Perspectives on 3D printed personalized medicines for pediatrics.

In recent years, the rapid advancement of three-dimensional (3D) printing technology has yielded distinct benefits across various sectors, including pharmaceuticals. The pharmaceutical industry has particularly experienced advantages from the utilization of 3D-printed medications, which have invigorated the development of tailored drug formulations. The approval of 3D-printed drugs by the U.S. Food and Drug Administration (FDA) has significantly propelled personalized drug delivery. Additionally, 3D printing technology can accommodate the precise requirements of pediatric drug dosages and the complexities of multiple drug combinations. This review specifically concentrates on the application of 3D printing technology in pediatric preparations, encompassing a broad spectrum of uses and refined pediatric formulations. It compiles and evaluates the fundamental principles associated with the application of 3D printing technology in pediatric preparations, including its merits and demerits, and anticipates its future progression. The objective is to furnish theoretical underpinning for 3D printing technology to facilitate personalized drug delivery in pediatrics and to advocate for its implementation in clinical settings.

Berberine prevents NAFLD and HCC by modulating metabolic disorders.

Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). Berberine (BBR), a naturally occurring plant component, has been demonstrated to have advantageous effects on a number of metabolic pathways as well as the ability to kill liver tumor cells by causing cell death and other routes. This permits us to speculate and make assumptions about the value of BBR in the prevention and defense against NAFLD and HCC by a global modulation of metabolic disorders. Herein, we briefly describe the etiology of NAFLD and NAFLD-related HCC, with a particular emphasis on analyzing the potential mechanisms of BBR in the treatment of NAFLD from aspects including increasing insulin sensitivity, controlling the intestinal milieu, and controlling lipid metabolism. We also elucidate the mechanism of BBR in the treatment of HCC. More significantly, we provided a list of clinical studies for BBR in NAFLD. Taking into account our conclusions and perspectives, we can make further progress in the treatment of BBR in NAFLD and NAFLD-related HCC.

High altitude hypoxia and oxidative stress: The new hope brought by free radical scavengers.

Various strategies can be employed to prevent and manage altitude illnesses, including habituation, oxygenation, nutritional support, and medication. Nevertheless, the utilization of drugs for the prevention and treatment of hypoxia is accompanied by certain adverse effects. Consequently, the quest for medications that exhibit minimal side effects while demonstrating high efficacy remains a prominent area of research. In this context, it is noteworthy that free radical scavengers exhibit remarkable anti-hypoxia activity. These scavengers effectively eliminate excessive free radicals and mitigate the production of reactive oxygen species (ROS), thereby safeguarding the body against oxidative damage induced by plateau hypoxia. In this review, we aim to elucidate the pathogenesis of plateau diseases that are triggered by hypoxia-induced oxidative stress at high altitudes. Additionally, we present a range of free radical scavengers as potential therapeutic and preventive approaches to mitigate the occurrence of common diseases associated with hypoxia at high altitudes.

Comprehensive Investigation of the Influence of High-Altitude Hypoxia on Clopidogrel Metabolism and Gut Microbiota.

BACKGROUND: The amount of metabolites converted into active metabolites is correspondingly reduced since only more than 50% of clopidogrel is absorbed. OBJECTIVE: Exploring the effect of gut microbiota altered by altitude hypoxia on the pre-absorption metabolism of clopidogrel. METHODS: In vitro and in vivo experiments were conducted to analyze the metabolism of clopidogrel through LCMS/ MS, while 16S rRNA analysis was used to investigate the changes in the gut microbiota of high-altitude animals. RESULTS: We demonstrated that the intestinal flora is involved in the metabolism of clopidogrel through in vivo and in vitro experiments. In addition, the plateau environment caused changes in the number and composition of intestinal microbes. Intriguingly, alterations in the microbial population could lead to an increase in the pre-absorption metabolism of clopidogrel after rapid entry into the plateau, the amount of absorbed blood is thus reduced, which may affect the bioavailability and therapeutic effect of clopidogrel. CONCLUSION: Our results not only as a first clinical reference for dose adjustment of clopidogrel in high-altitude environments but also would be helpful to provide a statement on the broader significance within the field of pharmacokinetics or personalized medicine.

Pharmacokinetics, absorption and transport mechanism for ginseng polysaccharides.

BACKGROUND: Ginseng polysaccharide (GP) is one of the most abundant components in Panax ginseng. However, the absorption pathways and mechanisms of GPs have not been investigated systematically due to the challenges of their detection. METHODS: The fluorescein isothiocyanate derivative (FITC) was employed to label GP and ginseng acidic polysaccharide (GAP) to obtain target samples. HPLC-MS/MS assay was used to determine the pharmacokinetics of GP and GAP in rats. The Caco-2 cell model was used to investigate the uptake and transport mechanisms of GP and GAP in rats. RESULTS: Our results demonstrated that the absorption of GAP was more than that of GP in rats after gavage administration, while there was no significant difference between both after intravenous administration. In addition, we found that GAP and GP were more distributed in the kidney, liver and genitalia, suggesting that GAP and GP are highly targeted to the liver, kidney and genitalia. Importantly, we explored the uptake mechanism of GAP and GP. GAP and GP are endocytosed into the cell via lattice proteins or niche proteins. Both are transported lysosomally mediated to the endoplasmic reticulum (ER) and then enter the nucleus through the ER, thus completing the process of intracellular uptake and transportation. CONCLUSION: Our results confirm that the uptake of GPs by small intestinal epithelial cells is primarily mediated via lattice proteins and the cytosolic cellar. The discovery of important pharmacokinetic properties and the uncovering of the absorption mechanism provide a research rationale for the research of GP formulation and clinical promotion.

Multiple initiatives to conquer KRAS G12C inhibitor resistance from the perspective of clinical therapy.

INTRODUCTION: KRAS G12C targeted covalent inhibitors for cancer therapy are revolutionary. However, resistance to KRAS G12C inhibitors in clinical trials is a proven fact. AREAS COVERED: The authors focus on providing coverage and emphasizing the strategy of conquering KRAS G12C inhibitor resistance from the perspective of clinical therapy. The authors also provide the readers with their expert perspectives for future development. EXPERT OPINION: It is essential to improve the therapeutic effect and achieve long-term disease control through accumulating rapid exploration of drug resistance mechanisms in preclinical trials and developing rational combination dosing approaches from clinical practice. Our presentation of the perspective provides insights into drug resistance in this groundbreaking area of research.

Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression.

A primary strategy employed in cancer therapy is the inhibition of topoisomerase II (Topo II), implicated in cell survival. However, side effects and adverse reactions restrict the utilization of Topo II inhibitors. Thus, investigations focus on the discovery of novel compounds that are capable of inhibiting the Topo II enzyme and feature safer toxicological profiles. Herein, we upgrade an old antibiotic chrysomycin A from Streptomyces sp. 891 as a compelling Topo II enzyme inhibitor. Our results show that chrysomycin A is a new chemical entity. Notably, chrysomycin A targets the DNA-unwinding enzyme Topo II with an efficient binding potency and a significant inhibition of intracellular enzyme levels. Intriguingly, chrysomycin A kills KRAS-mutant lung adenocarcinoma cells and is negligible cytotoxic to normal cells at the cellular level, thus indicating a capability of potential treatment. Furthermore, mechanism studies demonstrate that chrysomycin A inhibits the Topo II enzyme and stimulates the accumulation of reactive oxygen species, thereby inducing DNA damage-mediated cancer cell apoptosis. Importantly, chrysomycin A exhibits excellent control of cancer progression and excellent safety in tumor-bearing models. Our results provide a chemical scaffold for the synthesis of new types of Topo II inhibitors and reveal a novel target for chrysomycin A to meet its further application.

Novel Anticancer Strategy by Targeting the Gut Microbial Neurotransmitter Signaling to Overcome Immunotherapy Resistance.

Significance: Microbial neurotransmitters, as potential targets for cancer therapy, are expected to provide a new perspective on the interaction between the gut microbiome and cancer immunotherapy. Recent Advances: Mounting data reveal that most neurotransmitters can be derived from gut microbiota. Furthermore, modulation of neurotransmitter signaling can limit tumor growth and enhance antitumor immunity. Critical Issues: Here, we first present the relationships between microbial neurotransmitters and cancer cells mediated by immune cells. Then, we discuss the microbial neurotransmitters recently associated with cancer immunotherapy. Notably, the review emphasizes that neurotransmitter signaling plays a substantial role in cancer immunotherapy as an emerging cancer treatment target by regulating targeted receptors and interfering with the tumor microenvironment. Future Directions: Future studies are required to uncover the antitumor mechanisms of neurotransmitter signaling to develop novel treatment strategies to overcome cancer immunotherapy resistance. Antioxid. Redox Signal. 38, 298-315.

Changes in CYP3A4 Enzyme Expression and Biochemical Markers Under Acute Hypoxia Affect the Pharmacokinetics of Sildenafil.

To investigate the effects of pathological, physiological, biochemical and metabolic enzymes CYP3A4 on the pharmacokinetics of sildenafil under acute hypoxia, rats were randomly divided into the plain group (50 m above sea level), acute plateau group 1 (2300 m above sea level), and acute plateau group 2 (4300 m above sea level), and blood samples and liver tissues were collected. Our results showed that the blood gas, physiological and biochemical indexes of rats changed under acute hypoxia, and the protein expression of CYP3A4 enzyme decreased. The process of absorption, distribution, metabolism and excretion of sildenafil in rats has changed. Compared with the P group, the area under the drug-time curve and the average resident in the H2 group increased to 213.32 and 72.34%, respectively. The half-life and peak concentration increased by 44.27 and 133.67%, respectively. The clearance rate and apparent distribution volume decreased to 69.13 and 46.75%, respectively. There were no statistical differences in the pharmacokinetic parameters between the P group and the H1 group. In conclusion, the pharmacokinetic changes of sildenafil have a multi-factor regulation mechanism, and changes in blood gas, pathology, and biochemical indicators and metabolic enzymes affect the absorption, distribution, excretion, and metabolism of sildenafil, respectively. This study provides experimental evidence and new ideas for the rational use of sildenafil under acute hypoxic conditions.

Resistance looms for KRAS G12C inhibitors and rational tackling strategies.

KRAS mutations are one of the most frequent activating alterations in carcinoma. Recent efforts have witnessed a revolutionary strategy for KRAS G12C inhibitors with exhibiting conspicuous clinical responses across multiple tumor types, providing new impetus for renewed drug development and culminating in sotorasib with approximately 6-month median progression-free survival in KRAS G12C-driven lung cancer. However, diverse genomic and histological mechanisms conferring resistance to KRAS G12C inhibitors may limit their clinical efficacy. Herein, we first briefly discuss the recent resistance looms for KRAS G12C inhibitors, focusing on their clinical trials. We then comprehensively interrogate and underscore our current understanding of resistance mechanisms and the necessity of incorporating genomic analyses into the clinical investigation to further decipher resistance mechanisms. Finally, we highlight the future role of novel treatment strategies especially rational identification of targeted combinatorial approaches in tackling drug resistance, and propose our views on including the application of robust biomarkers to precisely guide combination medication regimens.

Composition Changes in Lycium ruthenicum Fruit Dried by Different Methods.

The fruit of Lycium ruthenicum (LRF), known as black wolfberry, is a medicinal and edible fruit. The fresh LRF is perishable and has only about 3 days of shelf life. Drying could prolong the shelf life of LRF. However, it could imply physical changes and chemical modification. This study evaluated the effect of sun drying (SD), hot air drying (HD), and freeze drying (FD) on the appearance characteristics, moisture content, bioactive compounds, amino acid composition, and antioxidant activity of LRF. The results showed that LRF dried by FD was round, expansive, fragile, and maintained the largest amount of appearance traits among the three drying methods. Drying methods had a significant effect on phytochemical content and antioxidant activity of LRF (P < 0.05). Principal component analysis (PCA) showed that procyanidin content (PAC), asparagine (Asn), total phenolic content (TPC), total anthocyanin content (TAC), and moisture content were the main sources of the difference in LRF dried by different methods. The characteristic of LRF in FD was low moisture content, and high TPC, Asn, PAC, and TAC. Sun drying was opposite to FD. Hot air drying was high TPC and low TAC content. The quality of LRF was in the order of FD > HD > SD based on comprehensive evaluation of the phytochemical component content and antioxidant capacity. Additionally, the water temperature and soaking time had different antioxidant activity effect on LRF dried by different methods. These findings will provide useful information for production and utilization of LRF.

Identification wild and cultivated licorice by multidimensional analysis.

Licorice is known as a botanical source in medicine and a sweetening agent in food products. Commercial licorice is from the source of wild and cultivated G. uralensis. It was recognized that the material basis of wild and cultivated licorice is different. This study systematically investigated the difference between them by multidimensional analysis technology. The results showed that the content of starch grain, total dietary fibre (TDF), and 11 secondary metabolite components was significantly different in wild and cultivated licorice. principal component analysis (PCA) and orthogonal partial least square (OPLS-DA) analyses showed that the wild and cultivated licorice samples could be clearly separated based on the acquired data of microscopic, macromolecular substance and secondary metabolite analysis. The main markers were starch grain, isoliquiritin apioside, liquirtin apioside and TDF. Additionally, NIR spectroscpy combined with PLS-DA has demonstrated a suitable, fast and nondestructive methodology for authentication of wild and cultivated licorice.

Enhanced P-glycoprotein expression under high-altitude hypoxia contributes to increased phenytoin levels and reduced clearance in rats.

To study the effect of plateau hypoxia on the concentration of P-glycoprotein (P-gp) substrate phenytoin, Wistar rats are randomly divided into the control group and the hypoxic group, including P-gp inhibited groups respectively. Blood, cerebrospinal fluid, brain tissue, and blood-brain barrier were collected in plain areas at an altitude of 1500 m and plateau areas at an altitude of 4010 m. Evans Blue exclusion was used to assess the integrity of the blood-brain barrier. Western blot and qPCR were used to detect changes in P-gp expression. LC-MS/MS was used to determine the concentration of phenytoin in plasma and cerebrospinal fluid. In the high-altitude plateau group, phenytoin AUC0-t, MRT0-t and t1/2 increased significantly by 60%, 48%, and 61%, respectively, and clearance decreased by 67% (p <0.05 for all parameter). The protein expression of P-gp in the blood-brain barrier of the plateau group was up-regulated 1.84 times and the gene expression was up-regulated 2.21 times. The concentrations of phenytoin in the CSF of rats in the plain and high-altitude groups were 864.7 ± 348.3 and 1000±273.9 ng•mL-1, respectively. However, after inhibiting P-gp, the concentration of phenytoin in the CSF decreased significantly. It indicates that the increased expression of P-gp on the blood-brain barrier may lead to an increase in the amount of phenytoin excreted from the blood into the CSF, which may cause neurotoxic side effects. These results demonstrate significant changes in the pharmacokinetics of phenytoin under hypoxic conditions, supporting the need for careful dose titration for drugs with a narrow therapeutic range under high-altitude conditions.

Effects of intestinal flora on the pharmacokinetics and pharmacodynamics of aspirin in high-altitude hypoxia.

Since hypobaric hypoxia significantly affects metabolic characteristics of intestinal flora, which plays an important role in the biotransformation of aspirin, high altitudes may influence the pharmacokinetics and therapeutic effects of aspirin in the intestines. In the present study, to test alterations of intestinal microbiota at high altitude comparing to that at low altitude, we analyzed rat feces from plain group and high-altitude group by 16S rRNA analysis. To detect concentrations of aspirin and salicylic acid, we established a reliable liquid chromatography tandem mass spectrometry method to measure aspirin and salicylic acid concentrations in fecal suspensions and plasma. Our study found that the plateau hypoxic environment caused a significant increase in Bacteroides in rat feces, while Corynebacterium, Prevotella, and Coprococcus were declined. In addition, compared with the plain group, the metabolic activity of fecal suspensions from the plateau group on aspirin was significantly reduced. More importantly, these changes in the intestinal microbiota led to increasing absorption of aspirin in the rats after rapidly ascent to the plateau, and a reduction in the pharmacodynamic index TXB2, which would possibly result in bleeding. In conclusion, our research provides new ideas for changes in plateau pharmacokinetics, and then guide the corresponding reduction in aspirin dose for the population quickly entering the plateau.

Gut Microbiota-Mediated Drug-Drug Interaction between Amoxicillin and Aspirin.

The effects of antibiotics on the intestinal flora can create potential drug-drug interactions. The combination of amoxicillin and aspirin is high and there is a high probability of interaction. We used 16S rRNA, incubation experiments and liquid chromatography-tandem mass spectrometry to analyze rat biological samples to characterize the effect of amoxicillin on the pharmacokinetics of aspirin metabolites. We first discovered that amoxicillin reduced the species and number of intestinal flora in rats, such as reducing the abundance of Helicobacter pylori and Prevotella_copri. After 12, 24, and 36 hours of incubation, the remaining amount of aspirin in the aspirin and amoxicillin treatment groups decreased, and salicylic acid production increased, suggesting that aspirin is metabolized by the intestinal flora, and the main metabolite is salicylic acid. As the incubation time prolonged, the reduction of aspirin and the production of salicylic acid in the amoxicillin treatment group were slower. It is indicated that the metabolic activity of aspirin through the intestinal flora is slowed down after administration of amoxicillin. The pharmacokinetic experiments showed that after administration of amoxicillin, the area under the salicylic acid curve increased by 91.38%, the peak concentration increased by 60.43%, and the clearance rate decreased by 43.55%.The results demonstrated that amoxicillin affected the pharmacokinetics of aspirin active metabolite salicylic acid by slowing down the metabolic activity of intestinal flora on aspirin. The interaction between amoxicillin and aspirin mediated by the intestinal flora may affect the efficacy of aspirin and cause more significant adverse effects.

[Modulation of drug-metabolizing enzymes and transporters under hypoxia environment].

Drug metabolism is significantly affected under hypoxia environment with changes of pharmacokinetics, expression and function of drug-metabolizing enzymes and transporters. Studies have shown that hypoxia increases the release of a series of inflammatory cytokines which can modulate drug metabolism. Besides, both hypoxia inducible factor 1α (HIF-1α) and microRNA-mediated pathways play a role in regulating drug metabolism. This article reviewed the impact and single-factor modulating mechanisms of drug metabolism under hypoxia, and put forward the speculation and prospects of multi-factor modulating mechanisms.

Disordered Metabolic Profiling in Plasma and Tissues of Mice Infected with Artemisinin-Sensitive and -Resistant Plasmodium berghei K173 Determined by 1H NMR Spectroscopy.

Artemisinin resistance has inevitably emerged in several malaria-endemic areas and led to an incremental clinical failure rate for artemisinin-based combination therapy (ACT), which is strongly recommended by the World Health Organization (WHO). Genetically resilient malaria parasites have evolved antimalarial drug-evasion mechanisms; meanwhile, the metabolic cross-talk between the malaria parasites and the host is of significance during the invasion. The intention of this work, therefore, is to propose a feasible method to discover the systematic metabolic phenotypes of mice invaded with artemisinin-sensitive or -resistant Plasmodium berghei K173 when compared with healthy mice. Biological samples, including plasma, liver, spleen, and kidney, of mice collected after euthanasia at day 7 were subjected to 1H nuclear magnetic resonance spectroscopy. Multivariable data analysis was utilized to estimate the metabolic characteristics of these samples from uninfected and infected mice. In contrast with healthy mice, both sensitive and resistant malaria-parasite-infected models displayed distinct metabolic profiles. Parasite invasion significantly changed the glycolysis, Kreb's cycle, and amino acid metabolism in plasma and tissues. Decreased N, N-dimethylglycine and glycine levels in plasma from the artemisinin-sensitive P. berghei-infected group and increased lactate, lipid, and aspartate in the artemisinin-resistant P. berghei-infected group were observed, respectively. In the liver, the artemisinin-sensitive group up-regulated the glutamate level and down-regulated glutamine. Artemisinin-resistant parasite exposure decreased ethanol and allantoin levels. The levels of myo-inositol and valine in the spleen were increased due to artemisinin-sensitive P. berghei infection, together with decreased trimethylamine N-oxide, phosphocholine, ß-glucose, and acetoacetic acid. In the artemisinin-resistant group, the spleen showed a remarkably increased phosphocholine content along with decreased dimethylglycine and arginine levels. In the kidney, artemisinin-sensitive P. berghei K173 caused increased lysine, glutamate, creatine, and 2-hydroxybutyrate as well as decreased ethanol. Artemisinin-resistant P. berghei led to low glycerophosphorylcholine and high acetate, betaine, and hypoxanthine. Mutual and specific altered metabolites and, accordingly, metabolic pathways induced by the infection of artemisinin-sensitive or -resistant P. berghei were therefore screened out. This should be considered a preliminary study to establish a direct relationship with the host metabolic background and artemisinin resistance.

Effects of Gut Microbiota on Drug Metabolism and Guidance for Rational Drug Use Under Hypoxic Conditions at High Altitudes.

BACKGROUND: Modern features of drug development such as low permeability, low solubility, and improved release affect the interplay of the gut microbiota and drug metabolism. In recent years, studies have established the impact of plateau hypoxia on gut microbiota, where drug use by plateau populations is affected by hypoxia- induced changes in intestinal microflora-mediated drug metabolism. METHODS: In this review, we summarized the effects of gut microbiota on drug metabolism, and of plateau hypoxia on the intestinal flora, with the aim of providing guidance for the rational use of drugs in high-altitude populations. RESULTS: The evidence clearly shows that alterations in gut microbiota can affect pro-drug activation, drug inactivation, and the biotransformation of xenobiotics. Additionally, plateau hypoxia alters drug metabolism by affecting intestinal flora. CONCLUSION: This review provides an overview of the effects of gut microbiota on drug metabolism and provides guidance for rational drug use under hypoxic conditions at high altitudes.

[Research progress of long chain non-coding RNA H19 in anoxic environment mechanism].

LncRNA H19 encoded by the H19 imprinting gene plays an important regulatory role in the cell. Recently study has found that in hypoxic cells, the expression of H19 gene changes, and the transcription factors and protein involved in the expression change accordingly. Through the involvement of specific protein 1 (SP1), hypoxia-inducible factor-1α (HIF-1α) binds directly to the H19 promoter and induces the up-regulation of H19 expression under hypoxic conditions. The tumor suppressor protein p53 may also mediate the expression of the H19 gene, in part by interfering with HIF-la activity under hypoxia stress. The miR675-5p encoded by exon 1 of H19 promotes hypoxia response by driving the nuclear accumulation of HIF-1α and reducing the expression of VHL gene, which is a physiological HIF-1α inhibitor. In addition, under the condition of hypoxia, the expression of transporter on cell membrane changes, and the transition of the intracellular glucose metabolism pathway from aerobic oxidation to anaerobic glycolysis is also involved in the involvement of H19. Therefore, H19 may be a key gene that maintains intracellular balance under hypoxic conditions and drives adaptive cell survival under conditions of hypoxia stress.

Gut microbiota modulates drug pharmacokinetics.

Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs.