Sarcandra glabra (Thunb.) Nakai alleviates DSS-induced ulcerative colitis by promoting restitution, restoring barrier function, and modulating IL-17/Notch1/FoxP3 pathway in intestinal cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Sarcandra glabra is officially named Zhong Jie Feng as a traditional medicine. In the nationality of Yao and Zhuang, it has been used to treat digestive diseases like stomachache and dysentery. Similarly, in Dai nationality, it has been used to treat intestinal diseases like gastric ulcers. However, the effect and mechanism of S. glabra on experimental ulcerative colitis (UC) are known. AIM OF STUDY: The main objective of this study was to investigate the effect and mechanism of S. glabra on experimental UC. MATERIALS AND METHODS: The chemical components in the water extract of S. glabra (ZJF) were analyzed by UPLC-MS/MS method. The HCoEpiC cell line was used to assess the promotive effect on intestinal proliferation and restitution. RAW264.7 cells were used to assess the in vitro anti-inflammatory effect of ZJF. The 3% DSS-induced colitis model was used to evaluate the in vivo effect of ZJF (4.5 g/kg and 9.0 g/kg). Mesalazine (0.5 g/kg) was used as the positive drug. ELISA, RT-qPCR, Western blot, and multiplex immunohistochemical experiments were used to test gene levels in the colon tissue. The H&E staining method was used to monitor the pathological changes of colon tissue. TUNEL assay kit was used to detect apoptosis of epithelial colonic cells. RESULTS: ZJF could alleviate the DSS-caused colitis in colon tissues, showing a comparative effect to that of the positive drug mesalazine. Mechanism study indicated that ZJF could promote normal colonic HCoEpiC cell proliferation and restitution, inhibit overexpression of pro-inflammatory cytokines, restore the M1/M2 ratio, decrease epithelial colonic cell apoptosis, rescue tight junction protein levels, and modulate IL-17/Notch1/FoxP3 pathway to treat experimental UC. CONCLUSION: Our results indicated that S. glabra can promote intestinal cell restitution, balance immune response, and modulate IL-17/Notch1/FoxP3 pathway to treat experimental UC.

Sophoridine exerts anti-arthritic effects on fibroblast-like synoviocytes and collagen-induced arthritis in rats.

The discovery of alternative medicines with fewer adverse effects is urgently needed for rheumatoid arthritis (RA). Sophoridine (SR), the naturally occurring quinolizidine alkaloid isolated from the leguminous sophora species, has been demonstrated to possess a wide range of pharmacological activities. However, the effect of SR on RA remains unknown. In this study, the collagen-induced arthritis (CIA) rat model and tumor necrosis factor alpha (TNFα)-induced fibroblast-like synoviocytes (FLSs) were utilized to investigate the inhibitory effect of SR on RA. The anti-arthritic effect of SR was evaluated using the CIA rat model in vivo and TNFα-stimulated FLSs in vitro. Mechanistically, potential therapeutic targets and pathways of SR in RA were analyzed through drug target databases and disease databases, and validation was carried out through immunofluorescence, immunohistochemistry, and Western blot. The in vivo results revealed that SR treatment effectively ameliorated synovial inflammation and bone erosion in rats with CIA. The in vitro studies showed that SR could significantly suppress the proliferation and migration in TNFα-induced arthritic FLSs. Mechanistically, SR treatment efficiently inhibited the activation of MAPKs (JNK and p38) and NF-κB pathways in TNFα-induced arthritic FLSs. These findings were further substantiated by Immunohistochemistry results in the CIA rat. SR exerts an anti-arthritic effect in CIA rats through inhibition of the pathogenic characteristic of arthritic FLSs via suppressing NF-κB and MAPKs (JNK and p38) signaling pathways. SR may have a great potential for development as a novel therapeutic agent for RA treatment.

Americanin B inhibits pyroptosis in lipopolysaccharide-induced septic encephalopathy mice through targeting NLRP3 protein.

BACKGROUND: Sepsis is considered as a severe illness due to its high mortality. Sepsis can cause septic encephalopathy, thus leading to brain injury, behavioral and cognitive dysfunction. Pyroptosis is a type of regulated cell death (RCD) and takes a crucial part in occurrence and development of sepsis. Americanin B (AMEB) is a lignan compounds, which is extracted from Vernicia fordii. In our previous study, AMEB could inhibit microglial activation in inflammatory cell model. However, the function of AMEB in septic encephalopathy mice is uncertain. It would be worthwhile to ascertain the role and mechanism of AMEB in sepsis. PURPOSE: Current study designs to certify the relationship between pyroptosis and septic encephalopathy, and investigate whether AMEB can restrain NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and restrict pyroptosis by targeting NLRP3 in septic mice model. STUDY DESIGN: C57BL/6 mice were utilized to perform sepsis model in vivo experiments. BV-2 cell lines were used for in vitro experiments. METHODS: In vivo sepsis model was established by lipopolysaccharide (LPS) intraperitoneal injection in male C57BL/6 J mice and in vitro model was exposed by LPS plus ATP in BV-2 cells. The survival rate was monitored on the corresponding days. NLRP3, apoptosis associated Speck-like protein (ASC), caspase-1, GasderminD (GSDMD), interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) level were detected by western blotting and immunofluorescence analysis. Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) experiments, RNAi transfection and quantitative real-time PCR were applied to confirm the potential target of AMEB. RESULTS: The results suggested that AMEB could rise survival percentage and lighten brain injury in LPS-induced sepsis mice. In addition, AMEB could inhibit pyroptosis and the activiation of NLRP3 inflammasome. The inhibiting function of AMEB on the activiation of NLRP3 inflammasome is weakened following si-NLRP3 transfection. Moreover, AMEB exerted anti-pyroptosis effect via targeting NLRP3 protein. CONCLUSIONS: Our findings first indicate NLRP3 is an effective druggable target for septic encephalopathy related brain injury, and also provide a candidate-AMEB for the treatment of septic encephalopathy. These emerging findings on AMEB in models of sepsis suggest an innovative approach that may be beneficial in the prevention of septic encephalopathy.

Distribution of LPRD in OSAHS Patients: Is There a Correlation?

Objective: Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) and Laryngopharyngeal Reflux Disease (LPRD) are interrelated medical conditions affecting the respiratory system. This article aimed to investigate the potential correlation between the two. Methods: This cross-sectional study was carried out on a total of 52 participants diagnosed with both OSAHS and LPRD. Clinical data of baseline demographics of year, sex, BMI, including clinical indicators such as AHI (Apnea Hypopnea Index), OSAHS severity grading, RFS (Reflux Finding Score), RSI (Reflux Symptom Index), and 24-hour pH level were collected. Statistical analysis was then conducted to evaluate the correlation between OSAHS and LPRD. Results: Among the 52 patients, the the average age was 43.3±11.6 years with a mean 24.7±2.9 kg/m2 BMI level. The mean duration of OSAHS was 4.1±1.7 years with mean 38.7±12 AHI scores and 30.8% mild OSAHS, 51.9% moderate OSAHS, and 17.3% severe OSAHS. Mean LPRD duration was 3.2±1.5 years with a mean 15.9±4.9 RFS score, mean 28.0±6.8 RSI score, and mean 3.9±0.8 24-hour pH level. There was a strong positive correlation between AHI scores and both the RFS score (r>0.9, P < .01) and RSI score (r>0.9, P < .01). While a strong negative correlation between AHI scores and 24-hour pH level was observed (r < -0.8, P < .01). And there was a strong positive correlation between OSAHS severity levels and both the RSF score (r>0.8, P < .01) and RSI score (r>0.79, P < .01). While a significant negative correlation between OSAHS severity and 24-hour pH level was detected (r < -0.7, P < .01). Conclusions: The findings of this cross-sectional study demonstrate a strong positive correlation between the severity of OSAHS, as indicated by AHI scores, and the severity of LPRD, as measured by RFS and RSI scores. A negative correlation was also observed between AHI scores and 24-hour pH level, indicating a connection between these two medical conditions.

Hyparillums A and B: polycyclic polyprenylated acylphloroglucinols from Hypericum patulum.

Hyparillums A (1) and B (2), two previously unidentified polycyclic polyprenylated acylphloroglucinols (PPAPs) with intricate architectures, were isolated from Hypericum patulum Thunb. Hyparillum A was the first PPAP with eight-carbon rings based on an unprecedented 6/6/5/6/6/5/6/4 octocyclic system featuring a rare heptacyclo[10.8.1.11,10.03,8.08,21.012,19.014,17]docosane core. In contrast, hyparillum B featured a novel heptacyclic architecture (6/6/5/6/6/5/5) based on a hexacyclo[9.6.1.11,9.03,7.07,18.011,16]nonadecane motif. Furthermore, hyparillums A and B demonstrated promising inhibitory effects on the proliferation of murine splenocytes stimulated by anti-CD3/anti-CD28 monoclonal antibodies and lipopolysaccharide, exhibiting half-maximal inhibitory concentration (IC50) values ranging from 6.13 ± 0.86 to 12.69 ± 1.31 µmol·L-1.

Physicochemical, Structural, and Functional Properties of Fructans from Single-Clove Garlic and Multiclove Garlic: A Comparison.

This study aimed to compare the structural features and functional properties of polysaccharides from single-clove garlic (SGPs) and multiclove garlic (MGPs) and to establish their structure-function relationships. Both SGPs and MGPs were identified as fructans consisting mainly of →1)-ß-d-Fruf (2→ and →6)-ß-d-Fruf (2→ residues but differed in average molecular weights (6.76 and 5.40 kDa, respectively). They shared similar thermodynamic properties, X-ray diffraction patterns, and high gastrointestinal digestive stability. These two purified fructans could dose-dependently scavenge free radicals, reduce oxidized metals, and effectively alleviate metronidazole-induced oxidative stress and CuSO4-induced inflammation in zebrafish via inhibiting the overexpression of inflammation-related proteins and cytokines. SGPs showed lower free radical scavenging activity in vitro than MGPs but higher antioxidant and anti-inflammatory activities in vivo. Taken together, the molecular weight was the main structural difference between the two garlic fructans of different varieties, which is a potential reason for their differences in biological activities.

Kellerin alleviates cerebral ischemic injury by inhibiting ferroptosis via targeting Akt-mediated transcriptional activation of Nrf2.

BACKGROUND: Ischemic stroke (IS) is characterized as a detrimental cerebrovascular disease with high mortality and disability. Ferroptosis is a novel mechanism involved in neuronal death. There is a close connection between IS and ferroptosis, and inhibiting ferroptosis may provide an effective strategy for treating IS. Our previous investigations have discovered that kellerin, the active compound of Ferula sinkiangensis K. M. Shen, possesses the capability to shield against cerebral ischemia injury. PURPOSE: Our objective is to clarify the relationship between the neuroprotective properties of kellerin against IS and its ability to modulate ferroptosis, and investigate the underlying regulatory pathway. STUDY DESIGN: We investigated the impact and mechanism of kellerin in C57BL/6 mice underwent middle cerebral artery occlusion/reperfusion (MCAO/R) as well as SH-SY5Y cells exposed to oxygen-glucose deprivation/ re-oxygenation (OGD/R). METHODS: The roles of kellerin on neurological severity, cerebral infarction and edema were investigated in vivo. The regulatory impacts of kellerin on ferroptosis, mitochondrial damage and Akt/Nrf2 pathway were explored. Molecular docking combined with drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) were performed to analyze the potential target proteins for kellerin. RESULTS: Kellerin protected against IS and inhibited ferroptosis in vivo. Meanwhile, kellerin improved the neuronal damage caused by OGD/R and suppressed ferroptosis by inhibiting the production of mitochondrial ROS in vitro. Further we found that kellerin directly interacted with Akt and enhanced its phosphorylation, leading to the increase of Nrf2 nuclear translocation and its downstream antioxidant genes expression. Moreover, kellerin's inhibitory effect on ferroptosis and mitochondrial ROS release was eliminated by inhibiting Akt/Nrf2 pathway. CONCLUSIONS: Our study firstly demonstrates that the neuroprotective properties of kellerin against IS are related to suppressing ferroptosis through inhibiting the production of mitochondrial ROS, in which its modulation on Akt-mediated transcriptional activation of Nrf2 plays an important role. This finding shed light on the potential mechanism that kellerin exerts therapeutic effects in IS.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation.

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

Research progress on the toxicity of toxic Traditional Herbals from Thymelaeaceae.

ETHNOPHARMACOLOGICAL RELEVANCE: Plants from the Thymelaeaceae family are widely distributed in tropical and temperate regions, with approximately 113 species used as Traditional Herbals. There are numerous applications for them, such as treating leukemia, AIDS, and liver cancer. It should be noted that around 20% of these plants have shown harmful side effects when used in clinical applications, including solid irritations to the skin and mucous membranes, carcinogenic effects, organ damage, vomiting, and diarrhea. AIM OF THE STUDY: This paper aims to review the toxic side effects, toxic compounds, toxic mechanisms, and detoxification methods of Traditional Herbals in Thymelaeaceae, guiding their safe clinical uses. MATERIALS AND METHODS: This review employed the keywords "Thymelaeaceae," 48 different "genus," 966 "species," and the combination of "toxicity" to identify the medicinal value and toxicity of plants from Thymelaeaceae in scientific databases (Pubmed, SciFinder Scholar, Elsevier, Web of Science, and CNKI). Information relevant to the toxicity of Traditional Herbals from Thymelaeaceae up to June 2023 has been summarized. The plant names have been checked with "World Flora Online" (www.worldfloraonline.org). RESULTS: 28 toxic Traditional Herbals from 13 genera within the Thymelaeaceae family were categorized. Toxicities were summarized at the cellular, animal, and clinical levels. The toxic substances are primarily concentrated in the Daphne L. and Wikstroemia Endl. genera, with terpenes being the main toxic components. The toxicity mechanism is primarily associated with the mitochondrial pathways. Detoxification and enhanced efficacy can be achieved through processing methods such as vinegar-processing and sweat-soaking. CONCLUSIONS: Medicinal plants in the Thymelaeaceae exhibit significant pharmacological activities, such as anti-HIV and anti-tumor effects, indicating a broad potential for application. However, their clinical uses are hindered by their inherent toxicity. Researching the toxic components and mechanisms of these Traditional Herbals and exploring more effective detoxification methods can contribute to unveiling the latent value of these medicinal plants from Thymelaeaceae.

Prenyllongnols A-D, New Prenylated Acylphloroglucinols that Fight Concanavalin A-Induced Autoimmune Hepatitis.

Autoimmune hepatitis is a serious hepatic disorder with unknown nosogenesis, and natural products have been deemed to be one of the most significant sources of new drugs against this disease. Prenyllongnols A-D (1-4), four undescribed prenylated acylphloroglucinols, were isolated from Hypericum longistylum. Compounds 1-4 exhibited remarkable immunosuppressive activities in murine splenocyte proliferation under the induction of concanavalin A (Con A), and IC50 values ranged from 2.98 ± 0.21 to 6.34 ± 0.72 µM. Furthermore, in a Con A-challenged autoimmune hepatitis mouse model, the mice in the group that were pretreated with isolate 2 significantly ameliorated liver injury and decreased proinflammatory cytokine production. Notably, natural product 2 was the first prenylated acylphloroglucinol to protect against concanavalin A-induced autoimmune hepatitis. This finding underscores the potential of prenylated acylphloroglucinol-type metabolites as promising candidates for designing novel immunosuppressors in the quest for new antiautoimmune hepatitis drugs.

Nutritional composition, health-promoting effects, bioavailability, and encapsulation of tree peony seed oil: a review.

Tree peony is cultivated worldwide in large quantities due to its exceptional ornamental and medicinal value. In recent years, the edible value of tree peony seed oil (TPSO) has garnered significant attention for its high content of alpha-linolenic acid (ALA, >40%) and other beneficial minor components, including phytosterols, tocopherols, squalene, and phenolics. This review provides a systematic summary of the nutritional composition and health-promoting effects of TPSO, with a specific focus on its digestion, absorption, bioavailability, and encapsulation status. Additionally, information on techniques for extracting and identifying adulteration of TPSO, as well as its commercial applications and regulated policies, is included. Thanks to its unique nutrients, TPSO offers a wide range of health benefits, such as hypolipidemic, anti-obesity, cholesterol-lowering, antioxidant and hypoglycemic activities, and regulation of the intestinal microbiota. Consequently, TPSO shows promising potential in the food and cosmetic industries and should be cultivated in more countries. However, the application of TPSO is hindered by its low bioavailability, poor stability, and limited water dispersibility. Therefore, it is crucial to develop effective delivery strategies, such as microencapsulation and emulsion, to overcome these limitations. In conclusion, this review provides a comprehensive understanding of the nutritional value of TPSO and emphasizes the need for further research on its nutrition and product development.

Enhancement of volatile fatty acids production through anaerobic co-digestion of navel orange residue and waste activated sludge: Effect of pre-treatment and substrate proportions.

In this study, the co-digestion system with Navel orange residues (NOR) and Waste activated sludge (WAS) was established, by pre-treating the NOR and setting different volatile solids (VS) ratios of NOR to WAS to motivate the production of volatile fatty acids (VFA). The pre-treatment method (pH 7 and temperature 70 °C) promoted the release of dissolved organic matter, and the concentration of soluble chemical oxygen demand (SCOD) increased by 45.56% compared with the untreated group (pH 3 and temperature 20 °C). In the co-digestion system, the highest VFA yield (5716.69 mg/L) was obtained at VS ratio of 2. When the VS ratio was increased to 4, the imbalance in proportions of carbon and nitrogen affected VFA production, and the high concentration of essential oils (EO) present in the NOR inhibited the methane production; the cumulative yield of methane gas decreased by 24.10% compared with the yield obtained when the VS ratio was 2. Analysis of microbial community revealed that an increase in the number of VFA-producing microbial populations and the abundance of Methanobacteria resulted in the accumulation of acetic acid. This study demonstrated that co-digestion of NOR with WAS improve VFA production, thus realizing the utilization of solid wastes and reducing environmental pollution.

"Closed-Loop" O2-Economizer Induced In Situ Therapeutic Vaccine against Hypoxic Tumors.

Therapeutic tumor vaccines, which use tumor antigens to stimulate a cancer patient's immune system to eventually kill the tumor tissues, have emerged as one of the most attractive strategies in anticancer research. Especially, exploring in situ vaccines has become a potential field in cancer immunotherapy. However, due to the hypoxic tumor microenvironment, the generation of tumor antigens is always mild and not sufficient. Hence, in this study, we designed a closed-loop mitochondrial oxygen-economizer (TPCA) to induce enhanced phototherapy-driven in situ vaccines. The O2-economizer was developed by the integration of the photosensitizer CyI and the mitochondrial inhibitor atovaquone into the PAMAM dendrimer. In vitro and in vivo studies showed that TPCA could enter the mitochondria through (3-propylcarboxyl) triphenylphosphine bromide (TPP) and effectively restrict the respiration of tumor cells to reduce tumor hypoxia, thus providing continuous oxygen for enhanced iodinated cyanine dye mediated photodynamic therapy, which could further induce in situ vaccines for ablating the primary tumor directly and inhibiting the tumor metastasis and recurrence. Furthermore, the antitumor mechanism revealed that O2-economizer-based oxygen-boosted PDT elicited immunogenic cancer cell death with enhanced exposure and release of DAMPs and altered the immunosuppressive tumor microenvironment with increased recruitment of T cells in tumors, thereby inducing in situ vaccines and provoking the systematic antitumor responses against CT26 tumors. This study will provide innovative approaches for local, abscopal, and metastatic tumor treatment.

Enhanced Antitumor Efficacy of Novel Biomimetic Platelet Membrane-Coated Tetrandrine Nanoparticles in Nonsmall Cell Lung Cancer.

Nonsmall cell lung cancer (NSCLC) remains one of the leading causes of cancer-related death worldwide, posing a serious threat to global health. Tetrandrine (Tet) is a small molecule in traditional Chinese medicine with proven primary efficacy against multiple cancers. Although previous studies have demonstrated the potential anticancer effects of Tet on NSCLC, its poor water solubility has limited its further clinical application. Herein, a novel nanoparticle-based drug delivery system, platelet membrane (PLTM)-coated Tet-loaded polycaprolactone-b-poly(ethylene glycol)-b-polycaprolactone nanoparticles (PTeNPs), is proposed to increase the potency of Tet against NSCLC. First, tetrandrine nanoparticles (TeNPs) are created using an emulsion solvent evaporation method, and biomimetic nanoparticles (PTeNPs) are prepared by coating the nanoparticles with PLTMs. When coated with PLTMs, PTeNPs are considerably less phagocytized by macrophages than Tet and TeNPs. In addition, compared with Tet and TeNPs, PTeNPs can significantly inhibit the growth and invasion of NSCLC both in vitro and in vivo. With reliable biosafety, this drug delivery system provides a new method of sustained release and efficient anticancer effects against NSCLC, facilitating the incorporation of Tet in modern nanotechnology.

Flavonoid compound from Agrimonia pilosa Ledeb improves adipose insulin resistance by alleviating oxidative stress and inflammation.

BACKGROUND: Researches and practice of traditional Chinese medicine indicated that Agrimonia pilosa Ledeb could improve insulin resistance (IR) and treat type 2 diabetes (T2DM). To reveal its underling mechanisms, we isolated Flavonoid component (FC) from Agrimonia pilosa Ledeb and elucidated its effects on glucose metabolism to improve IR by suppressing oxidative stress and inflammation. METHODS: Adipocytes or mice IR model was established with overdosed glucose and insulin or high-fat diet. The uptake of 2-NBDG and glucose consumption were measured to verify insulin sensitivity in vitro and vivo. Reactive oxidative species (ROS) were detected by flow cytometry, and superoxide dismutase (SOD) activity as well as the malondialdehyde (MDA) content were also measured. Meanwhile, factors associated with insulin signal pathway including PPARγ, insulin receptor substrate-1 (IRS-1), GLUT4, and oxidative stress including NF-E2-related factor 2 (Nrf2), as well as the related inflammatory cytokines such as NF-κB, IL-1ß, IL-6 and TNF-α were tested. Furthermore, the JNK/PI3K/Akt signal pathway was also explored. RESULTS: FC extracted from Agrimonia pilosa Ledeb ameliorated the impaired glucose metabolism significantly. Further study indicated that FC could regulate the insulin signal pathway to improve insulin resistance. Moreover, it could upregulate PPARγ with the similar efficacy as pioglitazone (Piog) straightway. FC also decreased the endogenous ROS and MDA content, increased SOD activity and Nrf2 expression to facilitate oxidative homeostasis. It attenuated expression and secretion of inflammatory cytokines obviously. At last, our results indicated JNK/PI3K/Akt pathway was regulated by FC in adipocytes and adipose tissue. CONCLUSION: FC could ameliorate glucose metabolism and improve IR. It exerted these effects by suppressing oxidative stress and inflammation. FC from Agrimonia pilosa Ledeb has a good prospect to be drugs or functional foods for IR and T2DM.

Extracts of Thesium chinense inhibit SARS-CoV-2 and inflammation in vitro.

CONTEXT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still spreading rapidly. Relevant research based on the antiviral effects of Thesium chinense Turcz (Santalaceae) was not found. OBJECTIVE: To investigate the antiviral and anti-inflammatory effects of extracts of T. chinense. MATERIALS AND METHODS: To investigate the anti-entry and replication effect of the ethanol extract of T. chinense (drug concentration 80, 160, 320, 640, 960 µg/mL) against the SARS-CoV-2. Remdesivir (20.74 µM) was used as positive control, and Vero cells were used as host cells to detect the expression level of nucleocapsid protein (NP) in the virus by real-time quantitative polymerase chain reaction (RT-PCR) and Western blotting. RAW264.7 cells were used as an anti-inflammatory experimental model under lipopolysaccharide (LPS) induction, and the expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The ethanol extract of T. chinense significantly inhibited the replication (half maximal effective concentration, EC50: 259.3 µg/mL) and entry (EC50: 359.1 µg/mL) of SARS-CoV-2 into Vero cells, and significantly reduced the levels of IL-6 and TNF-α produced by LPS-stimulated RAW264.7 cells. Petroleum ether (EC50: 163.6 µg/mL), ethyl acetate (EC50: 22.92 µg/mL) and n-butanol (EC50: 56.8 µg/mL) extracts showed weak inhibition of SARS-CoV-2 replication in Vero cells, and reduced the levels of IL-6 and TNF-α produced by LPS-stimulated RAW264.7 cells. CONCLUSION: T. chinense can be a potential candidate to fight SARS-CoV-2, and is becoming a traditional Chinese medicine candidate for treating COVID-19.

The Effect of Metformin on Triple-Negative Breast Cancer Cells and Nude Mice.

Triple-negative breast cancer (TNBC) presents the most adverse prognosis due to its pronounced invasive and metastatic features. Existing research has highlighted that metformin, a prevalent diabetes medication, possesses strong anti-tumor properties, particularly in inhibiting tumor invasion and metastasis. This study delves deeper into the impact of metformin on TNBC by examining changes in proliferation, apoptosis, invasion, migration, and adhesion of TNBC cells, specifically MDA-MB-231, post-metformin exposure. The treatment of MDA-MB-231 with metformin in immunodeficient nude mice led to discernible changes in tumor metrics such as size, weight, lymph node engagement, and angiogenesis. Post-treatment, MDA-MB-231 cells exhibited a marked decline in proliferation, invasion, migration, and adhesion, alongside a significant rise in apoptosis. In the in vivo model with nude mice, tumors displayed notable reductions in size and weight post-metformin exposure. Furthermore, there was a pronounced decline in lymph node plasma cell proliferation and tumor angiogenesis. Through the use of both Enzyme-Linked Immunosorbent Assay and Real-Time Fluorescence Quantification, it was ascertained that the expression of Signal Transducer and Activator of Transcription 3 (STAT3) saw significant augmentation, while expressions of Matrix Metallopeptidase-2 (MMP-2), Matrix Metallopeptidase-9 (MMP-9), Interleukin-6 (IL-6), and Interleukin-7 (IL-7) decreased markedly. This suggests metformin's potential efficacy against TNBC, potentially mediated via the STAT3 signaling pathway and interleukins 6 and 7.

Steerable Microneedles Enabling Deep Delivery of Photosensitizers and CRISPR/Cas9 Systems for Effective Combination Cancer Therapy.

Although gene therapy has shown prospects in treating triple-negative breast cancer, it is insufficient to treat such a malignant tumor. Herein, nanoparticles (NPs)-embedded dissolving microneedles (IR780-PL/pFBXO44@MNs) with steerable and flectional property were developed to achieve the codelivery of FBXO44-targeted CRISPR/Cas9 plasmids (pFBXO44) and hydrophobic photosensitizers. For improved NP penetration in tumor tissue, collagenase@MNs were preapplied to degrade the tumor matrix. Under light irradiation, IR780 exhibited remarkable phototherapy, while the escape efficiency of NPs from lysosomes was improved. pFBXO44 was subsequently released in tumor cell cytoplasm via reducing the disulfide bonds of NPs, which could specifically knock out the FBXO44 gene to inhibit the migration and invasion of tumor cells. As a result, tumor cells were eradicated, and lung metastasis was effectively suppressed. This micelle-incorporated microneedle platform broadens the potential of combining gene editing and photo synergistic cancer therapy.

Space Station-like Composite Nanoparticles for Co-Delivery of Multiple Natural Compounds from Chinese Medicine and Hydrogen in Combating Sensorineural Hearing Loss.

Ototoxic drugs such as aminoglycoside antibiotics and cisplatin (CDDP) can cause sensorineural hearing loss (SNHL), which is closely related to oxidative stress and the acidification of the inner ear microenvironment. Effective treatment of SNHL often requires multifaceted approach due to the complex pathology, and drug combination therapy is expected to be at the forefront of modern hearing loss treatment. Here, space-station-like composite nanoparticles (CCC@mPP NPs) with pH/oxidation dual responsiveness and multidrug simultaneous delivery capability were constructed and then loaded with various drugs including panax notoginseng saponins (PNS), tanshinone IIA (TSIIA), and ammonia borane (AB) to provide robust protection against SNHL. Molecular dynamics simulation revealed that carboxymethyl chitosan/calcium carbonate-chitosan (CCC) NPs and monomethoxy poly(ethylene glycol)-PLGA (mPP) NPs can rendezvous and dock primarily by hydrogen bonding, and electrostatic forces may be involved. Moreover, CCC@mPP NPs crossed the round window membrane (RWM) and entered the inner ear through endocytosis and paracellular pathway. The docking state was basically maintained during this process, which created favorable conditions for multidrug delivery. This nanosystem was highly sensitive to pH and reactive oxygen species (ROS) changes, as evidenced by the restricted release of payload at alkaline condition (pH 7.4) without ROS, while significantly promoting the release in acidic condition (pH 5.0 and 6.0) with ROS. TSIIA/PNS/AB-loaded CCC@mPP NPs almost completely preserved the hair cells and remained the hearing threshold shift within normal limits in aminoglycoside- or CDDP-treated guinea pigs. Further experiments demonstrated that the protective mechanisms of TSIIA/PNS/AB-loaded CCC@mPP NPs involved direct and indirect scavenging of excessive ROS, and reduced release of pro-inflammatory cytokines. Both in vitro and in vivo experiments showed the high biocompatibility of the composite NPs, even after long-term administration. Collectively, this work suggests that composite NPs is an ideal multi-drug-delivery vehicle and open new avenues for inner ear disease therapies.

1H NMR-guided isolation of hasubanan alkaloids from the alkaloidal extract of Stephania longa.

1H NMR-guided fractionation led to the isolation of 16 alkaloids from the alkaloidal extract of Stephania longa, including 11 new hasubanan alkaloids (1-11) and five known alkaloids (12-16). Interestingly, compounds 2 and 11 are typically considered protonated tertiary amine compounds, whereas compounds 1 and 10 are regarded as oxidized versions of the corresponding compounds. Their gross structures were determined through an extensive analysis of spectroscopic data (NMR (nuclear magnetic resonance) and HRESIMS (high resolution electrospray ionization mass spectroscopy)), and their absolute configurations were established by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. The new (3) and a known (12) compounds in all isolates displayed stronger antineuroinflammatory effects (IC50 values of 1.8 and 11.1 µM, respectively) than minocycline (IC50 value of 15.5 µM) against NO production on LPS-activated BV2 cells.