Ginsenoside Rh4 alleviates gastrointestinal mucositis and enhances chemotherapy efficacy through modulating gut microbiota.

BACKGROUND: Gastrointestinal mucositis stands as one of the most severe side effects of irinotecan (CPT-11). however, only palliative treatment is available at present. Therefore, there is an urgent need for adjunctive medications to alleviate the side effects of CPT-11. PURPOSE: In this study, our objective was to explore whether ginsenoside Rh4 could serve as a modulator of the gut microbiota and an adjunctive agent for chemotherapy, thereby alleviating the side effects of CPT-11 and augmenting its anti-tumor efficacy. STUDY DESIGN: A CPT-11-induced gastrointestinal mucositis model was used to investigate whether ginsenoside Rh4 alleviated CPT-11-induced gastrointestinal mucositis and enhanced the anti-tumor activity of CPT-11. METHODS: In this study, we utilized CT26 cells to establish a xenograft tumor model, employing transcriptomics, genomics, and metabolomics techniques to investigate the impact of ginsenoside Rh4 on CPT-11-induced gastrointestinal mucositis and the effect on the anti-tumor activity of CPT-11. Furthermore, we explored the pivotal role of gut microbiota and their metabolites through fecal microbiota transplantation (FMT) experiments and supplementation of the key differential metabolite, hyodeoxycholic acid (HDCA). RESULTS: The results showed that ginsenoside Rh4 repaired the impairment of intestinal barrier function and restored intestinal mucosal homeostasis in a gut microbiota-dependent manner. Ginsenoside Rh4 treatment modulated gut microbiota diversity and upregulated the abundance of beneficial bacteria, especially Lactobacillus_reuteri and Akkermansia_muciniphila, which further regulated bile acid biosynthesis, significantly promoted the production of the beneficial secondary bile acid hyodeoxycholic acid (HDCA), thereby alleviating CPT-11-induced gut microbiota dysbiosis. Subsequently, ginsenoside Rh4 further alleviated gastrointestinal mucositis through the TGR5-TLR4-NF-κB signaling pathway. On the other hand, ginsenoside Rh4 combination therapy could further reduce the weight and volume of colon tumors, promote tumor cell apoptosis, and enhance the anti-tumor activity of CPT-11 by inhibiting the PI3K-Akt signaling pathway, thus exerting a synergistic anti-tumor effect. CONCLUSION: In summary, our findings confirm that ginsenoside Rh4 can alleviate CPT-11-induced gastrointestinal mucositis and enhance the anti-tumor activity of CPT-11 by modulating gut microbiota and its related metabolites. Our study validates the potential of ginsenoside Rh4 as a modulator of the gut microbiota and an adjunctive agent for chemotherapy, offering new therapeutic strategies for addressing chemotherapy side effects and improving chemotherapy efficacy.

Mulberry Leaf Compounds and Gut Microbiota in Alzheimer's Disease and Diabetes: A Study Using Network Pharmacology, Molecular Dynamics Simulation, and Cellular Assays.

Recently, studies have reported a correlation that individuals with diabetes show an increased risk of developing Alzheimer's disease (AD). Mulberry leaves, serving as both a traditional medicinal herb and a food source, exhibit significant hypoglycemic and antioxidative properties. The flavonoid compounds in mulberry leaf offer therapeutic effects for relieving diabetic symptoms and providing neuroprotection. However, the mechanisms of this effect have not been fully elucidated. This investigation aimed to investigate the combined effects of specific mulberry leaf flavonoids (kaempferol, quercetin, rhamnocitrin, tetramethoxyluteolin, and norartocarpetin) on both type 2 diabetes mellitus (T2DM) and AD. Additionally, the role of the gut microbiota in these two diseases' treatment was studied. Using network pharmacology, we investigated the potential mechanisms of flavonoids in mulberry leaves, combined with gut microbiota, in combating AD and T2DM. In addition, we identified protein tyrosine phosphatase 1B (PTP1B) as a key target for kaempferol in these two diseases. Molecular docking and molecular dynamics simulations showed that kaempferol has the potential to inhibit PTP1B for indirect treatment of AD, which was proven by measuring the IC50 of kaempferol (279.23 µM). The cell experiment also confirmed the dose-dependent effect of kaempferol on the phosphorylation of total cellular protein in HepG2 cells. This research supports the concept of food-medicine homology and broadens the range of medical treatments for diabetes and AD, highlighting the prospect of integrating traditional herbal remedies with modern medical research.

Zhilong Huoxue Tongyu Capsule regulates the macrophage polarization and inflammatory response via the let-7i/TLR9/MyD88 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhilong Huoxue Tongyu Capsule (ZL) is clinically prescribed for acute ischemic stroke (AIS). However, only a few studies have addressed the mechanisms of ZL in treating AIS. AIM OF THE STUDY: To explore the underlying mechanism of macrophage polarization and inflammation mediated by ZL, and to provide a reference for AIS treatment. MATERIALS AND METHODS: Sixteen SD rats were fed with different dose of ZL (0, 0.4, 0.8, and 1.6 g/kg/d) for 4 days to prepare ZL serum. After 500 ng/mL lipopolysaccharide (LPS) stimulation, RAW264.7 cells were administrated with ZL serum. Then, experiments including ELISA, flow cytometry, real-time quantitative PCR and Western blot were performed to verify the effects of ZL on macrophage polarization and inflammation. Next, let-7i inhibitor was transfected in RAW264.7 cells when treated with LPS and ZL serum to verify the regulation of ZL on the let-7i/TLR9/MyD88 signaling pathway. Moreover, the interaction between let-7i and TLR9 was confirmed by the dual-luciferase assay. RESULTS: ZL serum significantly decreased the expression of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), and increased the expression of IL-10 and transforming growth factor ß1 (TGF-ß1) of LPS stimulated-macrophages. Furthermore, ZL serum polarized macrophages toward M2, decreased the expressions of TLR9, MyD88, and iNOS, as well as increased the expressions of let-7i, CHIL3, and Arginase-1. It is worth mentioning that the effect of ZL serum is dose-dependent. However, let-7i inhibitor restored all the above effects in LPS stimulated-macrophages. In addition, TLR9 was the target of let-7i. CONCLUSIONS: ZL targeted let-7i to inhibit TLR9 expression, thereby inhibiting the activation of the TLR9/MyD88 pathway, promoting the M2 polarization, and inhibiting the development of inflammation in AIS.

Phosphoproteomics Revealed Differentially Expressed Sites and Function of the Bovine Milk Fat Globule Membrane in Colostrum and Mature Milk.

One type of large and intricate post-translational modification of milk proteins that has significant biological implications is phosphorylation. The characterization of phosphoproteins found in the bovine milk fat globule membrane (MFGM) is still mostly unknown. Here, label-free phosphoproteomics was used to identify 94 phosphorylation sites from 54 MFGM phosphoproteins in bovine colostrum (BC) and 136 phosphorylation sites from 91 MFGM phosphoproteins in bovine mature milk (BM). αs1-Casein and ß-casein were the most phosphorylated proteins in bovine colostrum. In bovine mature milk, perilipin-2 was the protein with the greatest number of phosphorylation sites. The results show that bovine colostrum MFGM phosphoproteins were mainly involved in immune function, whereas bovine mature MFGM phosphoproteins were mainly involved in metabolic function. Plasminogen and osteopontin were the most strongly interacting proteins in colostrum, whereas perilipin-2 was the most strongly interacting protein in bovine mature milk. This work demonstrates the unique alterations in the phosphorylation manner of the bovine MFGM protein during lactation and further expands our knowledge of the site characteristics of bovine MFGM phosphoproteins. This result confirms the value of MFGM as a reference ingredient for infant formula during different stages.

NIR-Triggered Multifunctional NO Nanoplatform for Conquering Thermal Resistance in Biofilms.

Photothermal treatment (PTT) has emerged as a promising avenue for biofilm elimination, yet its potential drawbacks, such as local hyperpyrexia and bacterial heat resistance, have posed challenges. To address these concerns, an innovative nanoplatform (Au@mSiO2 -arg/ICG) is devised that integrates phototherapeutic and gas therapeutic functionalities. This multifaceted nanoplatform is composed of mesoporous silica-coated Au nanorods (Au@mSiO2 ), supplemented with l-arginine (l-arg) and indocyanine green (ICG), and is engineered for mild temperature PTT aimed at biofilm eradication. Au@mSiO2 -arg/ICG nanoparticles (NPs) show excellent antibacterial effects through the generation of nitric oxide (NO) gas, heat, and reactive oxygen species (ROS) under 808 nm light irradiation. The ROS generated by ICG initiates a cascade reaction with l-arg, ultimately yielding NO gas molecules. This localized release of NO not only effectively curbs the expression of heat shock proteins 70 mitigating bacterial thermoresistance, but also reduces extracellular polymeric substance allowing better penetration of the therapeutic agents. Furthermore, this nanoplatform achieves an outstanding biofilm elimination rate of over 99% in an abscess model under 808 nm light irradiation (0.8 W·cm-2 ), thereby establishing its potential as a dependable strategy for NO-enhanced mild PTT and antibacterial photodynamic therapy (aPDT) in clinical settings.

Multifunctional gelatin nanoparticle stabilized-Pickering emulsion hydrogel based on dextran and amikacin with controlled drug release and enhanced antibacterial capability for promoting infected wound healing.

Plant essential oils possess broad-spectral antimicrobial property, but the applications are impeded by their insolubility in water, extreme volatility, and strong irritation. Nanoparticle-stabilized emulsion (Pickering emulsion) gels are colloidal systems with ability to accommodate two immiscible phases in one system. The thick adsorption nanoparticle layers and the cross-linked networks in continuous phase could provide protective barriers for antibacterial oil and achieve on-demand controlled release. An emulsion hydrogel templated from gelatin nanoparticle-stabilized emulsion is one-pot constructed by conducting a tunable cross-linking process between oxidized dextran (Odex) and amikacin in the continuous phase and concomitantly trapping tea tree essential oil (TO) droplets in the three-dimensional network. The resulted emulsion hydrogel presents tunable gelation time, adequate mechanical strength, fascinating injectability, and self-healing capability. It is pH-responsiveness and presents controlled release of amikacin and TO, exhibiting a long-term bacteriostasis of 144 h. The emulsion hydrogel facilitates the outstanding wound healing efficiency in 14 days (95.2 ± 0.8 % of wound closure), accompanied with enhanced collagen deposition and angiogenic activities. The incorporation of TO into emulsion hydrogel system reduced its irritation and improved its biosafety, showing potential application in bacteria inhibition even as implants in vivo.

Supramolecular prodrug-like nanotheranostics with dynamic and activatable nature for synergistic photothermal immunotherapy of metastatic cancer.

Synergistic photothermal immunotherapy has attracted widespread attention due to the mutually reinforcing therapeutic effects on primary and metastatic tumors. However, the lack of clinical approval nanomedicines for spatial, temporal, and dosage control of drug co-administration underscores the challenges facing this field. Here, a photothermal agent (Cy7-TCF) and an immune checkpoint blocker (NLG919) are conjugated via disulfide bond to construct a tumor-specific small molecule prodrug (Cy7-TCF-SS-NLG), which self-assembles into prodrug-like nano-assemblies (PNAs) that are self-delivering and self-formulating. In tumor cells, over-produced GSH cleaves disulfide bonds to release Cy7-TCF-OH, which re-assembles into nanoparticles to enhance photothermal conversion while generate reactive oxygen species (ROSs) upon laser irradiation, and then binds to endogenous albumin to activate near-infrared fluorescence, enabling multimodal imaging-guided phototherapy for primary tumor ablation and subsequent release of tumor-associated antigens (TAAs). These TAAs, in combination with the co-released NLG919, effectively activated effector T cells and suppressed Tregs, thereby boosting antitumor immunity to prevent tumor metastasis. This work provides a simple yet effective strategy that integrates the supramolecular dynamics and reversibility with stimuli-responsive covalent bonding to design a simple small molecule with synergistic multimodal imaging-guided phototherapy and immunotherapy cascades for cancer treatment with high clinical value.

Biocompatible Ferrofluid-Based Millirobot for Tumor Photothermal Therapy in Near-Infrared-II Window.

Ferrofluidic robots with excellent deformability and controllability have been intensively studied recently. However, most of these studies are in vitro and the use of ferrofluids for in vivo medicinal applications remains a big challenge. The application of ferrofluidic robots to the body requires the solution of many key problems. In this study, biocompatibility, controllability, and tumor-killing efficacy are considered when creating a ferrofluid-based millirobot for in vivo tumor-targeted therapy. For biocompatibility problems, corn oil is used specifically for the ferrofluid robot. In addition, a control system is built that enables a 3D magnetic drive to be implemented in complex biological media. Using the photothermal conversion property of 1064 nm, the ferrofluid robot can kill tumor cells in vitro; inhibit tumor volume, destroy the tumor interstitium, increase tumor cell apoptosis, and inhibit tumor cell proliferation in vivo. This study provides a reference for ferrofluid-based millirobots to achieve targeted therapies in vivo.

Angong Niuhuang Wan inhibit ferroptosis on ischemic and hemorrhagic stroke by activating PPARγ/AKT/GPX4 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Angong Niuhuang Wan (AGNHW) is a prescription from traditional Chinese medicine (TCM) that has been used for centuries to treat ischemic stroke (IS) and hemorrhagic stroke (HS). According to a recent study, targeting ferroptosis might be effective in the management of IS and HS. However, the ferroptosis-related effects and mechanisms of AGNHW have not yet been reported. AIM OF THE STUDY: This research examines the anti-ferroptosis mechanisms of AGNHW in the treatment of IS and HS. MATERIALS AND METHODS: A system pharmacological approach including in vivo experiment, UHPLC-Q-Orbitrap HRMS, network pharmacology, molecular docking, microscale thermophoresis, and in vitro experiment was utilized to study the anti-ferroptosis mechanisms of AGNHW against IS and HS. RESULTS: In vivo experiments indicated that AGNHW enhanced nerve function, decreased cerebral infarct volume, ameliorated histological brain injuries, improved the structural integrity of the blood-brain barrier, ameliorated the mitochondrial dysfunction and morphology disruption, and inhibits ROS, LPO and Fe2+ accumulations in IS and HS rats. Using UHPLC-Q-Orbitrap HRMS, the key ingredients of AGNHW-containing serum were identified as bilirubin, berberine, baicalin, and wogonoside. According to the network pharmacology analyses, AGNHW could inhibit ferroptosis by modulating the PPAR and PI3K/AKT signaling pathways. The core targets are PPARγ, AKT, and GPX4. Molecular docking and microscale thermophoresis experiments further revealed that the key ingredients have strong interactions with ferroptosis-regulating core proteins. Moreover, in vitro experiment results showed that AGNHW alleviated ferroptosis injury induced by erastin in PC12 cells, increased cell viability, reduced the LPO and Fe2+ levels, and up-regulated mRNA expressions of PPARγ, AKT, and GPX4. AGNHW also up-regulated protein expressions of PPARγ, p-AKT/AKT, and GPX4 in IS and HS rats. CONCLUSIONS: AGNHW attenuated ferroptosis in treating IS and HS by targeting the PPARγ/AKT/GPX4 pathway. This work reveals AGNHW's anti-ferroptosis mechanism against IS and HS, but it also develops an integrated approach to demonstrate the common characteristics of drugs in treating different diseases.

Pediatric tuina for recurrent respiratory tract infection in children: A systematic review and meta-analysis.

BACKGROUND: To evaluate the effects and safety of pediatric tuina for recurrent respiratory tract infections (RRTIs). METHODS: Web of Science, PubMed, Cochrane Library, Embase, CNKI, Wanfang Data, VIP, and CBM databases were searched from inception to September 20 2023. Two authors independently selected studies, collected data, and evaluated methodological quality using the Cochrane Risk of Bias tool. Revman 5.4 was used for the meta-analysis. RESULTS: Fifteen randomized controlled trials involving 1420 pediatric patients were included in this meta-analysis. The meta-analysis indicated that pediatric tuina significantly reduced the incidence of RRTIs [MD -1.11, 95% confidence interval (CI) (-1.77, -0.46)], decreased infection duration (MD -1.16 days, 95% CI [- 1.66, - 0.66]), improved IgA (MD 0.25 g/L, 95% CI [0.09, 0.41]), IgG (MD 1.64 g/L; 95% CI [0.82, 2.45]), CD3+ (MD 3.33%, 95% CI [0.74, 5.92]), CD4+ (MD 4.78%, 95% CI [2.08, 7.48]), CD4+/CD8+ ratio (MD 0.27%, 95% CI [0.08, 0.47]), and total effective rate (RR 1.19, 95% CI [1.13, 1.25]). However, IgM levels (MD 0.26 g/L, 95% CI [-0.26, 0.81]) and CD8+ (MD -1.36%, 95% CI [- 3.12, 0.41]) were not significantly different between the groups. Moreover, no Tuina-linked adverse reactions were observed. CONCLUSION: Pediatric tuina has shown positive effects in RRTIs treatment. However, these results should be interpreted with caution owing to study quality. Further large-scale and high-quality randomized controlled trials are warranted to confirm these findings.

[Systematic review and Meta-analysis of efficacy and safety of Kushen Gelatum combined with antibiotics in treatment of bacterial vaginosis].

This study aims to systematically evaluate the clinical efficacy and safety of Kushen Gelatum combined with antibiotics for treating bacterial vaginosis. The randomized controlled trial(RCT) of Kushen Gelatum for treating bacterial vaginosis were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, and Cochrane Library with the time interval from inception to January 2023. Data were extracted from the included RCT by 2 investigators, including the sample size, characteristics of patients, interventions and controls, outcome indicators, and adverse effects. The Cochrane collaboration network's bias risk assessment tool was used for methodolo-gical quality evaluation of the included trials. RevMan 5.4 was employed to perform the Meta-analysis. A total of 19 RCTs were inclu-ded, involving 1 980 patients with bacterial vaginosis. Meta-analysis showed that, compared with nitroimidazoles alone, Kushen Gelatum + nitroimidazoles improved the total response rates in terms of clinical symptoms and laboratory tests(RR=1.24, 95%CI[1.13, 1.36], P<0.000 01), laboratory tests(RR=1.16, 95%CI[1.06, 1.26], P=0.000 9), and clinical symptoms(RR=1.26, 95%CI[1.08, 1.46], P=0.003), and reduced the leukocyte esterase positive rate(RR=0.29, 95%CI[0.17, 0.48], P<0.000 01) and the recurrence rate(RR=0.37, 95%CI[0.23, 0.58], P<0.000 1). Compared with lincomycin antibiotics(clindamycin) alone, Kushen Gelatum + lincomycin antibiotics(clindamycin) improved the total response rates in terms of clinical symptoms and laboratory tests(RR=1.18, 95%CI[1.06, 1.31], P=0.003) and laboratory tests(RR=1.27, 95%CI[1.04, 1.54], P=0.02), reduced the recurrence rate(RR=0.20, 95%CI[0.05, 0.75], P=0.02), and shortened the time to relief of burning sensation(MD=-1.70, 95%CI[-2.15,-1.26], P<0.000 01), vaginal itching(MD=-0.82, 95%CI[-1.30,-0.34], P=0.000 8), and abnormal leucorrhea(MD=-1.52, 95%CI[-1.98,-1.06], P<0.000 01). Compared with nitroimidazoles + probiotics, Kushen Gelatum + nitroimidazoles + probiotics improved the total response rate in terms of clinical symptoms and laboratory tests(RR=1.18, 95%CI[1.02, 1.36], P=0.03) and reduced the recurrence rate(RR=0.27, 95%CI[0.09, 0.76], P=0.01). Kushen Gelatum combined with antibiotics demonstrates a potential therapeutic effect on bacterial vaginosis, whereas the number and quality of the relevant clinical studies remain to be improved. The process of clinical trial should be standardized to improve the quality of evidence, so as to provide strong evidence to guide the application of Kushen Gelatum in clinical practice.

Unraveling the serial glycosylation in the biosynthesis of steroidal saponins in the medicinal plant Paris polyphylla and their antifungal action.

Sugar-sugar glycosyltransferases play important roles in constructing complex and bioactive saponins. Here, we characterized a series of UDP-glycosyltransferases responsible for biosynthesizing the branched sugar chain of bioactive steroidal saponins from a widely known medicinal plant Paris polyphylla var. yunnanensis. Among them, a 2'-O-rhamnosyltransferase and three 6'-O-glucosyltrasferases catalyzed a cascade of glycosylation to produce steroidal diglycosides and triglycosides, respectively. These UDP-glycosyltransferases showed astonishing substrate promiscuity, resulting in the generation of a panel of 24 terpenoid glycosides including 15 previously undescribed compounds. A mutant library containing 44 variants was constructed based on the identification of critical residues by molecular docking simulations and protein model alignments, and a mutant UGT91AH1Y187A with increased catalytic efficiency was obtained. The steroidal saponins exhibited remarkable antifungal activity against four widespread strains of human pathogenic fungi attributed to ergosterol-dependent damage of fungal cell membranes, and 2'-O-rhamnosylation appeared to correlate with strong antifungal effects. The findings elucidated the biosynthetic machinery for their production of steroidal saponins and revealed their potential as new antifungal agents.

Protective effect of carbon dots derived from scrambled Coptidis Rhizoma against ulcerative colitis in mice.

Introduction: Ulcerative colitis (UC) is a chronic and progressive inflammatory disease of the intestines. The primary symptoms, such as bloody diarrhea, can result in weight loss and significantly diminish the patient's quality of life. Despite considerable research endeavors, this disease remains incurable. The scrambled Coptidis Rhizoma (SCR) has a rich historical background in traditional Chinese medicine as a remedy for UC. Drawing from a wealth of substantial clinical practices, this study is focused on investigating the protective effects and underlying mechanisms of the active component of SCR, namely SCR-based carbon dots (SCR-CDs), in the treatment of UC. Methods: SCR-CDs were extracted and isolated from the decoction of SCR, followed by a comprehensive characterization of their morphological structure and functional groups. Subsequently, we investigated the effects of SCR-CDs on parameters such as colonic length, disease activity index, and histopathological architecture using the dextran sulfate sodium (DSS)-induced colitis mice model. Furthermore, we delved into the assessment of key aspects, including the expression of intestinal tight junction (TJ) proteins, inflammatory cytokines, oxidative stress markers, and gut microbial composition, to unravel the intricate mechanisms underpinning their therapeutic effects. Results: SCR-CDs displayed a consistent spherical morphology, featuring uniform dispersion and diameters ranging from 1.2 to 2.8 nm. These SCR-CDs also exhibited a diverse array of surface chemical functional groups. Importantly, the administration of SCR-CDs, particularly at higher dosage levels, exerted a noteworthy preventive influence on colonic shortening, elevation of the disease activity index and colonic tissue impairment caused by DSS. These observed effects may be closely associated with the hygroscopic capability and hemostatic bioactivity inherent to SCR-CDs. Concurrently, the application of SCR-CDs manifested an augmenting impact on the expression of intestinal TJ proteins, concomitantly leading to a significant reduction in inflammatory cell infiltration and amelioration of oxidative stress. Additionally, SCR-CDs treatment facilitated the restoration of perturbed gut microbial composition, potentially serving as a fundamental mechanism underlying their observed protective effects. Conclusion: This study demonstrates the significant therapeutic potential of SCR-CDs in UC and provides elucidation on some of their mechanisms. Furthermore, these findings hold paramount importance in guiding innovative drug discovery for anti-UC agents.

Vitamin B12 supplementation improves cognitive function in middle aged and elderly patients with cognitive impairment.

Introduction: Objectives: to determine the effects of vitamin B12 supplementation on neuropsychological function and disease progression in middle aged and elderly patients with cognitive impairment. Methods: this was a prospective case-control study. From May 2020 to May 2021, 307 participants clinically diagnosed with cognitive impairment in the Department of Neurology of the First Affiliated Hospital of Chongqing Medical University were enrolled. A total of 115 patients were included in this study. Meanwhile, 115 participants with cognitive impairment were randomly assigned in equal proportions to two groups: vitamin B12 treatment group (n = 58, vitamin B12 500 mg/d intramuscularly for seven days, followed by cobamamide 0.25 mg/d and methylcobalamin 0.50 mg/d) and the control group (n = 57). Demographic characteristics and blood biochemical variables were obtained from all participants. Cognitive performance was measured using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Cognitive performance was measured at baseline and after six months. Results: the vitamin B12 supplementation treatment patients who presented with cognitive impairment showed significant improvement, especially in attention, calculation (p < 0.01) and visual-constructional ability (p < 0.05), in their neuropsychological function compared to their matched group. Conclusion: vitamin B12 supplementation may improve frontal function in patients with cognitive decline. Vitamin B12 levels should be investigated in all patients with cognitive impairment.

Introducción: Objetivos: determinar los efectos de la suplementación con vitamina B12 en la función neuropsicológica y la progresión de la enfermedad en pacientes de mediana edad y adultos mayores con deterioro cognitivo. Métodos: se realizó un estudio prospectivo de casos y controles; se estudiaron 307 participantes, desde mayo de 2020 a mayo de 2021, diagnosticados clínicamente con deterioro cognitivo en el Departamento de Neurología, el Primer Hospital Anexado a la Universidad Médica de Chongqing. En el estudio se incluyeron un total de 115 pacientes con deterioro cognitivo que fueron asignados aleatoriamente en proporciones iguales a dos grupos: un grupo de tratamiento con vitamina B12 (n = 58, vitamina B12 500 mg/d intramuscular durante 7 días, seguido de cobamamida 0,25 mg/d y metilcobalamina 0,50 mg/d) y un grupo de control (n = 57). Se obtuvieron las características demográficas y las variables bioquímicas sanguíneas de todos los participantes. El rendimiento cognitivo se midió mediante el miniexamen del estado mental (MMSE) y la evaluación cognitiva de Montreal (Moca) al inicio del estudio y a los 6 meses. Resultados: los pacientes con deterioro cognitivo que recibieron tratamiento de suplementación con vitamina B12 mostraron una mejora significativa, especialmente en la atención, el cálculo (p < 0,01) y la capacidad visuoespacial (p < 0,05), en su función neuropsicológica en comparación con el grupo control. Conclusión: la suplementación con vitamina B12 puede mejorar la función frontal en pacientes con deterioro cognitivo. Los pacientes con deterioro cognitivo deben conocer sus propios niveles de vitamina B12.

[Chemical constituents from Paris rugosa rhizomes and their antimicrobial activities].

Paris rugosa(Melanthiaceae) only grows in Yunnan province of China at present, and its chemical constituents have not been systematically studied. In this study, nine compounds, including one new compound pariposide G(1) and eight known compounds of cerin(2), stigmast-4-en-3-one(3), ß-ecdysone(4), ophiopogonin C'(5), methyl protogracillin(6), gracillin(7), parissaponin H(8), and parisyunnanoside G(9), were isolated and identified from the ethanol extract of P. rugosa rhizomes by column chromatography methods and semi-preparative high-performance liquid chromatography(HPLC). Compounds 1-9 were isolated from this plant for the first time. The antibacterial and antifungal activities of all the compounds were evaluated. The results showed that ophiopogonin C' had strong inhibitory effects on Candida albicans [MIC_(90)=(4.68±0.01) µmol·L~(-1)] and the fluconazole-resistant strain of C. albicans [MIC_(90)=(4.66±0.02) µmol·L~(-1)].

Alterations in the phytochemical composition and antioxidant activity of Ligustrum robustum according to continuous wet- and dry-heat treatment.

Small-leaved Kuding tea (SLKDT) obtained from Ligustrum robustum is a traditional tea substitute in southern China and has a range of physiological effects. However, the changes in its phytochemical composition after various heat treatments are not reported yet. Thus, the phytochemical composition and antioxidant activities of fresh leaves of SLKDT (LrF1) and SLKDT after high-temperature wet-heat treatment (LrF2) and wet- and dry-heat treatments (LrF3) were assessed using liquid chromatography-mass spectrometry, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities and lipid peroxidation inhibition activity of LrF1 and LrF3 were investigated. The results indicated that the phytochemical composition of LrF1, LrF2, and LrF3 was significantly different. Overall, 258 and 83 differential constituents, respectively, were obtained in LrF1 versus LrF2 and LrF2 versus LrF3. The differential constituents mainly included amino acids and their derivatives, nucleosides, flavonoids, terpenoids, simple phenylpropanoids, and coumarins. After heat treatment, SLKDT exhibited obvious changes in sensory characteristics and physiological properties, which may be related to the changes in the levels of amino acids, linalool, beta-geraniol, myricetin, naringin, fraxetin, and isoacteoside. Moreover, the antioxidant activities significantly changed after heat treatment of SLKDT. Overall, our study demonstrated that heat treatment can alter the phytochemical composition of SLKDT, thus affecting its sensory properties and physiological properties. PRACTICAL APPLICATION: This study preliminarily assessed the changes in the composition of small-leaved Kuding tea (SLKDT) after various heat treatments and revealed that the composition of SLKDT tea can be adjusted by various heat and temperature treatments.

[CiteSpace knowledge map analysis of Angong Niuhuang Pills in recent twenty years].

Angong Niuhuang Pills, a classical formula in traditional Chinese medicine, are lauded as one of the "three treasures of febrile diseases" and have been widely used in the treatment of diverse disorders with definite efficacy. However, there is still a lack of bibliometric analysis of research progress and development trend regarding Angong Niuhuang Pills. Research articles on Angong Niuhuang Pills in China and abroad(2000-2022) were retrieved from CNKI and Web of Science. CiteSpace 6.1 was used to visualize the key contents of the research articles. In addition, the research status of Angong Niuhuang Pills was analyzed by information extraction to allow insight into the research trends and hotspots about Angong Niuhuang Pills. A total of 460 Chinese articles and 41 English articles were included. Beijing University of Chinese Medicine and Sun Yat-Sen University were the research institutions that have published the largest amount of research articles in Chinese and English. The keyword analysis showed that the Chinese articles focused on cerebral hemorrhage, stroke, neurological function, coma, cerebral infarction, craniocerebral injury, and clinical application, while the English articles focused on the mechanisms of cerebral ischemia, stroke, heavy metal, blood-brain barrier, and oxidative stress. Stroke, blood-brain barrier, and oxidative stress were presumably the research hotspots in the future. At present, the research on Angong Niuhuang Pills is still in the developing stage. It is necessary to highlight the in-depth research on the active components and mechanism of action and carry out large-scale randomized controlled clinical trials to provide references for the further development and application of Angong Niuhuang Pills.

Proteomic investigation and biomarker identification of lung and spleen deficiency syndrome in HIV/AIDS immunological nonresponders.

Background: Human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) immunological nonresponders (HIV/AIDS-INRs) whose CD4+ cell counts do not rebound after highly active antiretroviral therapy (HAART) treatment usually experience severely impaired immune function and high mortality. Traditional Chinese medicine (TCM) has many advantages in the field of AIDS, especially its promotion of patients' immune reconstitution. Accurate differentiation of TCM syndromes is a prerequisite for guiding an effective TCM prescription. However, the objective and biological evidence for identification of the TCM syndromes in HIV/AIDS-INRs remains lacking. Lung and spleen deficiency (LSD) syndrome, a typical HIV/AIDS-INR syndrome, was examined on in this study. Methods: We first performed a proteomic study of LSD syndrome in INRs (INRs-LSD) using tandem mass tag combined with liquid chromatography-tandem mass spectrometry (TMT-LC-MS/MS) and screened them against the healthy and undocumented identifiable groups. The TCM syndrome-specific proteins were subsequently validated based on bioinformatics analysis and enzyme-linked immunosorbent assay (ELISA). Results: A total of 22 differentially expressed proteins (DEPs) were screened in INRs-LSD compared to the healthy group. Based on bioinformatic analysis, these DEPs were found to be mainly associated with the immunoglobin A (IgA)-generated intestinal immune network. In addition, we examined the TCM syndrome-specific proteins alpha-2-macroglobulin (A2M) and human selectin L (SELL) with ELISA and found that they were both upregulated, which was consistent with the proteomic screening results. Conclusions: A2M and SELL were finally identified as potential biomarkers for INRs-LSD, providing a scientific and biological basis for identifying typical TCM syndromes in HIV/AIDS-INRs and an opportunity to build a more effective TCM treatment system for HIV/AIDS-INRs.

Melatonin blunts the tumor-promoting effect of cancer-associated fibroblasts by reducing IL-8 expression and reversing epithelial-mesenchymal transition.

BACKGROUND: Most studies on melatonin have focused on tumor cells but have ignored the tumor microenvironment (TME), especially one of its important components, the cancer-associated fibroblasts (CAFs). Therefore, we attempted to explore the role of melatonin in TME. METHODS: We investigated the regulatory role of melatonin in the tumor-promoting effect of CAFs and its underlying mechanism by using cell and animal models. RESULTS: CAFs promoted tumor progression, but melatonin weakened the tumor-promoting effect of CAFs. Compared with tumor cells, IL-8 was mainly expressed in CAFs. CAFs-overexpressing IL-8 induced the epithelial-mesenchymal transition (EMT) of tumor cells, and a positive crosstalk was observed between CAFs and tumor cells undergoing EMT, thereby further promoting the IL-8 expression. Melatonin suppressed this crosstalk by inhibiting the NF-κB pathway, thereby impeding the IL-8 expression from CAFs. Importantly, melatonin reversed CAFs-derived IL-8-mediated EMT by inhibiting the AKT pathway. Melatonin was found to directly and indirectly inhibit tumor progression. CONCLUSION: Our research reveals the potential action mechanism of melatonin in regulating the CAF-tumor cell interaction and suggests the potential of melatonin as an adjuvant of tumor therapy.

Formula Milk Supplementation and Bone Acquisition in 4-6 Years Chinese Children: A 12-Month Cluster-Randomized Controlled Trial.

Dairy foods are crucial for adequate calcium intake in young children, but scarce data are available on the effects of formula milk on bone acquisition. This cluster-randomized controlled trial investigated the effects of the supplementation of formula milk on bone health in rural children accustomed to a low-calcium diet between September 2021 and September 2022. We recruited 196 healthy children aged 4-6 years from two kindergartens in Huining County, Northwest China. A class-based randomization was used to assign them to receive 60 g of formula milk powder containing 720 mg calcium and 4.5 µg vitamin D or 20-30 g of bread per day for 12 months, respectively. Bone mineral density (BMD) and bone mineral content (BMC) at the left forearm and calcaneus, bone biomarkers, bone-related hormones/growth factors, and body measures were determined at baseline, 6, and 12 months. A total of 174 children completed the trial and were included in the analysis. Compared with the control group, formula milk intervention showed significant extra increments in BMD (3.77% and 6.66%) and BMC (4.55% and 5.76%) at the left forearm at 6th and 12th months post-intervention (all p < 0.001), respectively. Similar trends were observed in BMD (2.83%) and BMC (2.38%) in the left calcaneus at 6 months (p < 0.05). The milk intervention (vs. control) also showed significant changes in the serum concentrations of osteocalcin level (-7.59%, p = 0.012), 25-hydroxy-vitamin-D (+5.54%, p = 0.001), parathyroid hormone concentration (-15.22%, p = 0.003), and insulin-like growth factor 1 (+8.36%, p = 0.014). The percentage increases in height were 0.34%, 0.45%, and 0.42% higher in the milk group than in the control group after 3-, 6-, and 9-month intervention, respectively (p < 0.05). In summary, formula milk supplementation enhances bone acquisition at the left forearm in young Chinese children.