Preparation of etoposide liposomes for enhancing antitumor efficacy on small cell lung cancer and reducing hematotoxicity of drugs.

Etoposide (VP16) is commonly used in the treatment of small cell lung cancer (SCLC) in clinical practice. However, severe adverse reactions such as bone marrow suppression toxicity limit its clinical application. Although several studies on VP16 liposomes were reported, no significant improvement in bone marrow suppression toxicity has been found, and there was a lack of validation of animal models for in vivo antitumor effects. Therefore, we attempted to develop a PEGylated liposomal formulation that effectively encapsulated VP16 (VP16-LPs) and evaluated its therapeutic effect and toxicity at the cellular level and in animal models. First, we optimized the preparation process of VP16-LPs using an orthogonal experimental design and further prepared them into freeze-dried powder to improve storage stability of the product. Results showed that VP16-LPs freeze-dried powder exhibited good dispersibility and stability after redispersion. In addition, compared to marketed VP16 injection, VP16-LPs exhibited sustained drug release characteristics. At the cellular level, VP16-LPs enhanced the cellular uptake of drugs and exhibited strong cytotoxic activity. In animal models, VP16-LPs could target and aggregate in tumors and exhibit a higher anti-tumor effect than VP16-injection after intravenous injection. Most importantly, hematological analysis results showed that VP16-LPs significantly alleviated the bone marrow suppression toxicity of drug. In summary, our study confirmed that PEGylated liposomes could enhance therapeutic efficacy and reduce toxicity of VP16, which demonstrated that VP16-LPs had enormous clinical application potential.

Pharmacokinetics, safety, and tolerability of the novel tetrameric gadolinium-based MRI contrast agent gadoquatrane in healthy Chinese and Japanese men: Two randomized dose-escalation studies including concentration-QTc modeling.

PURPOSE: To investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). PARTICIPANTS AND METHODS: In two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01-0.1 mmol gadolinium/kg body weight) or placebo. Study procedures included blood sampling and collection of urine for pharmacokinetic analyses and safety assessments. RESULTS: Twenty-five healthy Japanese men (mean age ± standard deviation: 26±5.9 years) and 23 healthy Chinese men (31±7.6 years old) were evaluated. In both studies, the pharmacokinetic profile of gadoquatrane was characterized by rapid distribution of the drug into the extracellular space and fast renal elimination. Postdose gadolinium concentrations rapidly declined with a geometric mean effective half-life of 1.3-1.4 h. The exposure increased approximately dose-proportionally with dose. The body weight-normalized volume of distribution was constant across dose levels (0.21-0.24 L/kg). Total recovery of gadolinium in urine amounted to 82-95 % (Study 1) and 96-99 % (Study 2) of the dose administered. Only a few mild, transient adverse events were reported, none of which gave rise to any safety concerns. Exploratory drug concentration-QTc modeling indicated no risk of a clinically relevant QT/QTc prolongation at the anticipated diagnostic dose. CONCLUSION: Gadoquatrane was safe and well tolerated at all doses tested. The pharmacokinetic profile was essentially the same as that of other extracellular macrocyclic gadolinium-based contrast agents and was consequentially also similar for Japanese and Chinese participants.

Targeting inflammation as cancer therapy.

Inflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies.

Pharmacokinetics, Pharmacodynamics, and Safety of Evocalcet (KHK7580), a Novel Calcimimetic Agent: An Open-Label, Single- and Multiple-Dose, Phase I Trial in Healthy Chinese Subjects.

Purpose: This study explored the pharmacokinetics (PK), pharmacodynamics (PD), and safety of evocalcet (KHK7580), a new calcimimetic agent, in healthy Chinese subjects following single and multiple doses. Methods: This was a single-center, open-label phase I trial conducted in China. The study started from the single-dose cohorts (1, 3, 6, 12 mg evocalcet, step-by-step administration) and proceeded to the multiple-dose cohort (6 mg evocalcet once daily for eight days). Blood and urine samples were collected at the designated time points for pharmacokinetic and pharmacodynamic analysis. Safety was evaluated by treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, electrocardiograms (ECGs), and ophthalmological examination. Results: Among 42 enrolled subjects, eight in each single-dose cohort and 10 in multiple-dose cohort, 40 subjects completed the study. In single-dose cohorts, tmax was 1.00-2.00 h and declined biphasically. The mean t1/2 was 15.99-20.84 h. Evocalcet exposure in AUC0-inf, AUC0-t, and Cmax showed a dose-proportional increase. In the multiple-dose cohort, tmax was 2.00 h and declined biphasically after multiple administrations. The accumulation was negligible. Ctrough levels were similar across days and steady from 24 hours after the first administration. The mean t1/2 was 15.59 h. PD analysis showed that evocalcet decreased intact parathyroid hormone and corrected calcium levels in a dose-dependent manner. Seventeen (40.5%) subjects reported TEAEs. No serious or severe TEAE occurred. Conclusion: In healthy Chinese subjects, evocalcet demonstrated dose-dependent PK and PD properties and was well-tolerated.

Adenosine Triphosphate/Chitin Whisker/Phenylboronic Acid-Modified Wool Fabrics with Enhanced Dyeability.

Promoting the uptake of dyes is an important part of the sustainable processing of wool products. This study presents an effective modification approach to enhance the dyeability of wool fabric with adenosine triphosphate as an activator, 3-carboxyphenyl boronic acid as a ligand-binding agent, and chitin whisker as a couple agent. The structure and surface morphology of the as-prepared wool fabric was characterized in detail. Natural luteolin and acid red 1 were used to dye the modified wool fabric, and the effect of different dyeing parameters on dyeing properties was discussed. The results indicated that the modified wool gained better surface color depth (K/S) and uptake without additional agents than the untreated wool fabric. When the modified wool fabric was dyed at 45 °C with luteolin and at 60 °C with acid red 1, the dyeing processes of the two dyes on the modified wool fabrics followed the Langmuir isotherm and the pseudo-second-order kinetic model. Furthermore, the dyed modified wool fabrics possessed improved color fastness. Overall, this work offers a facile, effective, and sustainable way to improve the low-temperature dyeability of wool products.

A comparison study on polysaccharides extracted from banana flower using different methods: Physicochemical characterization, and antioxidant and antihyperglycemic activities.

This work investigated and compared the physicochemical characteristics, and antioxidant and antihyperglycemic properties in vitro of polysaccharides from a single banana flower variety (BFPs) extracted by different methods. BFPs extracted using hot water (HWE), acidic (CAE), alkaline (AAE), enzymatic (EAE), ultrasonic (UAE) and hot water-alkaline (HAE) methods showed different chemical composition, monosaccharide composition, molecular weight, chain conformation and surface morphology, but similar infrared spectra characteristic, main glycosidic residues, crystalline internal and thermal stability, suggesting that six methods have diverse impacts on the degradation of BFPs without changing the main structure. Then, among six BFPs, the stronger antioxidant activity in vitro was found in BFP extracted by HAE, which was attributed to its maximum uronic acid content (21.67 %) and phenolic content (0.73 %), and moderate molecular weight (158.48 kDa). The highest arabinose and guluronic acid contents (18.59 % and 1.31 % in molar ratios, respectively) and the lowest uronic acid content (14.30 %) in BFP extracted by HWE contributed to its better α-glucosidase inhibitory activity in vitro (66.55 %). The data offered theoretical evidence for choosing suitable extraction methods to acquire BFPs with targeted biological activities for applications, in which HAE and HWE could serve as beneficial methods for preparing antioxidant BFP and antihyperglycemic BFP, respectively.

Tanreqing injection inhibits dengue virus encephalitis by suppressing the activation of NLRP3 inflammasome.

BACKGROUND: Encephalitis caused by dengue virus (DENV) is considered a manifestation of severe dengue. Tanreqing injection (TRQ) is a well-known Chinese patented medicine, which has been used to treat brain-related disorders by inhibiting inflammation. Nevertheless, the effects of TRQ on DENV encephalitis have not been studied. The aim of this study was to evaluate the effects of TRQ on DENV encephalitis and to explore its potential mechanisms. METHODS: The cytotoxicity of TRQ was examined by MTT assay, and the anti-DENV activities of TRQ in BHK-21 baby hamster kidney fibroblast were evaluated through CCK-8 and plaque assays. The expression levels of NO, IL1B/IL-1ß, TNFα and IL6 were measured by qRT‒PCR and ELISA in the BV2 murine microglial cell line. The inhibitory effects of TRQ on NLRP3 inflammasome activation in BV2 cells were examined by Western blotting, qRT‒PCR and ELISA. The effects of TRQ on HT22 mouse hippocampal neuronal cells were examined by CCK-8 assay, morphology observation and flow cytometry. Moreover, a DENV-infected ICR suckling mouse model was developed to investigate the protective role of TRQ in vivo. RESULTS: TRQ decreased the release of NO, IL6, TNFα and IL1B from BV2 cells and inhibited the activation of NLRP3. The presence of the NLRP3 agonist nigericin reversed the anti-inflammatory activities of TRQ. Furthermore, TRQ inhibited the death of HT22 cells by decreasing IL1B in DENV-infected BV2 cells. In addition, TRQ significantly attenuated weight loss, reduced clinical scores and extended the survival in DENV-infected ICR suckling mice. Critically, TRQ ameliorated pathological changes in ICR suckling mice brain by inhibiting microglia and NLRP3 activation and decreasing the production of inflammatory factors and the number of dead neurons. CONCLUSION: TRQ exerts potent inhibitory effects on dengue encephalitis in vitro and in vivo by reducing DENV-2-induced microglial activation and subsequently decreasing the inflammatory response, thereby protecting neurons. These findings demonstrate the potential of TRQ in the treatment of dengue encephalitis.

Solute-particle separation in microfluidics enhanced by symmetrical convection.

The utilization of microfluidic technology for miniaturized and efficient particle sorting holds significant importance in fields such as biology, chemistry, and healthcare. Passive separation methods, achieved by modifying the geometric shapes of microchannels, enable gentle and straightforward enrichment and separation of particles. Building upon previous discussions regarding the effects of column arrays on fluid flow and particle separation within microchips, we introduced a column array structure into an H-shaped microfluidic chip. It was observed that this structure enhanced mass transfer between two fluids while simultaneously intercepting particles within one fluid, satisfying the requirements for particle interception. This enhancement was primarily achieved by transforming the originally single-mode diffusion-based mass transfer into dual-mode diffusion-convection mass transfer. By further optimizing the column array, it was possible to meet the basic requirements of mass transfer and particle interception with fewer microcolumns, thereby reducing device pressure drop and facilitating the realization of parallel and high-throughput microfluidic devices. These findings have enhanced the potential application of microfluidic systems in clinical and chemical engineering domains.

Structural and functional investigation on stem and peel polysaccharides from different varieties of pitaya.

Varieties of plant species may affect the composition and structures of the polysaccharides, thus have an impact on their chemical properties and biological activities. Herein, the present study comparatively evaluated the differences in the chemical composition, morphological structures, antioxidant activity, and anti-inflammatory activity of the stem and peel polysaccharides from different varieties of pitaya. The FT-IR and NMR spectra indicated that the six polysaccharides had similar structural features, whereas the physicochemical characterization showed that they differed significantly in terms of the monosaccharide composition, molecular weight, and surface morphology. In addition, different varieties of pitaya polysaccharides exhibited different antioxidant activities and similar anti-inflammatory activities. These data suggested that varietal differences resulted in pitaya stem and peel polysaccharides with different monosaccharide compositions and molecular weights, thus led to different antioxidant activities and protection against oxidative damage, while similar structural features were closely related to their similar anti-inflammatory activities. Therefore, the study of the stem and peel polysaccharides from different varieties of pitaya can help us to better understand the relationship between their composition and structure and their biological activities. In addition, pitaya stem and peel polysaccharides have the potential to act as antioxidants or to treat inflammatory damage.

Enhancement of the Physical and Functional Properties of Chitosan Films by Incorporating Galla chinensis Extract.

Composite films based on chitosan (CS) incorporating Galla chinensis extract (GCNE) at different CS/GCNE weight ratios, which are both biodegradable and multifunctional, were fabricated using the solution-casting method. The FTIR analyses indicated that a good interaction was presented among the GCNE and CS through an intermolecular hydrogen bond. The incorporation of the GCNE improved the films' elongation at break, UV-light blocking, and decreased the moisture regain (from 16.68% to 10.69%) and water absorption (from 80.65% to 54.74%). Moreover, the CS/GCNE films exhibited a strong antioxidant activity (from 57.11% to 70.37% of DPPH and from 35.53% to 46.73% of ABTS scavenging activities) mainly due to the high content of phenolic compounds in the incorporated GCNE. The CS/GCNE film-forming solution coatings demonstrated their effectiveness in preserving the quality of postharvest mangoes, specifically by minimizing the change in the firmness, weight loss, titratable acidity, and total phenolic and ascorbic acids. These findings suggest that the multifunctional composite films possess a high application potential to preserve postharvest fruits.

Inhibiting mtDNA-STING-NLRP3/IL-1ß axis-mediated neutrophil infiltration protects neurons in Alzheimer's disease.

Neutrophil is a pathophysiological character in Alzheimer's disease. The pathogen for neutrophil activation in cerebral tissue is the accumulated amyloid protein. In our present study, neutrophils infiltrate into the cerebra in two models (transgenic model APP/PS1 and stereotactic injection model) and promote neuron apoptosis, releasing their cellular constituents, including mitochondria and mitochondrial DNA (mtDNA). We found that both Aß1-42 and mtDNA could provoke neutrophil infiltration into the cerebra, and they had synergistic effects when they presented together. This neutrophillic neuroinflammation upregulates expressions of STING, NLRP3 and IL-1ß. These inflammatory cytokines with mtDNA constitute the mtDNA-STING-NLRP3/IL-1ß axis, which is the prerequisite for neutrophil infiltration. When any factor in this pathway is depleted, the migration of neutrophils into cerebral tissue is ceased, with neurons and cognitive function being protected. Thus, we provide a novel perspective to alleviate the progression of Alzheimer's disease.

Strategies for the development and approval of COVID-19 vaccines and therapeutics in the post-pandemic period.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant casualties and put immense strain on public health systems worldwide, leading to economic recession and social unrest. In response, various prevention and control strategies have been implemented globally, including vaccine and drug development and the promotion of preventive measures. Implementing these strategies has effectively curbed the transmission of the virus, reduced infection rates, and gradually restored normal social and economic activities. However, the mutations of SARS-CoV-2 have led to inevitable infections and reinfections, and the number of deaths continues to rise. Therefore, there is still a need to improve existing prevention and control strategies, mainly focusing on developing novel vaccines and drugs, expediting medical authorization processes, and keeping epidemic surveillance. These measures are crucial to combat the Coronavirus disease (COVID-19) pandemic and achieve sustained, long-term prevention, management, and disease control. Here, we summarized the characteristics of existing COVID-19 vaccines and drugs and suggested potential future directions for their development. Furthermore, we discussed the COVID-19-related policies implemented over the past years and presented some strategies for the future.

Can AMH levels predict the need to step up FSH dose for controlled ovarian stimulation following a long GnRH agonist protocol in PCOS women?

BACKGROUND: To explore the role of anti-Mullerian hormone (AMH) in predicting the need to step up recombinant FSH (rFSH) dose following long GnRH agonist protocol in IVF/ICSI cycles of polycystic ovarian syndrome (PCOS) women. METHODS: This is a retrospective cohort study of 825 PCOS women undergoing long GnRH agonist protocol enrolled from Jan 2019 to Dec 2021. The daily rFSH dose at which the first response to rFSH were recorded. The dose at which the first response to rFSH was based on folliculometry during follow up in which two or more follicles reached ≥ 11 mm. A receiver operating characteristic (ROC) curve analysis was done to investigate the ability of AMH to predict the need to step up initial rFSH dose. RESULTS: PCOS women who needed to step up initial rFSH dose had a significantly higher AMH compared with those didn't step up initial rFSH dose (11.37 ± 3.25ng/ml vs. 8.69 ± 3.16ng/ml, p < 0.001). In multivariate logistic regression analysis, increased AMH level was an independent factor for the need to step up initial rFSH dose in PCOS patients after adjusted for confounding factors. ROC curve analysis showed AMH could predict the need to step up initial rFSH dose (AUC = 0.738, 95%CI: 0.704-0.773), having 75.4% specificity and 63% sensitivity when the threshold AMH concentration was 9.30ng/ml. 58.8% PCOS women with AMH > 9.30 ng/ml required increased rFSH dose compared to 18.8% of women with AMH ≤ 9.30ng/ml (p < 0.001). Although the clinical pregnancy rate and live birth rate were not significantly different, there was a higher incidence of OHSS among women with AMH > 9.30 ng/ml vs. AMH ≤ 9.30ng/ml (20.8% vs. 15.3%, p = 0.043). CONCLUSION: PCOS women with AMH > 9.30 ng/ml were resistant to rFSH stimulation and require increased dose for the cycle recruitment of ovarian follicles.

LncRNA IGFBP4-1 promotes tumor development by activating Janus kinase-signal transducer and activator of transcription pathway in bladder urothelial carcinoma: retraction.

[This retracts the article DOI: 10.7150/ijbs.46986.].

Molecular simulations required to target novel and potent inhibitors of cancer invasion.

INTRODUCTION: Computer-aided drug design (CADD) is a computational approach used to discover, develop, and analyze drugs and active molecules with similar biochemical properties. Molecular simulation technology has significantly accelerated drug research and reduced manufacturing costs. It is an optimized drug discovery method that greatly improves the efficiency of novel drug development processes. AREASCOVERED: This review discusses the development of molecular simulations of effective cancer inhibitors and traces the main outcomes of in silico studies by introducing representative categories of six important anticancer targets. The authors provide views on this topic from the perspective of both medicinal chemistry and artificial intelligence, indicating the major challenges and predicting trends. EXPERT OPINION: The goal of introducing CADD into cancer treatment is to realize a highly efficient, accurate, and desired approach with a high success rate for identifying potent drug candidates. However, the major challenge is the lack of a sophisticated data-filtering mechanism to verify bottom data from mixed-quality references. Consequently, despite the continuous development of algorithms, computer power, and interface optimization, specific data filtering mechanisms will become an urgent and crucial issue in the future.

Combined ICP-OES and XPS analysis to evaluate the [AlO4]0 concentration in quartz: limiting the formation temperature of quartz.

A proposed quartz thermometer is based on the concentration of [AlO4]0 tetrahedra determined by combining inductively coupled plasma optical emission spectrometry (ICP-OES) with X-ray photoelectron spectroscopy (XPS) data. The concentration of [AlO4]0 tetrahedra in the quartz lattice (C[AlO4]0/ppm) and the formation temperatures of quartz (TQ/°C) from agate, gold deposits, and granodiorite are calculated by C[AlO4]0 = CAl total (ppm) × k and TQ (°C) = 3.6 × CAl total (ppm) × k + 33.0, respectively. Where CAl total is the total Al concentration of quartz measured by ICP-OES and k is the relative percentage of [AlO4]0 tetrahedra in the quartz lattice and can be obtained by fitting the Al(2p) XPS spectrum. The obtained formation temperatures of quartz (TQ) agree well with the equilibrium formation temperature (TE) calculated by oxygen isotope data. By comparing the relative positions of the two temperature curves of quartz (TQ and TE), the composition of the mineral-forming fluid can be inferred. The proposed quartz thermometer can be applied to quartz formed under equilibrium conditions and in Al-saturated environments over a wide temperature range (152-566 °C). The use of the quartz thermometer effectively eliminates interference from different fluid compositions and satisfies the requirements of convenience and economy.

JMJD6 in tumor-associated macrophage regulates macrophage polarization and cancer progression via STAT3/IL-10 axis.

The tumor-associated macrophage (TAM) is the most abundant group of immune cells in the tumor microenvironment (TME), which plays a critical role in the regulation of tumor progression and treatment resistance. Based on different polarization status, TAMs may also induce antitumor immune responses or immunosuppression. The present study identified JMJD6 (Jumonji domain-containing 6) as a novel modulator of TAM activation, the upregulation of which was associated with the immunosuppressive activities of TAMs. JMJD6 deficiency attenuated the growth of both Lewis lung carcinoma (LLC) tumors and B16F10 melanomas by reversing M2-like activation of macrophages, and sensitized tumors to immune checkpoint blockades (ICBs). Moreover, the JMJD6-induced inhibition of M2 polarization was potentially mediated by the STAT3/IL-10 signaling. These findings highlight the regulatory activities of JMJD6 in TAM polarization, and the therapeutic potential of JMJD6/STAT3/IL-10 axis blockades to enhance the efficacy of ICBs in cancer treatment.

Vaccine adjuvants: mechanisms and platforms.

Adjuvants are indispensable components of vaccines. Despite being widely used in vaccines, their action mechanisms are not yet clear. With a greater understanding of the mechanisms by which the innate immune response controls the antigen-specific response, the adjuvants' action mechanisms are beginning to be elucidated. Adjuvants can be categorized as immunostimulants and delivery systems. Immunostimulants are danger signal molecules that lead to the maturation and activation of antigen-presenting cells (APCs) by targeting Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) to promote the production of antigen signals and co-stimulatory signals, which in turn enhance the adaptive immune responses. On the other hand, delivery systems are carrier materials that facilitate antigen presentation by prolonging the bioavailability of the loaded antigens, as well as targeting antigens to lymph nodes or APCs. The adjuvants' action mechanisms are systematically summarized at the beginning of this review. This is followed by an introduction of the mechanisms, properties, and progress of classical vaccine adjuvants. Furthermore, since some of the adjuvants under investigation exhibit greater immune activation potency than classical adjuvants, which could compensate for the deficiencies of classical adjuvants, a summary of the adjuvant platforms under investigation is subsequently presented. Notably, we highlight the different action mechanisms and immunological properties of these adjuvant platforms, which will provide a wide range of options for the rational design of different vaccines. On this basis, this review points out the development prospects of vaccine adjuvants and the problems that should be paid attention to in the future.