Advances in herbal polysaccharides-based nano-drug delivery systems for cancer immunotherapy.

The boom in cancer immunotherapy has provided many patients with a better chance of survival, but opportunities often come with challenges. Single immunotherapy is not good enough to eradicate tumours, and often fails to achieve the desired therapeutic effect because of the low targeting of immunotherapy drugs, and causes more side effects. As a solution to this problem, researchers have developed several nano Drug Delivery Systems (NDDS) to deliver immunotherapeutic agents to achieve good therapeutic outcomes. However, traditional drug delivery systems (DDS) have disadvantages such as poor bioavailability, high cytotoxicity, and difficulty in synthesis, etc. Herbal Polysaccharides (HPS), derived from natural Chinese herbs, inherently possess low toxicity. Furthermore, the biocompatibility, biodegradability, hydrophilicity, ease of modification, and immunomodulatory activities of HPS offer unique advantages in substituting traditional DDS. This review initially addresses the current developments and challenges in immunotherapy. Subsequently, it focuses on the immunomodulatory mechanisms of HPS and their design as nanomedicines for targeted drug delivery in tumour immunotherapy. Our findings reveal that HPS-based nanomedicines exhibit significant potential in enhancing the efficacy of cancer immunotherapy, providing crucial theoretical foundations and practical guidelines for future clinical applications.

Isolation, Purification, and Structural Characterization of Polysaccharides from Codonopsis pilosula and Their Anti-Tumor Bioactivity by Immunomodulation.

The activity of polysaccharides is usually related to molecular weight. The molecular weight of polysaccharides is critical to their immunological effect in cancer therapy. Herein, the Codonopsis polysaccharides of different molecular weights were isolated using ultrafiltration membranes of 60- and 100-wDa molecular weight cut-off to determine the relationship between molecular weight and antitumor activities. First, three water-soluble polysaccharides CPPS-I (<60 wDa), CPPS-II (60-100 wDa), and CPPS-III (>100 wDa) from Codonopsis were isolated and purified using a combination of macroporous adsorption resin chromatography and ultrafiltration. Their structural characteristics were determined through chemical derivatization, GPC, HPLC, FT-IR, and NMR techniques. In vitro experiments indicated that all Codonopsis polysaccharides exhibited significant antitumor activities, with the tumor inhibition rate in the following order: CPPS-II > CPPS-I > CPPS-III. The treatment of CPPS-II exhibited the highest inhibition rate at a high concentration among all groups, which was almost as efficient as that of the DOX·HCL (10 µg/mL) group at 125 µg/mL concentration. Notably, CPPS-II demonstrated the ability to enhance NO secretion and the antitumor ability of macrophages relative to the other two groups of polysaccharides. Finally, in vivo experiments revealed that CPPS-II increased the M1/M2 ratio in immune system regulation and that the tumor inhibition effect of CPPS-II + DOX was superior to that of DOX monotherapy, implying that CPPS-II + DOX played a synergistic role in regulating the immune system function and the direct tumor-killing ability of DOX. Therefore, CPPS-II is expected to be applied as an effective cancer treatment or adjuvant therapy.

Role of Doping Effect and Chemical Pressure Effect Introduced by Alkali Metal Substitution on 1144 Iron-Based Superconductors.

CaAFe4As4 with A = K, Rb, and Cs are close to the doped 122 system, and the parent material can reach a superconducting transition temperature of 31-36 K without doping. To study the role of alkali metals, we investigated the induced hole doping and chemical pressure effects as a result of the introduction of alkali metals using density-functional-based methods. These two effects can affect the superconducting transition temperature by changing the number of electrons and the structure of the FeAs conductive layer, respectively. Our study shows that the dxz and dyz orbitals, which are degenerate in CaFe2As2, become nondegenerate in CaAFe4As4 due to two nonequivalent arsenic atoms (As1 and As2). The unusual oblate ellipsoid hole pocket at Γ point in CaAFe4As4 results from a divalent cation Ca2+ replaced by a monovalent cation A+. It shows one of the main differences in fermiology compared to a particular form of CaFe2As2 with reduced 1144 symmetry, due to the enhancement of As2-Fe hybridization. The unusual band appears in CaFe2As2 (1144) and gradually disappears in the change of K to Cs. Further analysis shows that this band is contributed by As1 and has strong dispersion perpendicular to the FeAs layer, suggesting that it is related to the peculiar van Hove singularity below the Fermi level. In addition, various aspects of CaFe2As2 (1144) and CaAFe4As4 in the ground state are discussed in terms of the influence of hole doping and chemical pressure.

Rhodiola rosea polysaccharides-based nanoparticles loaded with DOX boosts chemo-immunotherapy for triple-negative breast cancer by re-educating Tumor-associated macrophages.

Hydrophobic drug delivery vectors suffer significant challenges in cancer therapy, including efficient encapsulation and tumor targeting ability. In the present study, Rhodiola rosea polysaccharides (RHPs), which have the ability to modulate Tumor-associated macrophages and typical structural characteristics, were employed as an immunoactive vector for drug delivery. Folic acid (FA) and stearic acid (SA) were chemically modified to the backbone of RHPs to obtain the self-assembly and tumor-targeting behavior. Further, the hydrophobic drug, doxorubicin (DOX), was encapsulated in the RHPs derivatives (FA-RHPs-SA) with high efficiency. Additionally, the optimally formed DOX@FA-RHPs-SA had a uniform size distribution of approximately 196 nm and a pH-sensitive release capacity in different acidic conditions. In vitro experiments demonstrated that tumor cells could efficiently uptake DOX@FA-RHPs-SA. Furthermore, the modulatory function of the FA-RHPs-SA on RAW264.7 macrophages was also demonstrated in the transition from M0 to M1 phenotypes, and the M2 differentiated into the M1. Finally, the in vivo antitumor study revealed that the inhibitory effect of DOX@FA-RHPs-SA was superior to the DOX monotherapy treatment, and the new preparation functioned synergistically by inducing tumor cell apoptosis and modulating immune cell function. In conclusion, this study described an RHPs-based hydrophobic delivery vector and achieved an additional helpful antitumor effect by modulating Tumor-associated macrophages.

The regulatory mechanism and potential application of IL-23 in autoimmune diseases.

IL-23 is a heterodimeric pro-inflammatory cytokine secreted by dendritic cells and macrophages that belongs to the IL-12 family. It has pro-inflammatory effects and is a key cytokine and upstream regulatory cytokine involved in protective immune responses, stimulating the differentiation and proliferation of downstream effectors such as Th17 cells. It is expressed in various autoimmune diseases such as psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA). The IL-23/TH17 axis formed by IL-23 and TH17 has been confirmed to participate in autoimmune diseases pathogenesis. IL-23R is the receptor for IL-23 and plays an activating role. Targeting IL-23 is currently the main strategy for the treatment of various autoimmune diseases. In this review we summarized the mechanism of action and clinical application potential of IL-23 in autoimmune diseases by summarizing the latest research results and reviewing the literature, which would help to further understand IL-23 and provide a theoretical basis for future clinical targeting and drug development.

The Pathological Mechanism and Potential Application of IL-38 in Autoimmune Diseases.

Interleukin-38 (IL-38), a new cytokine of interleukin-1 family (IL-1F), is expressed in the human heart, kidney, skin, etc. Recently, new evidence indicated that IL-38 is involved in the process of different autoimmune diseases. Autoimmune diseases are a cluster of diseases accompanied with tissue damage caused by autoimmune reactions, including rheumatoid arthritis (RA), psoriasis, etc. This review summarized the links between IL-38 and autoimmune diseases, as well as the latest knowledge about the function and regulatory mechanism of IL-38 in autoimmune diseases. Especially, this review focused on the differentiation of immune cells and explore future prospects, such as the application of IL-38 in new technologies. Understanding the function of IL-38 is helpful to shed light on the progress of autoimmune diseases.

Effects of a Lysine-Involved Maillard Reaction on the Structure and In Vitro Activities of Polysaccharides from Longan Pulp.

The effects of amino acid-involved Maillard reactions (MRs) on the structure and activities of longan pulp polysaccharides (LPs), which were heteropolysaccharides mainly composed of glucose, galactose, mannose, rhamnose, glucuronic acid, ribose, and galacturonic acid, were investigated. The changes of browning degree and molecular weight (Mw) distribution in the MR systems containing LPs and amino acids (lysine, proline, or glycine) indicated that lysine was more active in conjugating with LPs. The MR-modified LPs (MLPs) obtained via a 4 h MR between LPs and lysine showed obvious structural differences from LPs. Specifically, particle-like LPs contained 94% fractions with a Mw less than 7.07 kDa, by contrast, network-like MLPs contained 45% fractions with a Mw larger than 264.1 kDa. Moreover, MLPs showed stronger radical scavenging abilities and macrophage immunostimulating effects, but weaker cancer cell growth-inhibitory abilities. The results indicate that the amino acid-involved MR is a promising method to modify native polysaccharides for better biological properties.

The protective effect of polysaccharide extracted from Portulaca oleracea L. against Pb-induced learning and memory impairments in rats.

This paper studied the extraction of polysaccharide from Portulaca oleracea L. (POP) by hot water extraction and ethanol precipitation. Structural properties of the extracted polymers were determined. POP was composed of rhamnose, arabinose and galactose in ratios of 1: 2.34: 3.07 with a molecular weight of 1.55 × 107 Da. The neuroprotective effect of POP on Pb-induced neuronal toxicity was then evaluated in vitro and in vivo test. Treatment with POP markedly increased the survival of PC12 cells and repressed the generation of reactive oxygen species following Pb exposure. In Morris water maze analysis, Pb exposure led to an increase in escape latency and a decrease in platform crossing times of rats in the probe test, which could be attenuated by POP treatment. Additionally, the Pb-induced loss of dendritic spine was recovered after feeding rats with POP at 600 mg/kg/day. These results indicated that Pb-induced cognitive impairments could be inhibited by POP.

Investigation of the Maillard Reaction between Polysaccharides and Proteins from Longan Pulp and the Improvement in Activities.

The purpose of this study was to investigate the Maillard reaction between polysaccharides and proteins from longan pulp and the effects of reaction on their in vitro activities. The polysaccharide-protein mixtures of fresh longan pulp (LPPMs) were co-prepared by an alkali extraction-acid precipitation method. They were then dry-heated under controlled conditions for monitoring the characterization of the Maillard reaction by the measurement of the free amino group content, ultraviolet-visible spectrum, Fourier transform infrared spectrum and molecular weight distribution. All the physicochemical analyses indicated the development of the Maillard reaction between polysaccharides and proteins. The in vitro activity evaluation indicated that the Maillard reaction could effectively enhance the antioxidant, antitumor and immunostimulating activities of LPPMs. The enhancement of 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity and ferric reducing antioxidant power displayed both a positive correlation with the reaction time (p < 0.05). LPPMs dry-heated for three days obtained relatively strong inhibitory activity against HepG2 cells and SGC7901 cells, as well as strong immunostimulating effects on the nitric oxide production and tumor necrosis factor α secretion of macrophages. Maillard-type intermacromolecular interaction is suggested to be an effective and controllable method for improving the functional activities of polysaccharides and proteins from longan pulp.

Streptomycin ototoxicity in rat cochlear organotypic cultures.

The purpose of this study is to investigate the ototoxic effect of streptomycin on cochlear hair cells, spiral ganglion cells, and nerve fibers in cochlear organ cultures. The cochlear basilar membrane of three- or four-day-old F344 rats was cultured and treated with various doses of streptomycin for 24 h. Cochlear hair cells and the spiral ganglion neurons were stained with immunofluorescence and were observed under confocal microscope. The increase in hair cell loss was concomitant with the increase in streptomycin sulfate concentrations. Streptomycin impaired both the inner and outer hair cells at a similar degree. The damage to hair cells was more severe at basal turn than apical turn. In contrast, the spiral ganglion neurons and auditory nerve fibers were intact. Streptomycin primarily caused hair cell loss, but not significant impairment in the neural structure in vitro. Streptomycin-induced cochlear hair cell lesion was initiated at the basal turn and extended towards the apical turn. Streptomycin ototoxicity was dose-dependent under in vitro conditions.

[FGF-21 protects H9c2 cardiomyoblasts against hydrogen peroxide-induced oxidative stress injury].

Fibroblast growth factor-21 (FGF-21) is an important metabolism regulator, however, whether FGF-21 has effects on cardiovascular remains unclear. In this study, H2O2-induced injury in H9c2 cells was used as a cell model, the anti-apoptosis potential and mechanism of FGF-21 against oxidative injury were evaluated by MTT assay, flow cytometry assay and real-time PCR. The results showed that FGF-21 could increase the cell survival of H2O2-induced injury in H9c2 cells and prevent H9c2 cells from oxidative stress-induced apoptosis. Furthermore, FGF-21 can elevate SOD activity and regulate Bcl-2/Bax expression in H9c2 cells. The results suggest that FGF-21 have protective effect against the H2O2-induced apoptosis in H9c2 cells.

[Study on environmental and psychological risk factors for female infertility].

OBJECTIVE: To investigate the environmental and psychological risk factors for female infertility and to provide a scientific basis for the prevention and control of female infertility. METHODS: In a hospital-based case-control study, a self-designed questionnaire was used to survey the cases and controls (1:1) with nation and age (± 2 years) as matching variables. Univariate and multivariate conditional logistic regression models were employed to analyze the datasets. RESULTS: The univariate analysis showed that female infertility was related to the following factors: eating fried foods, alcohol consumption, smoking, staying up late, perm, housing decoration, contact with heavy metals, exposure to radiation, contact with pesticides, working in hot environment, mental stress, uneasiness, helplessness, and despair. The multivariate analysis showed that staying up late (OR = 2.937), housing decoration (OR = 2.963), exposure to radiation (OR = 2.506), contact with pesticides (OR = 2.908), and mental stress (OR = 4.101) were the main risk factors for female infertility. Furthermore, there was an interaction between staying up late and mental stress. CONCLUSION: Female infertility is caused by multiple factors including staying up late, housing decoration, exposure to radiation, contact with pesticides, and mental stress, and there is an interaction between staying up late and mental stress.

[Therapeutic effect of fibroblast growth factor 21 on hypertension induced by insulin resistance].

This study is to evaluate the therapeutic effect of fibroblast growth factor 21 (FGF21) on hypertension induced by insulin resistance in rats and to provide mechanistic insights into its therapeutic effect. Male Sprague-Dawley (SD) rats were fed with high-fructose (10%) water to develop mild hypertensive models within 4 weeks, then randomized into 4 groups: model control, FGF21 0.25, 0.1 and 0.05 micromol x kg(-1) x d(-1) groups. Five age-matched normal SD rats administrated with saline were used as normal controls. The rats in each group were treated once a day for 4 weeks. Body weight was measured weekly, systolic blood pressure (SBP) was measured noninvasively using a tail-cuff method, insulin sensitivity was assessed using oral glucose tolerance test (OGTT) and HOMA-IR assay. At the end of the treatment, blood samples were collected, and blood glucose, serum cholesterol, serum triglyceride and serum insulin were measured. The results showed that blood pressure of the rats treated with different doses of FGF21 returned to normal levels [(122.2 +/- 3.5) mmHg, P < 0.01] after 4-week treatment, whereas, SBP of untreated (model control) rats maintained a high level [(142.5 +/- 4.5) mmHg] throughout the treatment. The observation of blood pressure in 24 h revealed that SBP of FGF21 treated-rats maintained at (130 +/- 4.5) mmHg vs. (143 +/- 5.5) mmHg for model control (P < 0.01). FGF21 treatment groups improved serum lipids obviously, total cholesterol (TC) and triglyceride (TG) levels decreased significantly to normal levels. The serum NO levels of three different doses FGF21 treatment group were significantly higher than that of the model control group [(7.32 +/- 0.11), (7.24 +/- 0.13), (6.94 +/- 0.08) vs. (6.56 +/- 0.19) micromol x L(-1), P < 0.01], and the degree of improvement showed obvious dose-dependent manner, indicating that FGF21 can significant increase serum NO in fructose-induced hypertension rat model and improve endothelial NO release function. The results of OGTT and HOMA-IR showed that insulin resistance state was significantly relieved in a dose-dependent manner. Thus, this study demonstrates that FGF21 significantly ameliorates blood pressure in fructose-induced hypertension model by relieving insulin resistance. This finding provides a theoretical support for clinical application of FGF21 as a novel therapeutics for treatment of essential hypertension.

[Antitumor activity of the recombinant rClone30-CD/5-FC system].

5-Flucytosine (5-FC) could be changed to 5-fluorouracil (5-FU) by cytosine deaminase (CD), the latter is able to kill cancer cells. However, there is no efficient method to deliver the CD gene into the tumor cells, which hampers the application of the suicide gene system. In this experiment, for the first time, the NDV has been utilized as a vector to deliver the CD gene into the cancer cells, the virus can infect the cancer cells specifically, replicate and assemble, while the cytosine deaminase is expressed. Then the CD converts the prodrug 5-FC into 5-FU to achieve the purpose of inhibiting tumor. Firstly, the whole genome of E. coli JM109 was extracted, and the CD gene was obtained by cloning method. Then the CD and IRES-EGFP were ligated into the pEE12.4 expression vector to become a recombinant pEE12.4IE-CD eukaryotic expression plasmid. The human liver cancer cells were transfected with the plasmid. The cells were treated with different concentrations of 5-FC, MTT method was used to determine the killing effect of CD/5-FC system on the human liver cancer cells. The cell deaths were 18.07%, 42.98% and 62.20% respectively when the concentrations of prodrug were at 10, 20 and 30 mmol x L(-1). In 5-FC acute toxicity experiment, Kunming mice were injected with different concentrations of 5-FC at intervals of 1:0.5. The LD50 of 5-FC through iv injection was determined by improved Karber's method, the LD50 was 507 mg x kg(-1) and the 95% confidence limit was 374-695 mg x kg(-1). According to the maximum LD0 dose of the LD50, the maximum safe dose was 200 mg x kg(-1). Body weight and clinic symptoms of the experimental animals were observed. These results laid the foundation to verify the antitumor effect and safety of CD/5-FC system in animal models. The CD gene was ligated into the NDV (rClone30) carrier, then the tumor-bearing animal was established to perform the tumor inhibiting experiment. The result showed that the recombinant rClone30-CD/5-FC system has a high antitumor activity in vivo. To summarize, CD gene has been cloned and its bioactivity has been confirmed in the mammalian cells. It is the first time in this study to utilize the recombinant NDV to deliver the CD gene into the tumor cells; our result proves the rClone30-CD/5-FC system is a potential method for cancer therapy.

[Therapeutic effect of fibroblast growth factor 21 on NAFLD in MSG-iR mice and its mechanism].

This study is to evaluate the therapeutic effect of fibroblast growth factor 21 (FGF21) on NAFLD in MSG-IR mice and to provide mechanism insights into its therapeutic effect. The MSG-IR mice with insulin resistance were treated with high dose (0.1 micromol.kg-1d-1) and low dose (0.025 micromol.kg-1d-1) of FGF21 once a day for 5 weeks. Body weight was measured weekly. At the end of the experiment, serum lipids, insulin and aminotransferases were measured. Hepatic steatosis was observed. The expression of key genes regulating energy metabolism were detected by real-time PCR. The results showed that after 5 weeks treatment, both doses of FGF21 reduced body weight (P<0.01), corrected dyslipidemia (P<0.01), reversed steatosis and restored the liver morphology in the MSG model mice and significantly ameliorated insulin resistance. Additionally, real-time PCR showed that FGF21 significantly reduced transcription levels of fat synthetic genes, decreased fat synthesis and promoted lipolysis and energy metabolism by up-regulating key genes of lipolysis, thereby liver fat accumulation was reduced and liver function was restored to normal levels. In conclusion, FGF21 significantly reduces body weight of the MSG-IR mice, ameliorates insulin resistance, reverses hepatic steatosis. These findings provide a theoretical support for clinical application of FGF21 as a novel therapeutics for treatment of NAFLD.

[Brain-derived neurotrophic factor and repair of retinal ganglion cells after injury].

Blocking of retrograde transport after the optic nerve injury results in deprivation of neurotrophic support to retinal ganglion cells (RGCs), and leads to apoptotic cell death in glaucoma. As an important member of neurotrophins, the brain-derived neurotrophic factor (BDNF) plays a substantial role in the repair of retinal ganglion cells injury, but its signaling pathway in the pathogenesis of glaucoma remains unclear. This review focuses on the structure, distribution and receptors of BDNF and its effects on RGC survival, axon regeneration and relevant signaling pathway, to provide theoretical foundation for neuroprotective treatment of glaucoma.