancer is a crucial determinant of their health and well-being, and addressing nutrition-related functioning conditions is essential for maintaining physical activity levels and participating in daily activities. AIM: This study aims to identify an evidence-based International Classification of Functioning, Disability and Health (ICF) scale using item response theory for nutrition conditions in patients with cancer, which can differentiate and assess nutrition-related functioning conditions of cancer survivors. DESIGN: Cross-sectional study. SETTING: Sir Run Run Hospital, Nanjing Medical University. POPULATION: One hundred cancer patients were enrolled. METHODS: Via convenience sampling, the study administered a questionnaire consisting of 89 ICF items to participants. The original five-point rating system was binarized (1 = no problem, 0 = problem). Through data shaping, non-parametric IRT analysis and parametric IRT analysis, psychometric properties of nutritional ICF scale were calculated using R software. RESULTS: The study extracted a unidimensional scale with 32 items and constructed 2-parameter logistic model with good fitness, whose root mean square error approximation (RMSEA) = 0.0759, Tucker-Lewis Index (TLI) = 0.9655, and Comparative Fit Index (CFI) = 0.9677. The model demonstrated high reliability, as indicated by a Cronbach's α of 0.95, Guttman λ2 of 0.95, Molenaar Sijtsma statistic of 0.96 and a latent class reliability coefficient (LCRC) of 0.98. Besides, there was a strong correlation between the total score of 32 ICF items and the score of Patient-Generated Subjective Global Assessment (PG-SGA, P<0.001, r=-0.77) and Mini Nutritional Assessment (MNA, P<0.001, r=0.76), suggesting the 32-item scale had high validity. CONCLUSIONS: The study constructed an evidence-based ICF scale for nutrition conditions in patients with cancer with 32-item and 2PLM for evaluating nutrition-associated health level in persons with cancer, including high validity and reliability. CLINICAL REHABILITATION IMPACT: The IRT model based on ICF provided a promising assessment tool to discriminate nutrition-associated health level of persons with cancer, and offered an auxiliary method for selecting rehabilitation intervention targets. This has the potential to lead to improved outcomes in cancer treatment and increased quality of life for cancer survivors.

The protective effects of baicalin for respiratory diseases: an update and future perspectives.

Background: Respiratory diseases are common and frequent diseases. Due to the high pathogenicity and side effects of respiratory diseases, the discovery of new strategies for drug treatment is a hot area of research. Scutellaria baicalensis Georgi (SBG) has been used as a medicinal herb in China for over 2000 years. Baicalin (BA) is a flavonoid active ingredient extracted from SBG that BA has been found to exert various pharmacological effects against respiratory diseases. However, there is no comprehensive review of the mechanism of the effects of BA in treating respiratory diseases. This review aims to summarize the current pharmacokinetics of BA, baicalin-loaded nano-delivery system, and its molecular mechanisms and therapeutical effects for treating respiratory diseases. Method: This review reviewed databases such as PubMed, NCBI, and Web of Science from their inception to 13 December 2022, in which literature was related to "baicalin", "Scutellaria baicalensis Georgi", "COVID-19", "acute lung injury", "pulmonary arterial hypertension", "asthma", "chronic obstructive pulmonary disease", "pulmonary fibrosis", "lung cancer", "pharmacokinetics", "liposomes", "nano-emulsions", "micelles", "phospholipid complexes", "solid dispersions", "inclusion complexes", and other terms. Result: The pharmacokinetics of BA involves mainly gastrointestinal hydrolysis, the enteroglycoside cycle, multiple metabolic pathways, and excretion in bile and urine. Due to the poor bioavailability and solubility of BA, liposomes, nano-emulsions, micelles, phospholipid complexes, solid dispersions, and inclusion complexes of BA have been developed to improve its bioavailability, lung targeting, and solubility. BA exerts potent effects mainly by mediating upstream oxidative stress, inflammation, apoptosis, and immune response pathways. It regulates are the NF-κB, PI3K/AKT, TGF-ß/Smad, Nrf2/HO-1, and ERK/GSK3ß pathways. Conclusion: This review presents comprehensive information on BA about pharmacokinetics, baicalin-loaded nano-delivery system, and its therapeutic effects and potential pharmacological mechanisms in respiratory diseases. The available studies suggest that BA has excellent possible treatment of respiratory diseases and is worthy of further investigation and development.

Therapeutic application of natural products: NAD+ metabolism as potential target.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) metabolism is involved in the entire physiopathological process and is critical to human health. Long-term imbalance in NAD+ homeostasis is associated with various diseases, including non-alcoholic fatty liver disease, diabetes mellitus, cardiovascular diseases, neurodegenerative disorders, aging, and cancer, making it a potential target for effective therapeutic strategies. Currently, several natural products that target NAD+ metabolism have been widely reported to have significant therapeutic effects, but systematic summaries are lacking. PURPOSE: To summarize the latest findings on the prevention and treatment of various diseases through the regulation of NAD+ metabolism by various natural products in vivo and in vitro models, and evaluate the toxicities of the natural products. METHODS: PubMed, Web of Science, and ScienceDirect were searched using the keywords "natural products sources," "toxicology," "NAD+ clinical trials," and "NAD+," and/or paired with "natural products" and "diseases" for studies published within the last decade until January 2023. RESULTS: We found that the natural products mainly include phenols (curcumin, cyclocurcumin, 4-hydroxybenzyl alcohol, salvianolic acid B, pterostilbene, EGCG), flavonoids (pinostrobin, apigenin, acacetin, tilianin, kaempferol, quercetin, isoliquiritigenin, luteolin, silybin, hydroxysafflor yellow A, scutellarin), glycosides (salidroside), quinones (emodin, embelin, ß-LAPachone, shikonin), terpenoids (notoginsenoside R1, ginsenoside F2, ginsenoside Rd, ginsenoside Rb1, ginsenoside Rg3, thymoquinone, genipin), pyrazines (tetramethylpyrazine), alkaloids (evodiamine, berberine), and phenylpropanoids (ferulic acid). These natural products have antioxidant, energy-producing, anti-inflammatory, anti-apoptotic and anti-aging effects, which mainly influence the NAMPT/NAD+/SIRT, AMPK/SIRT1/PGC-1α, Nrf2/HO-1, PKCs/PARPs/NF-κB, and AMPK/Nrf2/mTOR signaling pathways, thereby regulating NAD+ metabolism to prevent and treat various diseases. These natural products have been shown to be safe, tolerable and have fewer adverse effects in various in vivo and in vitro studies and clinical trials. CONCLUSION: We evaluated the toxic effects of natural products and summarized the available clinical trials on NAD+ metabolism, as well as the recent advances in the therapeutic application of natural products targeting NAD+ metabolism, with the aim to provide new insights into the treatment of multiple disorders.

A Universal Strategy to Promote Secretion of G+/G- Bacterial Extracellular Vesicles and Its Application in Host Innate Immune Responses.

Both Gram-positive and Gram-negative bacteria release nanosized extracellular vesicles called membrane vesicles (MVs, 20-400 nm), which have great potential in various biomedical applications due to their abilities to deliver effector molecules and induce therapeutic responses. To fully utilize bacterial MVs for therapeutic purposes, regulated and enhanced production of MVs would be highly advantageous. In this study, we developed a universal method to enhance MV yields in both G+/G- bacteria through an autonomous controlled peptidoglycan hydrolase (PGase) expression system. A significant increase (9.37-fold) of MV concentration was observed in engineered E. coli Nissle 1917 compared to the wild-type. With the help of this autonomous system, for the first time we experimentally confirmed horizontal gene transfer and nutrient acquisition in a cocultured bacterial consortium. Furthermore, the engineered probiotic E. coli strains with high yield of MVs showed higher activation of the innate immune responses in human embryonic kidney 293T (HEK293T) and human colorectal carcinoma cells (HCT116), thereby demonstrating the great potential of engineering probiotics in immunology and further living therapeutics in humans.

Recent advances in ginsenosides against respiratory diseases: Therapeutic targets and potential mechanisms.

BACKGROUND: Respiratory diseases mainly include asthma, influenza, pneumonia, chronic obstructive pulmonary disease, pulmonary hypertension, lung fibrosis, and lung cancer. Given their high prevalence and poor prognosis, the prevention and treatment of respiratory diseases are increasingly essential. In particular, the development for the novel strategies of drug treatment has been a hot topic in the research field. Ginsenosides are the major component of Panax ginseng C. A. Meyer (ginseng), a food homology and well-known medicinal herb. In this review, we summarize the current therapeutic effects and molecular mechanisms of ginsenosides in respiratory diseases. METHODS: The reviewed studies were retrieved via a thorough analysis of numerous articles using electronic search tools including Sci-Finder, ScienceDirect, PubMed, and Web of Science. The following keywords were used for the online search: ginsenosides, asthma, influenza, pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung fibrosis, lung cancer, and clinical trials. We summarized the findings and the conclusions from 176 manuscripts on ginsenosides, including research articles and reviews. RESULTS: Ginsenosides Rb1, Rg1, Rg3, Rh2, and CK, which are the most commonly reported ginsenosides for treating of respiratory diseases, and other ginsenosides such as Rh1, Rk1, Rg5, Rd and Re, all primarily reduce pneumonia, fibrosis, and inhibit tumor progression by targeting NF-κB, TGF-ß/Smad, PI3K/AKT/mTOR, and JNK pathways, thereby ameliorating respiratory diseases. CONCLUSION: This review provides novel ideas and important aspects for the future research of ginsenosides for treating respiratory diseases.

Panax ginseng against myocardial ischemia/reperfusion injury: A review of preclinical evidence and potential mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C. A. Meyer (P. ginseng) is effective in the prevention and treatment of myocardial ischemia-reperfusion (I/R) injury. The mechanism by which P. ginseng exerts cardioprotective effects is complex. P. ginseng contains many pharmacologically active ingredients, such as molecular glycosides, polyphenols, and polysaccharides. P. ginseng and each of its active components can potentially act against myocardial I/R injury. Myocardial I/R was originally a treatment for myocardial ischemia, but it also induced irreversible damage, including oxygen-containing free radicals, calcium overload, energy metabolism disorder, mitochondrial dysfunction, inflammation, microvascular injury, autophagy, and apoptosis. AIM OF THE STUDY: This study aimed to clarify the protective effects of P. ginseng and its active ingredients against myocardial I/R injury, so as to provide experimental evidence and new insights for the research and application of P. ginseng in the field of myocardial I/R injury. MATERIALS AND METHODS: This review was based on a search of PubMed, NCBI, Embase, and Web of Science databases from their inception to February 21, 2022, using terms such as "ginseng," "ginsenosides," and "myocardial reperfusion injury." In this review, we first summarized the active ingredients of P. ginseng, including ginsenosides, ginseng polysaccharides, and phytosterols, as well as the pathophysiological mechanisms of myocardial I/R injury. Importantly, preclinical models with myocardial I/R injury and potential mechanisms of these active ingredients of P. ginseng for the prevention and treatment of myocardial disorders were generally summarized. RESULTS: P. ginseng and its active components can regulate oxidative stress related proteins, inflammatory cytokines, and apoptosis factors, while protecting the myocardium and preventing myocardial I/R injury. Therefore, P. ginseng can play a role in the prevention and treatment of myocardial I/R injury. CONCLUSIONS: P. ginseng has a certain curative effect on myocardial I/R injury. It can prevent and treat myocardial I/R injury in several ways. When ginseng exerts its effects, should be based on the theory of traditional Chinese medicine and with the help of modern medicine; the clinical efficacy of P. ginseng in preventing and treating myocardial I/R injury can be improved.

Exploration of the underlying biological differences and targets in ovarian cancer patients with diverse immunotherapy response.

Background: Preclinical trials of immunotherapy in ovarian cancer (OC) have shown promising results. This makes it meaningful to prospectively examine the biological mechanisms explaining the differences in response performances to immunotherapy among OC patients. Methods: Open-accessed data was obtained from the Cancer Genome Atlas and Gene Expression Omnibus database. All the analysis was conducted using the R software. Results: We firstly performed the TIDE analysis to evaluate the immunotherapy response rate of OC patients. The machine learning algorithm LASSO logistic regression and SVM-RFE were used to identify the characteristic genes. The genes DPT, RUNX1T1, PTPRN, LSAMP, FDCSP and COL6A6 were selected for molecular typing. Our result showed that the patients in Cluster1 might have a better prognosis and might be more sensitive to immunotherapy, including PD-1 and CTLA4 therapy options. Pathway enrichment analysis showed that in Cluster2, the pathway of EMT, TNFα/NF-kB signaling, IL2/STAT5 signaling, inflammatory response, KRAS signaling, apical junction, complement, interferon-gamma response and allograft rejection were significantly activated. Also, genomic instability analysis was performed to identify the underlying genomic difference between the different Cluster patients. Single-cell analysis showed that the DPT, COL6A6, LSAMP and RUNX1T1 were mainly expressed in the fibroblasts. We then quantified the CAFs infiltration in the OC samples. The result showed that patients with low CAFs infiltration might have a lower TIDE score and a higher proportion of immunotherapy responders. Also, we found all the characteristic genes DPT, RUNX1T1, PTPRN, LSAMP, FDCSP and COL6A6 were upregulated in the patients with high CAFs infiltration. Immune infiltration analysis showed that the patients in Cluster2 might have a higher infiltration of naive B cells, activated NK cells and resting Dendritic cells. Conclusions: In summary, our study provides new insights into ovarian cancer immunotherapy. Meanwhile, specific targets DPT, RUNX1T1, PTPRN, LSAMP, FDCSP, COL6A6 and CAFs were identified for OC immunotherapy.

Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response.

The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8+ T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen-bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2180-188)-encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti-programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.

Biotransformation, Pharmacokinetics, and Pharmacological Activities of Ginsenoside Rd Against Multiple Diseases.

Panax ginseng C.A. Mey. has a history of more than 4000 years and is widely used in Asian countries. Modern pharmacological studies have proved that ginsenosides and their compounds have a variety of significant biological activities on specific diseases, including neurodegenerative diseases, certain types of cancer, gastrointestinal disease, and metabolic diseases, in which most of the interest has focused on ginsenoside Rd. The evidentiary basis showed that ginsenoside Rd ameliorates ischemic stroke, nerve injury, cancer, and other diseases involved in apoptosis, inflammation, oxidative stress, mitochondrial damage, and autophagy. In this review, we summarized available reports on the molecular biological mechanisms of ginsenoside Rd in neurological diseases, cancer, metabolic diseases, and other diseases. We also discussed the main biotransformation pathways of ginsenoside Rd obtained by fermentation.

Rational construction of polycystine-based nanoparticles for biomedical applications.

Polypeptide-based nanoparticles are one of the promising excipients of nanomedicines due to their excellent biosafety and flexible modification. Among all the types of polypeptide nanoparticles, polycystine (PCys2)-based ones draw increasing attention due to their unique properties. On the one hand, the uniformed nanogels can be easily obtained through the crosslinking of two active centers during polymerization without additional step of self-assembly. On the other hand, the Cys2-based nanoparticles always showed reduction-responsiveness owing to the inherent disulfide bond. With the development of advanced diagnostic and therapeutic technologies, the multi-functional PCys2-based nanoparticles were achieved via rational construction of the polymer structure. This review summarizes the overall development of Cys2-based polypeptide nanoparticles, especially the structural design for the generation of multi-functional nanoparticles, along with their corresponding biomedical applications.

Gut Microbiota: Therapeutic Targets of Ginseng Against Multiple Disorders and Ginsenoside Transformation.

Panax ginseng, as the king of Chinese herb, has significant therapeutic effects on obesity, type 2 diabetes mellitus, fatty liver disease, colitis, diarrhea, and many other diseases. This review systematically summarized recent findings, which show that ginseng plays its role by regulating gut microbiota diversity, and gut microbiota could also regulate the transformation of ginsenosides. We conclude the characteristics of ginseng in regulating gut microbiota, as the potential targets to prevent and treat metabolic diseases, colitis, neurological diseases, cancer, and other diseases. Ginseng treatment can increase some probiotics such as Bifidobacterium, Bacteroides, Verrucomicrobia, Akkermansia, and reduce pathogenic bacteria such as Deferribacters, Lactobacillus, Helicobacter against various diseases. Meanwhile, Bacteroides, Eubacterium, and Bifidobacterium were found to be the key bacteria for ginsenoside transformation in vivo. Overall, ginseng can regulate gut microbiome diversity, further affect the synthesis of secondary metabolites, as well as promote the transformation of ginsenosides for improving the absorptivity of ginsenosides. This review can provide better insight into the interaction of ginseng with gut microbiota in multiple disorders and ginsenoside transformation.

Prevention Effect of Protopanaxadiol-Type Saponins Saponins and Protopanaxatriol-Type Saponins on Myelosuppression Mice Induced by Cyclophosphamide.

Ginsenosides from ginseng are used as a therapeutic agent for various diseases. They enhance the immunomodulatory effect in cyclophosphamide (CP)-treated tumor disease. The structural characteristics of steroidal saponins are mainly divided into protopanaxadiol-type saponin (PDS) and protopanaxatriol-type saponin (PTS). At present, few researchers have studied which kind of saponin plays a more important role, thus, we compared the prevention effect of PDS and PTS on myelosuppression mice induced by CP. The components and contents of saponin and monosaccharide were analyzed by using ultra high performance liquid chromatography-charged aerosol detector (UPLC-CAD) and reversed phase-high performance liquid chromatography (RP-HPLC), respectively. Thirty-two mice were randomly divided into four groups, including control, model (CP), CP+PDS, and CP+PTS. The mice were orally administered with PDS or PTS for 28 days and then injected with CP saline solution on 25, 26, 27, and 28 days at a dose of 50 mg × kg-1. After the end of modeling, the whole blood of mice from the ophthalmic venous plexus was collected to detect routine blood tests, inflammatory cytokines, and hematopoiesis-related cytokines. Cell cycle and the apoptosis of bone marrow in the right femur were detected. The spleen and thymus were used to calculate the organ index and histological examination, and splenocytes were used to detect the percentage of CD4+ and CD25+ T cells. In the saponins analysis, PDS mainly included the Rb1, Rc, Rb2, and Rd of protopanaxadiol-type ginsenosides (accounted for 91.64%), and PTS mainly included the Re, Rg1, and Rf of protopanaxatriol-type ginsenosides (accounted for 75.46%). The animal results showed that both PDS and PTS improved the most indicators of myelosuppression mice induced by CP, including increased weight, blood cell numbers, hematopoiesis-related cytokines, and inflammatory cytokines; promoted the cell cycle of bone marrow and inhibited the apoptosis of bone marrow; elevated the spleen and thymus indexes and CD4+ count of splenocytes. The prevention effect of PDS was better than PTS in some indicators, such as red blood cells, hemoglobin, interleukin (IL)-1ß, IL-4, IL-10, tumor necrosis factor-α, CD4+, and thymus index. These results suggest both PDS and PTS can prevent myelosuppression of mice induced by CP. Meanwhile, PDS and its metabolite showed higher bioavailability and bioactivity compared with PTS.