Positive Synergy between the Helical Poly(phenylacetylene) Backbones and the Helical L-Proline Oligopeptide Pendants for Enhanced Enantioseparation Properties.

A series of optically active helical poly(phenylacetylene)s (PPA-Pro1, PPA-Pro3, PPA-Pro6, PPA-Pro9, and PPA-Pro12) bearing different chain lengths of L-proline oligopeptide in the side chains were obtained by polymerizing the corresponding novel phenylacetylene monomers. The monomer adopted a trans-rich helix structure when the L-proline oligopeptide chain length was longer, according to the optical activities and 2D-NMR analysis. The helical structure could be maintained and significantly influenced the polymers' helical conformation by introducing the L-proline oligopeptide to the pendants. By the way, the morphology of PPA-Pro3 was observed by atomic force microscope (AFM) on highly oriented pyrolytic graphite (HOPG), and the information on the helix direction, pitch, and chain arrangement was obtained. Also, the chiral separation properties of these polymer-based chiral stationary phases (CSPs) were investigated using high-performance liquid chromatography (HPLC). The poly(phenylacetylene)s showed enhanced enantioseparation properties toward various racemates depending on the longer chain length of the L-proline oligopeptide in the pendants and the positive synergy between the helical backbone and helical side chains. Particularly, PPA-Pro9 showed comparable or even superior enantioseparation properties for racemates 2 and 9 to four commercial columns (Daicel Chiralpak or Chiralcel AD, AS, OD, and OT), indicating that these poly(phenylacetylene)-based CSPs have potential practical values. This work presented here provides inspiration for the further development of CSPs based on a new paradigm.

Synthesis of the Ag2S/PANI@PES Composite Membrane and Its Antipollution Properties.

Membrane separation technology offers a sustainable and efficient solution to wastewater management; however, membrane fouling significantly impedes its application. Photocatalytic membranes, integrating photocatalytic and membrane separation technologies, enhance membrane separation efficacy while effectively mitigating organic and biological contaminations. In this work, Ag2S/PANI@PES composite membranes were prepared via a facile in situ polymerization and successive layer adsorption technique. The modified poly(ether sulfone) (PES) membrane demonstrated improved hydrophilicity and separation performance, and its heterostructure between polyaniline (PANI), Ag0, and Ag2S effectively addressed organic fouling issues. Moreover, Ag2S/PANI@PES exhibited outstanding antimicrobial properties, as well as chemical and mechanical stability.

Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

Display of porcine epidemic diarrhea virus spike protein B-cell linear epitope on Lactobacillus mucosae G01 S-layer surface induce a robust immunogenicity in mice.

The Porcine epidemic diarrhea virus (PEDV) presents a substantial risk to the domestic pig industry, resulting in extensive and fatal viral diarrhea among piglets. Recognizing the mucosal stimulation triggered by PEDV and harnessing the regulatory impact of lactobacilli on intestinal function, we have developed a lactobacillus-based vaccine that is carefully designed to elicit a strong mucosal immune response. Through bioinformatics analysis, we examined PEDV S proteins to identify B-cell linear epitopes that meet the criteria of being non-toxic, soluble, antigenic, and capable of neutralizing the virus. In this study, a genetically modified strain of Lactobacillus mucosae G01 (L.mucosae G01) was created by utilizing the S layer protein (SLP) as a scaffold for surface presentation. Chimeric immunodominant epitopes with neutralizing activity were incorporated at various sites on SLP. The successful expression of SLP chimeric immunodominant epitope 1 on the surface of L.mucosae G01 was confirmed through indirect immunofluorescence and transmission electron microscopy, revealing the formation of a transparent membrane. The findings demonstrate that the oral administration of L.mucosae G01, which expresses the SLP chimeric immunodominant gene epitope1, induces the production of secreted IgA in the intestine and feces of mice. Additionally, there is an elevation in IgG levels in the serum. Moreover, the levels of cytokines IL-2, IL-4, IFN-γ, and IL-17 are significantly increased compared to the negative control group. These results suggest that L. mucosae G01 has the ability to deliver exogenous antigens and elicit a specific mucosal immune response against PEDV. This investigation presents new possibilities for immunoprophylaxis against PEDV-induced diarrhea.

Magnetic-guided nanocarriers for ionizing/non-ionizing radiation synergistic treatment against triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with the worst prognosis. Radiotherapy (RT) is one of the core modalities for the disease; however, the ionizing radiation of RT has severe side effects. The consistent development direction of RT is to achieve better therapeutic effect with lower radiation dose. Studies have demonstrated that synergistic effects can be achieved by combining RT with non-ionizing radiation therapies such as light and magnetic therapy, thereby achieving the goal of dose reduction and efficacy enhancement. METHODS: In this study, we applied FeCo NPs with magneto thermal function and phototherapeutic agent IR-780 to construct an ionizing and non-ionizing radiation synergistic nanoparticle (INS NPs). INS NPs are first subjected to morphology, size, colloidal stability, loading capacity, and photothermal conversion tests. Subsequently, the cell inhibitory and cellular internalization were evaluated using cell lines in vitro. Following comprehensive assessment of the NPs' in vivo biocompatibility, tumor-bearing mouse model was established to evaluate their distribution, targeted delivery, and anti-tumor effects in vivo. RESULTS: INS NPs have a saturation magnetization exceeding 72 emu/g, a hydrodynamic particle size of approximately 40 nm, a negatively charged surface, and good colloidal stability and encapsulation properties. INS NPs maintain the spectral characteristics of IR-780 at 808 nm. Under laser irradiation, the maximum temperature was 92 °C, INS NPs also achieved the effective heat temperature in vivo. Both in vivo and in vitro tests have proven that INS NPs have good biocompatibility. INS NPs remained effective for more than a week after one injection in vivo, and can also be guided and accumulated in tumors through permanent magnets. Later, the results exhibited that under low-dose RT and laser irradiation, the combined intervention group showed significant synergetic effects, and the ROS production rate was much higher than that of the RT and phototherapy-treated groups. In the mice model, 60% of the tumors were completely eradicated. CONCLUSIONS: INS NPs effectively overcome many shortcomings of RT for TNBC and provide experimental basis for the development of novel clinical treatment methods for TNBC.

FTO-mediated m 6A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis.

The activation of hepatic stellate cells (HSCs) is central to the occurrence and development of liver fibrosis. Our previous studies showed that autophagy promotes HSC activation and ultimately accelerates liver fibrosis. Unc-51-like autophagy activating kinase 1 (ULK1) is an autophagic initiator in mammals, and N 6-methyladenosine (m 6A) modification is closely related to autophagy. In this study, we find that the m 6A demethylase fat mass and obesity-associated protein (FTO), which is the m 6A methylase with the most significant difference in expression, is upregulated during HSC activation and bile duct ligation (BDL)-induced hepatic fibrosis. Importantly, we identify that FTO overexpression aggravates HSC activation and hepatic fibrosis via autophagy. Mechanistically, compared with other autophagy-related genes, ULK1 is a target of FTO because FTO mainly mediates the m 6A demethylation of ULK1 and upregulates its expression, thereby enhancing autophagy and the activation of HSCs. Notably, the m 6A reader YTH domain-containing protein 2 (YTHDC2) decreases ULK1 mRNA level by recognizing the m 6A binding site and ultimately inhibiting autophagy and HSC activation. Taken together, our findings highlight m 6A-dependent ULK1 as an essential regulator of HSC autophagy and reveal that ULK1 is a novel potential therapeutic target for hepatic fibrosis treatment.

Synergistic Ionic Liquid in Hole Transport Layers for Highly Stable and Efficient Perovskite Solar Cells.

Perovskite solar cells (PSCs) with n-i-p structures often utilize an organic 2,2',7,7'-tetrakis (N, N-di-p-methoxyphenyl-amine) 9,9'-spirobifluorene (spiro-OMeTAD) along with additives of lithium bis(trifluoromethanesulfonyl)imide salt (LiTFSI) and tert-butylpyridine as the hole transporting layer (HTL). However, the HTL lacks stability in ambient air, and numerous defects are often present on the perovskite surface, which is not conducive to a stable and efficient PSC. Therefore, constructive strategies that simultaneously stabilize spiro-OMeTAD and passivate the perovskite surface are required. In this work, it is demonstrated that a novel ionic liquid of dimethylammonium bis(trifluoromethanesulfonyl)imide (DMATFSI) could act as a bifunctional HTL modulator in n-i-p PSCs. The addition of DMATFSI into spiro-OMeTAD can effectively stabilize the oxidized spiro-OMeTAD+ cation radicals through the formation of spiro-OMeTAD+ TFSI- because of the excellent charge delocalization of the conjugated CF3 SO2 - moiety within TFSI- . In addition, DMA+ cations could move toward the perovskite from the HTL, resulting in the passivation of defects at the perovskite surface. Accordingly, a power conversion efficiency of 23.22% is achieved for PSCs with DMATFSI and LiTFSI co-doped spiro-OMeTAD. Moreover, benefiting from the improved ion migration barrier and hydrophobicity of the HTL, still retained nearly 80% of their initial power conversion efficiency after 36 days of exposure to ambient air.

Hybridization of helical poly(phenylacetylene)s bearing L-proline tripeptide pendants into porous silica microspheres as a solvent-tolerable chiral stationary phase for liquid chromatography.

A novel one-handed helical copoly(phenylacetylene) (CPA) bearing L-proline tripeptide pendants and a few triethoxysilyl residues was synthesized and hybridized into SiO2 porous microspheres (PMSs) during microsphere growth through the hydrolytic polycondensation of ethoxysilyl groups. Nuclear magnetic resonance and Fourier transform infrared spectroscopy results verified the successful preparation of CPA and its hybrid product using SiO2 PMSs. The chiral recognition ability of the resulting CPA with a hybridized-type chiral stationary phase (HCSP) for high-performance liquid chromatography (HPLC) was investigated, revealing its high recognition ability for selected racemates. Moreover, the HCSP showed good solvent tolerability, thus broadening the selection of suitable eluents. The separation effect of the HCSP for the racemate N,N-diphenylcyclohexane-1,2-dicarboxamide (7) improved significantly after introducing CHCl3 in the eluent, resulting in separation factors equivalent or superior to common commercially available polysaccharide-based chiral stationary phases. The proposed preparation strategy provides a new and valuable method for obtaining poly(phenylacetylene)-based HCSPs suitable for a wide range of applications and eluent conditions.

Efficient removal of uranium (VI) from water by a hyper-cross-linked polymer adsorbent modified with polyethylenimine via phosphoramidate linkers.

Practical adsorbents with high efficiency are essential to effectively treating wastewater. Herein, a novel porous uranium adsorbent (PA-HCP) having a considerable amount of amine and phosphoryl groups was designed and synthesized by grafting polyethyleneimine (PEI) on a hyper-cross-linked fluorene-9-bisphenol skeleton via phosphoramidate linkers. Furthermore, it was used to treat uranium contamination in the environment. PA-HCP exhibited a large specific surface area (up to 124 m2/g) and a pore diameter of 2.5 nm. Batch uranium adsorptions on PA-HCP were investigated methodically. PA-HCP demonstrated a uranium sorption capacity of >300 mg/g in the pH range of 4-10 (C0 = 60 mg/L, T = 298.15 K), with its maximum capacity reaching 573.51 mg/g at pH = 7. The uranium sorption process obeyed the pseudo-second-order model and fitted well with the Langmuir isothermal. In the thermodynamic experiments, uranium sorption on PA-HCP was revealed to be an endothermic, spontaneous process. Even in the presence of competing metal ions, PA-HCP exhibited excellent sorption selectivity for uranium. Additionally, excellent recyclability can be achieved after six cycles. Based on FT-IR and XPS measurements, both the PO and -NH2 (and/or -NH-) groups on PA-HCP contributed to efficient uranium adsorption as a result of the strong coordination between these groups and uranium. Furthermore, the high hydrophilicity of the grafted PEI improved the dispersion of the adsorbents in water and facilitated uranium sorption. These findings suggest that PA-HCP can be used as an efficient and economical sorbent to remove U(VI) from wastewater.

A novel linear displacement isothermal amplification with strand displacement probes (LDIA-SD) in a pocket-size device for point-of-care testing of infectious diseases.

Nucleic acid amplification is crucial for disease diagnosis, especially lethal infectious diseases such as COVID-19. Compared with PCR, isothermal amplification methods are advantageous for point-of-care testing (POCT). However, complicated primer design limits their application in detecting some short targets or sequences with abnormal GC content. Herein, we developed a novel linear displacement isothermal amplification (LDIA) method using two pairs of conventional primers and Bacillus stearothermophilus (Bst) DNA polymerase, and reactions could be accelerated by adding an extra primer. Pseudorabies virus gE (high GC content) and Salmonella fimW (low GC content) genes were used to evaluate the LDIA assay. Using strand displacement (SD) probes, a LDIA-SD method was developed to realize probe-based specific detection. Additionally, we incorporated a nucleic acid-free extraction step and a pocket-sized device to realize POCT applications of the LDIA-SD method. The LDIA-SD method has advantages including facile primer design, high sensitivity and specificity, and applicability for POCT, especially for amplification of complex sequences and detection of infectious diseases.

Occurrence of Powdery Mildew Caused by Erysiphe astragali on Astragalus scaberrimus in Inner Mongolia, China.

Astragalus scaberrimus Bunge, a perennial herb, is widely distributed in North and central China, Russia, and Mongolia (POWO, 2023). Due to its tolerance to drought, cold, high salt, low nutrients and alkaline soil, this plant is widely cultivated in China as a forage crop, for water and soil conservation, and for its medicinal properties (Meng, 2015). In 2022, powdery mildew-like signs and symptoms were seen on leaves of A. scaberrimuns cultivated on the campus of Inner Mongolia Agricultural University, Hohhot, Inner Mongolia China. White powder-like masses covered up to 99% of the leaf area with infected plants showing weak growth and senescence. More than 70% of plants (n = 180) exhibited these powdery mildew-infected symptoms. Conidiophores were 70-120 µm long (n = 20) and composed of a basal foot cell, followed by two cells and a conidium. Cylindrical- or ovoid-shaped conidia were 30-45µm long by 9-15 µm wide (n = 20). Brown or light-brown chasmothecia were 100-140 µm in diameter, with flexuous appendages. Based on these morphological characteristics, the fungus was tentatively identified as an Erysiphe sp. (Braun and Cook, 2012; Schmidt and Braun, 2020). Fungal structures were isolated from diseased leaves and genomic DNA of the pathogen was extracted utilizing the method described by Zhu et al. (2022). The internal transcribed spacer (ITS) region was amplified by PCR employing the primers PMITS1/PMITS2 (Cunnington et al., 2003) and the amplicon sequenced by Invitrogen (Shanghai, China). The sequence for the powdery mildew fungus (GenBank accession no.: MW142495) showed 100% identity (645/645 bp) with Erysiphe astragali, which was reported on A. glycyphyllos in Golestan province, Iran (accession no. OP806834). Pathogenicity tests were conducted by brushing the conidia from infected A. scaberrimus leaves onto leaves of four healthy plants, while, the four control plants were brushed in the same manner. All the treated plants were placed in separate growth chambers maintained at 19℃, 65% humidity, with 16 h light/8 h dark photoperiod. Nine days post inoculation, powdery mildew disease signs appeared on inoculated plants, whereas control plants remained asymptomatic. The same results were obtained for two repeated pathogenicity experiments. The powdery mildew fungus was reisolated and identified as E. astragali based on morphological and molecular analysis, thereby fulfilling Koch's postulates. E. astragali causing powdery mildew on A. glycyphyllus were previously reported in Germany with Genbank accesion number of MZ265150 and MZ265151 (Bradshaw et al., 2022). This, to our knowledge, is the first report of powdery mildew caused by E. astragali on A. scaberrimus. The severe occurrence of this destructive powdery mildew disease on A. scaberrimus may adversely affect the utility of the plant for soil conservation or cultivation for medicinal purposes. Identifying the causal agent of powdery mildew will support efforts for the future control and management of diseases on A. scaberrimus.

Ellagic Acid from Hull Blackberries: Extraction, Purification, and Potential Anticancer Activity.

Ellagic acid (EA) is present at relatively high concentrations in many berries and has many beneficial health effects, including anticancer properties. To improve the development and utilization of blackberry fruit nutrients, we divided Hull blackberry fruits into five growth periods according to color and determined the EA content in the fruits in each period. The EA content in the green fruit stage was the highest at 5.67 mg/g FW. Single-factor tests and response surface methodology were used to optimize the extraction process, while macroporous resin adsorption and alkali dissolution, acid precipitation, and solvent recrystallization were used for purification. The highest purity of the final EA powder was 90%. The anticancer assessment results determined by MTT assay showed that EA inhibited HeLa cells with an IC50 of 35 µg/mL, and the apoptosis rate of the cells increased in a dose-dependent manner, with the highest rate of about 67%. We evaluated the changes in the mRNA levels of genes related to the EA-mediated inhibition of cancer cell growth and initially verified the PI3K/PTEN/AKT/mTOR pathway as the pathway by which EA inhibits HeLa cell growth. We hope to provide a theoretical basis for the deep exploration and utilization of this functional food.

Transcriptomic and Metabolomic Profiling Reveals the Variations in Carbohydrate Metabolism between Two Blueberry Cultivars.

Blueberry is a high-quality fruit tree with significant nutritional and economic value, but the intricate mechanism of sugar accumulation in its fruit remains unclear. In this study, the ripe fruits of blueberry cultivars 'Anna' and 'Misty' were utilized as experimental materials, and physiological and multi-omics methodologies were applied to analyze the regulatory mechanisms of the difference in sugar content between them. The results demonstrated that the 'Anna' fruit was smaller and had less hardness than the 'Misty' fruit, as well as higher sugar content, antioxidant capability, and lower active substance content. A total of 7067 differentially expressed genes (DEGs) (3674 up-regulated and 3393 down-regulated) and 140 differentially abundant metabolites (DAMs) (82 up-regulated and 58 down-regulated) were identified between the fruits of the two cultivars. According to KEGG analysis, DEGs were primarily abundant in phenylpropanoid synthesis and hormone signal transduction pathways, whereas DAMs were primarily enriched in ascorbate and aldarate metabolism, phenylpropanoid biosynthesis, and the pentose phosphate pathway. A combined multi-omics study showed that 116 DEGs and 3 DAMs in starch and sucrose metabolism (48 DEGs and 1 DAM), glycolysis and gluconeogenesis (54 DEGs and 1 DAM), and the pentose phosphate pathway (14 DEGs and 1 DAM) were significantly enriched. These findings suggest that blueberries predominantly increase sugar accumulation by activating carbon metabolism network pathways. Moreover, we identified critical transcription factors linked to the sugar response. This study presents new understandings regarding the molecular mechanisms underlying blueberry sugar accumulation and will be helpful in improving blueberry fruit quality through breeding.

[Research progress on chemical constituents and pharmacological activities of Viola plants].

There are 500 species of Viola(Violaceae) worldwide, among which 111 species are widely distributed in China and have a long medicinal history and wide varieties. According to the authors' statistics, a total of 410 compounds have been isolated and identified from plants of this genus, including flavonoids, terpenoids, phenylpropanoids, organic acids, nitrogenous compounds, sterols, saccharides and their derivatives, volatile oils and cyclotides. The medicinal materials from these plants boast anti-microbial, anti-viral, anti-oxidant and anti-tumor activities. This study systematically reviewed the chemical constituents and pharmacological activities of Viola plants to provide a basis for further research and clinical application.

[Prediction of quality markers and medicinal value of sea buckthorn leaves based on network pharmacology, content determination, and activity evaluation].

The leaves of sea buckthorn(Hippophae rhamnoides), considered as common food raw materials, have records of medicinal use and diverse pharmacological activities, showing a potential medicinal value. However, the active substances in the sea buckthorn leaves and their mechanisms of action remain unclear. In addition, due to the extensive source and large variety variations, the quality evaluation criteria of sea buckthorn leaves remain to be developed. To solve the problems, this study predicted the main active components, core targets, key pathways, and potential pharmacological effects of sea buckthorn leaves by network pharmacology and molecular docking. Furthermore, ultra-performance liquid chromatography with diode-array detection(UPLC-DAD) was employed to determine the content of active components and establish the chemical fingerprint, on the basis of which the quality markers of sea buckthorn leaves were predicted and then verified by the enzyme activity inhibition method. The results indicated that sea buckthorn leaves had potential therapeutic effects on a variety of digestive tract diseases, metabolic diseases, tumors, and autoimmune diseases, which were consistent with the ancient records and the results of modern pharmacological studies. The core targets of sea buckthorn leaves included PTPN11, AKT1, PIK3R1, ESR1, and SRC, which were mainly involved in the PI3K-AKT, MAPK, and HIF-1 signaling pathways. In conclusion, the active components of sea buckthorn leaves are associated with the rich flavonoids and tannins, among which quercitrin, narcissoside, and ellagic acid can be used as the quality markers of sea buckthorn leaves. The findings provide a reference for the quality control and further development and utilization of sea buckthorn leaves as medicinal materials.

Topical astilbin ameliorates imiquimod-induced psoriasis-like skin lesions in SKH-1 mice via suppression dendritic cell-Th17 inflammation axis.

Astilbin, an essential component of Rhizoma smilacis glabrae, exerts significant antioxidant and anti-inflammatory effects against various autoimmune diseases. We have previously reported that astilbin decreases proliferation and improves differentiation of HaCaT keratinocytes in a psoriatic model. The present study was designed to evaluate the potential therapeutic effects of topical administration of astilbin on an imiquimod (IMQ)-induced psoriasis-like murine model and to reveal their underlying mechanisms. Topical administration of astilbin at a lower dose alleviated IMQ-induced psoriasis-like skin lesions by inducing the differentiation of epidermal keratinocytes in mice, and the therapeutic effect was even better than that of calcipotriol. Moreover, the inflammatory skin disorder was relieved by astilbin treatment characterized by a reduction in both IL-17-producing T cell accumulation and psoriasis-specific cytokine expression in skin lesions. Furthermore, we found that astilbin inhibited R837-induced maturation and activation of bone marrow-derived dendritic cells and decreased the expression of pro-inflammatory cytokines by downregulating myeloid differentiation factor 88. Our findings provide the convincing evidence that lower doses of astilbin might attenuate psoriasis by interfering with the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions. Our results strongly support the pre-clinical application of astilbin for psoriasis treatment.

Robust immune response stimulated by in situ injection of CpG/αOX40/cGAMP in αPD-1-resistant malignancy.

Recently, the emergence of immunotherapy has revolutionized traditional tumour treatment. However, effective treatments for patients exhibiting αPD-1 resistance are still lacking. In our study, a combination of cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODNs), anti-OX40 and cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) injection in situ systematically generated a robust antitumour immune response in TC1 and B16 cells, which are αPD-1-resistant malignancies. More precisely, this method activates both adaptive and innate immunity. Additionally, in situ vaccination with CpG/αOX40/cGAMP fully activates the production of cytokines. However, the combination of αPD-1 does not improve the efficacy of triple therapy, prompting further questions. Collectively, the combination of CpG/αOX40/cGAMP causes the regression of various αPD-1-resistant tumours through the full mobilization of innate and adaptive immunity. In addition, we explored the therapeutic effect of triple therapy on the αPD-1-sensitive cell line CT26. The results showed that triple therapy could significantly enhance the therapeutic effect of αPD-1, and some mice even achieved complete tumour regression after the combined application of αPD-1 and triple treatment.

Stimulation of endogenous pulsatile growth hormone secretion by activation of growth hormone secretagogue receptor reduces the fat accumulation and improves the insulin sensitivity in obese mice.

Obese individuals often show low growth hormone (GH) secretion, which leads to reduced lipid mobilization and further fat accumulation. Pharmacological approaches to increase GH levels in obese individuals by GH injection or GH-releasing hormone receptor agonist showed promising effects on fat reduction. However, side effects on glucose metabolism and the heavy costs on making large peptides hindered their clinical application. Here, we tested whether stimulation of endogenous GH secretion by a synthetic GH secretagogue receptor (GHSR) agonist, hexarelin, improved the metabolism in a hyperphagic obese mouse model. Male melanocortin 4 receptor knockout mice (MC4RKO) were pair-fed and received continuous hexarelin (10.56 µg/day) or vehicle infusion by an osmotic pump for 3-4 weeks. Hexarelin treatment significantly increased the pulsatile GH secretion without detectable alteration on basal GH secretion in MC4RKO mice. The treated mice showed increased lipolysis and lipid oxidation in the adipose tissue, and reduced de novo lipogenesis in the liver, leading to reduced visceral fat mass, reduced triglyceride content in liver, and unchanged circulating free fatty acid levels. Importantly, hexarelin treatment improved the whole-body insulin sensitivity but did not alter glucose tolerance, insulin levels, or insulin-like growth factor 1 (IGF-1) levels. The metabolic effects of hexarelin were likely through the direct action of GH, as indicated by the increased expression level of genes involved in GH signaling pathways in visceral adipose tissues and liver. In conclusion, hexarelin treatment stimulated the pulsatile GH secretion and reduced the fat accumulation in visceral depots and liver in obese MC4RKO mice with improved insulin sensitivity without altered levels of insulin or IGF-1. It provides evidence for managing obesity by enhancing pulsatile GH secretion through activation of GHSR in the pituitary gland.

Intraventricular colistin sulphate as a last resort therapy in a patient with multidrug-resistant Acinetobacter baumannii induced post-neurosurgical ventriculitis.

Limited therapeutic options exist for multidrug-resistant/extensively drug-resistant Acinetobacter baumannii (MDR/XDR-Ab) meningitis/ventriculitis. A combination of intravenous and intraventricular (IVT)/intrathecal (IT) polymyxins achieves good therapeutic outcomes for cases of healthcare-associated MDR/XDR-Ab meningitis/ventriculitis. Colistin is commercially available as colistin sulphate and its sulphomethylated derivative. However, the effect and safety of colistin sulphate in the treatment of MDR/XDR-Ab meningitis/ventriculitis has not been reported. We report on a 66-year-old male patient who developed post-neurosurgical ventriculitis caused by MDR-Ab. IVT concomitant intravenous colistin sulphate was used as a last-resort antimicrobial therapy, the patient's ventriculitis was dramatically improved, and the concentrations of CSF colistin were higher than the MIC breakpoint throughout the treatment. Meanwhile, no nephrotoxicity or neurotoxicity was observed during the treatment.

Trough polymyxin B plasma concentration is an independent risk factor for its nephrotoxicity.

AIMS: Data regarding clinical pharmacokinetic/toxicodynamic (PK/TD) of polymyxin B is short of direct quantitative data. This study aims to investigate the risk factors of polymyxin B associated acute kidney injury (AKI) and to assess the relationship between polymyxin B plasma levels and its nephrotoxicity. METHODS: A retrospective study was performed in adult patients treated with polymyxin B. Risk factors associated with AKI and plasma trough concentrations of polymyxin B were identified via medical record review. A multivariate logistic regression model was established and the risk of polymyxin B-associated AKI were predicted by a receiver operating characteristic curve, with maximal Youden index used to identify safety thresholds among the study population. RESULTS: Fifty-four adult patients were included in the study. AKI was detected in 14 patients during polymyxin B treatment (25.9%, 14 out of 54). Cmin (odds ratio [OR] 2.071; 95% confidence interval [CI] 1.235-3.472) and baseline serum creatinine (OR 1.024; 95% CI 1.005-1.043) were significant independent risk factors for developing AKI. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was at maximum, the optimal cut-off point was 6.678 of the ROC curve. When Cmin ≥ 3.13 mg/L, the probability of AKI was more than 50%. CONCLUSION: In this study, when the calculated combined predictor value was >6.678, there was an increased risk of AKI. Maintaining a polymyxin B Cmin level below 3.13 mg/L may be helpful in reducing the incidence of polymyxin B associated nephrotoxicity.