Progress in the Preparation and Application of Inulin-Based Hydrogels.

Inulin, a natural polysaccharide, has emerged as a promising precursor for the preparation of hydrogels due to its biocompatibility, biodegradability, and structural versatility. This review provides a comprehensive overview of the recent progress in the preparation, characterization, and diverse applications of inulin-based hydrogels. Different synthesis strategies, including physical methods (thermal induction and non-thermal induction), chemical methods (free-radical polymerization and chemical crosslinking), and enzymatic approaches, are discussed in detail. The unique properties of inulin-based hydrogels, such as stimuli-responsiveness, antibacterial activity, and their potential as fat replacers, are highlighted. Special emphasis is given to their promising applications in drug delivery systems, especially for colon-targeted delivery, due to the selective degradation of inulin via colonic microflora. The ability to incorporate both hydrophilic and hydrophobic drugs further expands their therapeutic potential. In addition, the applications of inulin-based hydrogels in responsive materials, the food industry, wound dressings, and tissue engineering are discussed. While significant progress has been achieved, challenges and prospects in optimizing synthesis, improving mechanical properties, and exploring new functionalities are discussed. Overall, this review highlights the remarkable properties of inulin-based hydrogels as a promising class of biomaterials with immense potential in the biomedical, pharmaceutical, and materials science fields.

Quercetin exerts anti-tumor immune mechanism by regulating IL-6/JAK2/STAT3 signaling pathway to deplete Treg cells.

Breast cancer is still the leading cause of death among women worldwide. Due to the lack of effective drug targets, triple-negative breast cancer has a worse prognosis and higher mortality compared with other types of breast cancer, and chemotherapy is still the main treatment for triple-negative breast cancer at present. Quercetin (QUE) is a flavonoid compound found in a variety of fruits and vegetables. The mechanism of QUE has been extensively studied, such as prostate cancer, colon cancer, ovarian cancer, etc. However, the anti-tumor immune mechanism of QUE in triple-negative breast cancer remains unclear. Therefore, we assessed the anti-tumor immune effects of QUE on triple-negative breast cancer using both 4T1 cells and a xenograft mouse model of 4T1 cells. In vitro, we examined the inhibitory effects of QUE on 4T1 cells and its molecular mechanisms through MTT, Transwell, ELISA, and Western blotting. In vivo, by establishing a xenograft mouse model, we utilized flow cytometry, immunohistochemistry, ELISA, and Western blotting to evaluate the anti-tumor immune effects of QUE on triple-negative breast cancer. The results indicate that QUE inhibits the proliferation, migration, and invasion of 4T1 cells, concurrently significantly suppressing the IL-6/JAK2/STAT3 signaling pathway. Furthermore, it depletes Treg cell content in 4T1 xenograft mice, thereby improving the tumor immune microenvironment and promoting the cytotoxicity of relevant tumor immune cells. These findings suggest that QUE may serve as a potential adjuvant for immune therapy in triple-negative breast cancer.

Oxyimperatorin attenuates LPS-induced microglial activation in vitro and in vivo via suppressing NF-κB p65 signaling.

BACKGROUND: Microglia-mediated neuroinflammation is an important pathological feature in many neurological diseases; thus, suppressing microglial activation is considered a possible therapeutic strategy for reducing neuronal damage. Oxyimperatorin (OIMP) is a member of furanocoumarin, isolated from the medicinal herb Glehnia littoralis. However, it is unknown whether OIMP can suppress the neuroinflammation. PURPOSE: To investigate the neuroprotective activity of oxyimperatorin (OIMP) in LPS-induced neuroinflammation in vitro and in vivo models. METHODS: In vitro inflammation-related assays were performed with OIMP in LPS-induced BV-2 microglia. In addition, intraperitoneal injection of LPS-induced microglial activation in the mouse brain was used to validate the anti-neuroinflammatory activity of OIMP. RESULTS: OIMP was found to suppress LPS-induced neuroinflammation in vitro and in vivo. OIMP significantly attenuated LPS-induced the production of free radicals, inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokines in BV-2 microglia without causing cytotoxicity. In addition, OIMP could reduce the M1 pro-inflammatory transition in LPS-stimulated BV-2 microglia. The mechanistic study revealed that OIMP inhibited LPS-induced NF-κB p65 phosphorylation and nuclear translocation. However, OIMP did not affect LPS-induced IκB phosphorylation and degradation. In addition, OIMP also was able to reduce LPS-induced microglial activation in mice brain. CONCLUSION: Our findings suggest that OIMP suppresses microglia activation and attenuates the production of pro-inflammatory mediators and cytokines via inhibition of NF-κB p65 signaling.

Recent Advances in Quaternary Ammonium Monomers for Dental Applications.

Resin-based dental materials have been one of the ideal choices among various materials in the treatment of dental caries. However, resin-based dental materials still have some drawbacks, such as the lack of inherent antibacterial activity. Extensive research has been conducted on the use of novel quaternary ammonium monomers (QAMs) to impart antibacterial activity to dental materials. This review provides a comprehensive overview of the recent advances in quaternary ammonium monomers (QAMs) for dental applications. The current progress and limitations of QAMs are discussed based on the evolution of their structures. The functional diversification and enhancement of QAMs are presented. QAMs have the potential to provide long-term antibacterial activity in dental resin composites, thereby prolonging their service life. However, there is a need to balance antibacterial performance with other material properties and the potential impact on the oral microbiome and general health. Finally, the necessity for further scientific progress in the development of novel quaternary ammonium monomers and the optimization of dental resin formulations is emphasized.

Apigenin promotes apoptosis of 4T1 cells through PI3K/AKT/Nrf2 pathway and improves tumor immune microenvironment in vivo.

The 2022 US Cancer Statistics show that breast cancer is one of the most common cancers in women. Epidemiology has shown that adding flavonoids to the diet inhibits cancers that arise in particular women, such as cervical cancer, ovarian cancer, and breast cancer. Although there have been research reports on apigenin (API) and breast cancer, its anti-tumor effect and potential mechanism on breast cancer have not yet been clarified. Therefore, in this study, we used 4T1 cells and a 4T1 xenograft tumor mouse model to investigate the antitumor effect of API on breast cancer and its underlying mechanism. In vitro, we used MTT, transwell, staining, and western blotting to investigate the inhibitory effect of apigenin on 4T1 and the underlying molecular mechanism. In vivo by establishing a xenograft tumor model, using immunohistochemistry, and flow cytometry to study the inhibitory effect of apigenin on solid breast tumors and its effect on the tumor immune microenvironment. The results showed that API can induce breast cancer cell apoptosis through the PI3K/AKT/Nrf2 pathway and can improve the tumor immune microenvironment in mice with breast tumors, thereby inhibiting the growth of breast cancer. Thus, API may be a promising agent for breast cancer treatment.

Strategies targeting endoplasmic reticulum stress to improve Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. ER stress triggers the activation of unfolded protein response (UPR) to reduce stress and restore ER function. However, excessive and continuous ER stress and UPR exacerbate the risk of DA neuron death through crosstalk with other PD events. Thus, ER stress is considered a promising therapeutic target for the treatment of PD. Various strategies targeting ER stress through the modulation of UPR signaling, the increase of ER's protein folding ability, and the enhancement of protein degradation are developed to alleviate neuronal death in PD models. In this review, we summarize the pathological role of ER stress in PD and update the strategies targeting ER stress to improve ER protein homeostasis and PD-related events.

Comparison of pregnancy outcomes in infertile patients with different types of adenomyosis treated with high-intensity focused ultrasound.

OBJECTIVE: This study assessed the improvement of symptoms and pregnancy outcomes in infertile patients with various types of adenomyosis who were treated with high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: Between October 2017 and January 2022, 129 infertile patients with adenomyosis who wished to conceive were treated with HIFU. Based on the relationship between the adenomyotic lesion, the endometrium, and the subserosa of the uterus on magnetic resonance imaging, the adenomyotic lesions were divided into internal, external, intramural, and full-thickness types. Menstruation pain score, menstruation blood volume score, anti-Müllerian hormone (AMH) levels, reproductive results, pregnancy and delivery complications, and other clinical variables were compared among these four groups. RESULTS: Patients with external adenomyosis had the greatest menstrual distress, whereas patients with internal adenomyosis had the greatest menstrual blood volume. Dysmenorrhea and heavy menstruation were significantly improved after HIFU treatment in all groups. AMH levels were not significantly different before and six months after HIFU. Of the 129 patients, 50 (38.7%) became pregnant after HIFU, and patients with internal adenomyosis had the highest pregnancy rate. Patients with adenomyotic lesions located in the posterior wall of the uterus had a higher pregnancy rate than those with lesions located in the fundus of the uterus. CONCLUSIONS: The classification of adenomyosis is closely related to distinctions in clinical symptoms and pregnancy outcomes. Infertile patients with different types of adenomyosis could be effectively treated with HIFU. HIFU can be considered as an option for infertile patients with adenomyosis who want to maintain their fertility.

Focused ultrasound: a novel therapy for improving vaginal microecology in patients with high-risk HPV infection.

OBJECTIVES: To investigate changes in vaginal microecology in women with high-risk human papillomavirus (HR-HPV) infection after focused ultrasound (FU) treatment. MATERIALS AND METHODS: We collected vaginal secretions at the time of admission and 3 months after FU treatment from 169 women who received FU treatment for cervical HR-HPV infection between July 2020 and September 2022. Among them, there were 101 patients with cute vaginitis, we also collected their vaginal secretions after one week of drug treatment. These samples were evaluated for vaginal microecology and HPV-DNA examination. RESULTS: Of the 169 patients, 101 (59.7%) suffered from acute vaginitis at the time of admission. After one week of targeted antibiotics drug treatment, there were no pathogens or pus cells on the field of microscopic vision, but there was no significant difference(p > 0.05) in the diversity and density of vaginal flora, the proportion and function of Lactobacillus (H2O2 negative rate) between one week after treatment and at the time of admission. At the time of admission of the 169 patients, the normal flora rate was 40.3%, which increased to 93.5% three months after FU treatment. The differences in vaginal secretion parameters at the time of admission and 3 months after FU treatment were as follows: H2O2 negative rate (37.3% vs. 3.6%), leukocyte esterase positive rate (54.4% vs. 5.9%), sialidase positive rate (38.5% vs. 4.1%), bacterial vaginitis positive rate (55% vs. 4.7%), fungal vaginitis positive rate (44.4% vs. 5.9%), and trichomonal vaginitis positive rate (7.1% vs. 0). The difference was statistically significant (p < 0.01). The pH value and Nagent score at the time of admission were significantly higher than those three months after FU. Three months after FU, the positive rate of HPV was 5.8% in the group of patients with normal vaginal microecology at the time of admission and post-FU; it was 6.7% in the group of patients with abnormal vaginal microecology at the time of admission and normal vaginal microecology post-FU; and it was 100% in the group patients with abnormal vaginal microecology at the time of admission and post-FU. A significant difference was observed among the three groups (p < 0.01). CONCLUSION: FU is an effective treatment for patients with cervical HR-HPV infection. FU does not interfere with the vaginal microecology of HR-HPV positive patients with normal vaginal microecology.FU followed by antibiotic drug therapy for pathogens is beneficial to restore the function of Lactobacillus vaginalis in HR-HPV positive patients with acute vaginitis,so as to improve the vaginal microecology of HR-HPV positive patients with abnormal vaginal microecology.

Enhancing surfactin production in B. velezensis Bs916 combined cumulative mutagenesis and expression key enzymes.

Surfactin is a lipopeptide which has attracted massive attention due to its versatile bioactive properties, although it has less commercial application due to its low yield in wild strains. The B. velezensis Bs916 has enable commercial production of surfactin due to its outstanding capacity to synthesize lipopeptides and amenable to genetically engineering. In this study, 20 derivatives with high surfactin production were obtained firstly by transposon mutagenesis and knockout techniques, and the surfactin yield of the derivative H5 (△GltB) was increased approximately 7-folds, reaching to 1.48 g/L. The molecular mechanism of high yielding surfactin in △GltB was investigated by the transcriptomic and KEGG pathway analysis. The results indicated that △GltB enhanced its ability to synthesize surfactin mainly by promoting transcription of the srfA gene cluster and inhibiting degradation of some key precursors such as fatty acid. Secondly, we obtained a triple mutant derivative BsC3 by cumulative mutagenesis of the negative genes GltB, RapF, and SerA, and it could increase the surfactin titer by twofold, reaching to 2.98 g/L. Thirdly, we achieved overexpression of two key rate-limiting enzyme genes, YbdT, and srfAD, and the derivative BsC5 which further increased the surfactin titer by 1.3-fold, reaching to 3.79 g/L. Finally, the yield of surfactin by derivatives was significantly increased under the optimal medium, particularly the BsC5 increased the surfactin titer to 8.37 g/L. To the best of our knowledge, this is one of the highest yields that have been reported. Our work may pave way for large scale production of surfactin by B. velezensis Bs916. KEY POINTS: • Elucidation of the molecular mechanism of surfactin high-yielding transposon mutant. • Genetically engineering of B. velezensis Bs916 surfactin titer to 8.37 g/L for large scale preparation.

Genome Sequencing and Genetic Engineering Reveal the Contribution of Bacitracin Produced by Bacillus paralicheniformis CPL618 to Anti-Staphylococcus aureus Activity.

Staphylococcus aureus is one of the important pathogens causing human diseases, especially its treatment has great challenges due to its resistance to methicillin and vancomycin. The Bacillus strains are known to be major sources of second metabolites that can function as drugs. Therefore, it is of great value to excavate metabolites with good inhibitory activity against S. aureus from Bacillus strains. In this study, a strain Bacillus paralicheniformis CPL618 with good antagonistic activity against S. aureus was isolated and genome analysis showed that the size was 4,447,938 bp and contained four gene clusters fen, bac, dhb, and lch which are potentially responsible for four cyclic peptides fengycin, bacitracin, bacillibactin, and lichenysin biosynthesis, respectively. These gene clusters were knockout by homologous recombination. The bacteriostatic experiment results showed that the antibacterial activity of ∆bac decreased 72.3% while Δfen, Δdhb, and ΔlchA did not significantly changed as that of wild type. Interestingly, the maximum bacitracin yield was up to 92 U/mL in the LB medium, which was extremely unusual in wild type strains. To further improve the production of bacitracin, transcription regulators abrB and lrp were knocked out, the bacitracin produced by ΔabrB, Δlrp, and ΔabrB + lrp was 124 U/mL, 112 U/mL, and 160 U/ml, respectively. Although no new anti-S. aureus compounds was found by using genome mining in this study, the molecular mechanisms of high yield of bacitracin and anti-S. aureus in B. paralicheniformis CPL618 were clarified. Moreover, B. paralicheniformis CPL618 was further genetically engineered for industrial production of bacitracin.

Transcriptome investigation on the multicellular behavior of Bacillus velezensis Bs916 anchoring surfactin.

AIMS: To provide valuable information for a comprehensive understanding of the multicellular behavior of Bacillus velezensis Bs916 regulated by surfactin and other natural signals by Transcriptome. METHODS AND RESULTS: Transcriptomics revealed a distinct effect on gene expression alterations caused by disruption of the surfactin gene cluster(Δsrf) and 100 µg/ml surfactin addition(Δsrf + SRF). A total of 1573 differential expression genes were identified among Bs916, Δsrf, and Δsrf + SRF and grouped into eight categories based on their expression profiles. RT-qPCR analysis of 30 candidate genes showed high consistency with those of transcriptome. Additionally, the expression of eight candidate genes regulated by surfactin in a dose-dependent manner was revealed by lacZ fusion. Based on the above evidence, we proposed that surfactin can act as an extracellular signal for monitoring biofilm formation in Bs916 by directly regulating the expression of AbrB, DegS-degU, and SinI-SinR, and indirectly regulating the phosphorylation of ComA and Spo0A. CONCLUSIONS: The biofilm of Δsrf was unable to restore significantly by surfactin addition, combined inclusion of surfactin (SRF), exopolysaccharide (EPS), and γ-poly-dl-glutamic acid (γ-PGA), results in significant restoration of Δsrf biofilm formation, thereby a preliminary model was presented about the molecular mechanism by which the signaling molecule surfactin regulates Bs916 multicellular behavior.

The effects of bioactive components from the rhizome of gastrodia elata blume (Tianma) on the characteristics of Parkinson's disease.

Parkinson's disease (PD) is an age-related chronic neurodegenerative disease caused by the death and degeneration of dopaminergic neurons in the substantia nigra of the midbrain. The decrease of the neurotransmitter dopamine in the patient's brain leads to various motor symptoms. PD drugs mainly enhance dopamine levels but cannot prevent or slow down the loss of dopaminergic neurons. In addition, they exhibit significant side effects and addiction issues during long-term use. Therefore, it is particularly urgent to develop novel drugs that have fewer side effects, can improve PD symptoms, and prevent the death of dopaminergic neurons. The rhizome of Gastrodia elata Blume (Tianma) is a well-known medicinal herb and has long been used as a treatment of nervous system-related diseases in China. Several clinical studies showed that formula comprising Tianma could be used as an add-on therapy for PD patients. Pharmacological studies indicated that Tianma and its bioactive components can reduce the death of dopaminergic neurons, α-synuclein accumulation, and neuroinflammation in various PD models. In this review, we briefly summarize studies regarding the effects of Tianma and its bioactive components' effects on major PD features and explore the potential use of Tianma components for the treatment of PD.

Targeting PGAM1 in cancer: An emerging therapeutic opportunity.

Glycolysis is a preferred metabolic pattern of cancer cells. Phosphoglycerate mutase 1 (PGAM1) is a pivotal glycolytic enzyme that catalyzes the reciprocal conversion between 2-phosphoglycerate and 3-phosphoglycerate. It also stimulates anabolic pathways, generates adenosine triphosphate, and keeps redox balance under hypoxic conditions. Mounting evidence supports that PGAM1 is overexpressed in many cancers and promotes their progression. The critical roles of PGAM1 in tumorigenesis make it a promising theranostical target for cancer. The aberrant expression of PGAM1 enables it to become a potential diagnosis gene for several cancers, and its heterogeneous regulations via interacting with its different ligands increase the possibility of it as a target for cancer therapy and discovery of tens of PGAM1 inhibitors, which can provide the potential feasibility for cancer treatment. This review provides insights into structure, function, and regulation of PGAM1, summarizes its mechanism in tumorigenesis, reviews the advanced status of PGAM1 inhibitors in cancer diagnosis and treatment, and finally emphasizes PGAM1 as an appealing theranostical target for cancer.

Andrographolide Derivative AL-1 Ameliorates LPS-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome and Lung Permeability.

BACKGROUND: Acute lung injury (ALI) is a serious respiratory disease with a high mortality rate, and there is an urgent need for a more effective treatment strategy. Andrographolide derivative AL-1 has been identified to possess anti-inflammatory activity. However, whether it could reduce LPS-induced lung injury in mice through inhibiting NLRP3 inflammasome activation and protecting lung permeability has not yet been elucidated. In the present research, we investigated the protective effect of AL-1 on ALI mice and demonstrated the potential mechanisms. METHODS: Male Balb/c mice were anesthetized with isoflurane, and ALI mice were induced by intratracheal instillation of LPS. The mice were euthanized after LPS administration for 12 h, then bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The levels of inflammatory factors were measured by ELISA assay, and HE staining and lung injury scoring were used to evaluate the pathological changes in the pulmonary tissues. Immunohistochemistry and immunofluorescence examination were conducted to detect the expression levels of related proteins. Western blot was performed to measure the levels of NLRP3 inflammasome and tight junction proteins. RESULTS: The study indicated that AL-1 effectively alleviated lung injury by reduction of proinflammatory cytokine levels, MPO activity, lung W/D ratio, and total protein levels. Furthermore, AL-1 improved pathological changes in lung tissue and significantly reduced the infiltration of inflammatory cells. Administration with AL-1 markedly inhibited the expression of NLRP3, ASC, Caspase-1, IL-1ß, gasdermin D (GSDMD), and VCAM-1 but increased the expression of ZO-1, Occludin, JAM-A, and Claudin-1. CONCLUSION: Taken together, these results demonstrated that AL-1 ameliorated pulmonary damage by inhibiting the activation of the NLRP3 inflammasome pathway and restoring TJ protein expression.

The Potentials of Uncariae Ramulus Cum Uncis for the Treatment of Migraine: Targeting CGRP in the Trigeminovascular System.

Migraine is a common chronic neurovascular disease characterized by headaches. Calcitonin gene-related peptide (CGRP) signaling in the trigeminovascular system plays a critical role in the development of migraine. The monoclonal antibodies against CGRP and its receptor have been used clinically for the prevention of migraine; however, they may not be a cost-effective option for patients with low-frequency episodic migraine. Thus, it is quite valuable to search for an alternative strategy to downregulate CGRP signaling. Uncariae Ramulus Cum Uncis (UR) has a longterm history for the treatment of cardiovascular and central nervous systems disorders in China and Eastern Asia. Several clinical studies showed that famous herbal formulas comprising UR were able to improve headaches in migraineurs. In addition, increasing in vivo studies further indicated that migraine-related changes, such as CGRP increase, inflammation, nitric oxide increase, and spontaneous behavior problems could be reduced by UR extraction and its active constituents. In this review, we summarize the pathophysiological factors affecting abnormal CGRP release in the trigeminovascular system during a migraine, and for the first time, analyze the effects of UR on these factors and evaluate the potentials of UR for the treatment of migraine.

Protective Effect of Iridoid Glycosides of the Leaves of Syringa oblata Lindl. on Dextran Sulfate Sodium-Induced Ulcerative Colitis by Inhibition of the TLR2/4/MyD88/NF-κB Signaling Pathway.

Iridoid glycoside (IG) is the major active fraction extracted from the leaves of Syringa oblata Lindl. In view of its antimicrobial and antidiarrheal potential, it could be beneficial for the treatment of ulcerative colitis (UC). In the present study, IG (20, 40, and 80 mg/kg) was administered orally for 14 days to dextran sulfate sodium- (DSS-) induced colitis rats. The anti-inflammatory effects of IG on DSS-induced UC were evaluated by comparing observations in DSS-induced colitis and drug-treated groups using disease activity index (DAI), macroscopic score, histological analysis, and apoptosis assay. To elucidate the antioxidant mechanisms of IG on NOX-dependent ROS production, the activities of 8-OHdG, NOX1, and NOX2 in DSS-induced colitis were determined. The levels of proinflammatory cytokines such as IL-2, IL-4, IL-5, IL-12p40, and IL-13 were detected. The inflammation-associated protein and mRNA expressions of TLR-2, TLR-4, MyD88, and NF-κBp65 were assessed by immunohistochemistry and real-time quantitative PCR, respectively. The results suggested that IG treatment significantly reduced DAI, macroscopic score, and histological damage compared to untreated animals (p < 0.01), whereas administration of IG remarkably attenuated the upregulation of 8-OHdG, NOX1, and NOX2 and the expression of proinflammatory cytokines such as IL-2, IL-4, IL-5, IL-12p40, and IL-13 in DSS-treated rats in a concentration-dependent manner. In addition, IG treatment could dose dependently suppress the protein and mRNA levels of TLR-2, TLR-4, MyD88, and NF-κBp65. The dose of IG that produced the most significant protective effect was 80 mg/kg. The above results demonstrate that IG exerts its inhibitory effect on cell apoptosis, oxidative stress, and proinflammatory cytokines in DSS-induced colitis through modulation of the TLR2/4/MyD88/NF-κB signaling pathway.