Phase-Controlled Cobalt Catalyst Boosting Hydrogenation of 5-Hydroxymethylfurfural to 2,5-Dimethylfuran.

The search for non-noble metal catalysts for chemical transformations is of paramount importance. In this study, an efficient non-noble metal catalyst for hydrogenation, hexagonal close-packed cobalt (HCP-Co), was synthesized through a simple one-step reduction of ß-Co(OH)2 nanosheets via a temperature-induced phase transition. The obtained HCP-Co exhibited several-times-higher catalytic efficiency than its face-centered cubic cobalt (FCC-Co) counterpart in the hydrogenation of the C=C/C=O group, especially for the 5-hydroxymethylfurfural (HMF) hydrogenation (8.5-fold enhancement). Density functional theory calculations demonstrated that HMF molecules were adsorbed more firmly on the (112_0) facet of HCP-Co than that on the (111) facet of FCC-Co, favoring the activation of the C=O group in the HMF molecule. The stronger adsorption on the (112_0) facet of HCP-Co also led to lower activation energy than that on the (111) facet of FCC-Co, thereby resulting in high activity and selectivity. Moreover, HCP-Co exhibited outstanding catalytic stability during the hydrogenation of HMF. These results highlight the possibility of fabricating hydrogenation catalysts with satisfactory catalytic properties by precisely tuning their active crystal phase.

Annexin A2: The diversity of pathological effects in tumorigenesis and immune response.

Annexin A2 (ANXA2) is widely used as a marker in a variety of tumors. By regulating multiple signal pathways, ANXA2 promotes the epithelial-mesenchymal transition, which can cause tumorigenesis and accelerate thymus degeneration. The elevated ANXA2 heterotetramer facilitates the production of plasmin, which participates in pathophysiologic processes such as tumor cell invasion and metastasis, bleeding diseases, angiogenesis, inducing the expression of inflammatory factors. In addition, the ANXA2 on the cell membrane mediates immune response via its interaction with surface proteins of pathogens, C1q, toll-like receptor 2, anti-dsDNA antibodies and immunoglobulins. Nuclear ANXA2 plays a role as part of a primer recognition protein complex that enhances DNA synthesis and cells proliferation by acting on the G1-S phase of the cell. ANXA2 reduction leads to the inhibition of invasion and metastasis in multiple tumor cells, bleeding complications in acute promyelocytic leukemia, retinal angiogenesis, autoimmunity response and tumor drug resistance. In this review, we provide an update on the pathological effects of ANXA2 in both tumorigenesis and the immune response. We highlight ANXA2 as a critical protein in numerous malignancies and the immune host response.

Erlotinib is effective against FLT3-ITD mutant AML and helps to overcome intratumoral heterogeneity via targeting FLT3 and Lyn.

Erlotinib has potential therapeutic effect on acute myeloid leukemia (AML) in patients, but the mechanism is not clear. Effective tumor biomarkers for erlotinib in the treatment of AML remain poorly defined. Here, we demonstrate that erlotinib in vitro significantly inhibits the growth of the FLT3-ITD mutant AML cell MV4-11 and Ba/F3-FLT3-ITD cell via targeting FLT3, a certified valid target for the effective treatment of AML. In vivo, oral administration of erlotinib at 100 mg/kg/day induced rapid MV4-11 tumor regression and significantly prolonged the survival time of bone marrow engraftment AML mice via inhibiting the FLT3 signal. Thus, the therapeutic benefits of erlotinib on AML are due to its ability to target FLT3. FLT3-ITD mutation is an effective biomarker for erlotinib during AML treatment. In addition, we also demonstrate that erlotinib inhibits the activity of AML cell KG-1 (no FLT3 expression) by targeting Lyn. Recently, single cell analysis demonstrated that intratumoral heterogeneity are one of the contributors in the relapse and FLT3 inhibitor resistance. Erlotinib could effectively inhibit the MV4-11 cells via targeting FLT3, and inhibit KG-1 cells via targeting Lyn. Therefore, Erlotinib also has the potential to overcome intratumoral heterogeneity via targeting FLT3 and Lyn.

A review of pharmacological and pharmacokinetic properties of stachydrine.

Stachydrine is extracted from the leaves of Leonurus japonicus Houtt (or Motherwort, "Yi Mu Cao" in Traditional Chinese Medicine) and is the major bioactive ingredient. So far, stachydrine has demonstrated various bioactivities for the treatment of fibrosis, cardiovascular diseases, cancers, uterine diseases, brain injuries, and inflammation. The pharmacological and pharmacokinetic properties of stachydrine up to 2019 have been comprehensively searched and summarized. This review provides an updated summary of recent studies on the pharmacological activities of stachydrine. Many studies have demonstrated that stachydrine has strong anti-fibrotic properties (on various types of fibrosis) by inhibiting ECM deposition and decreasing inflammatory and oxidative stress through multiple molecular mechanisms (including TGF-ß, ERS-mediated apoptosis, MMPs/TIMPs, NF-κB, and JAK/STAT). The cardioprotective and vasoprotective activities of stachydrine are related to its inhibition of ß-MHC, excessive autophagy, SIRT1, eNOS uncoupling and TF, promotion of SERCA, and angiogenesis. In addition to its anticancer action, regulation of the uterus, neuroprotective effects, etc. the pharmacokinetic properties of stachydrine are also discussed.

Clonazepam add-on therapy for drug-resistant epilepsy.

BACKGROUND: This is an updated version of the original Cochrane Review published in 2018, Issue 5. Epilepsy affects over 70 million people worldwide, and nearly a quarter of patients with seizures have drug-resistant epilepsy. People with drug-resistant epilepsy have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. OBJECTIVES: To assess the efficacy and tolerability of clonazepam when used as an add-on therapy for adults and children with drug-resistant focal onset or generalised onset epileptic seizures, when compared with placebo or another antiepileptic agent. SEARCH METHODS: For the latest update we searched the following databases on 4 June 2019: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid) 1946 to 3 June, 2019. The Cochrane Register of Studies (CRS Web) includes the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), and randomised or quasi-randomised, controlled trials from Embase, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: Double-blind randomised controlled studies of add-on clonazepam in people with resistant focal or generalised onset seizures, with a minimum treatment period of eight weeks. The studies could be of parallel or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted relevant data, and assessed trial quality. We contacted study authors for additional information. MAIN RESULTS: We found no double-blind randomised controlled trials which met the inclusion criteria. AUTHORS' CONCLUSIONS: There is no evidence from double-blind randomised controlled trials for or against the use of clonazepam as an add-on therapy for adults and children with drug-resistant focal or generalised onset epileptic seizures. Since the last version of this review no new studies have been found.

Isoliquiritigenin, an Orally Available Natural FLT3 Inhibitor from Licorice, Exhibits Selective Anti-Acute Myeloid Leukemia Efficacy In Vitro and In Vivo.

Licorice is a medicinal herb widely used to treat inflammation-related diseases in China. Isoliquiritigenin (ISL) is an important constituent of licorice and possesses multiple bioactivities. In this study, we examined the selective anti-AML (acute myeloid leukemia) property of ISL via targeting FMS-like tyrosine kinase-3 (FLT3), a certified valid target for treating AML. In vitro, ISL potently inhibited FLT3 kinase, with an IC50 value of 115.1 ± 4.2 nM, and selectively inhibited the proliferation of FLT3-internal tandem duplication (FLT3-ITD) or FLT3-ITD/F691L mutant AML cells. Moreover, it showed very weak activity toward other tested cell lines or kinases. Western blot immunoassay revealed that ISL significantly inhibited the activation of FLT3/Erk1/2/signal transducer and activator of transcription 5 (STAT5) signal in AML cells. Meanwhile, a molecular docking study indicated that ISL could stably form aromatic interactions and hydrogen bonds within the kinase domain of FLT3. In vivo, oral administration of ISL significantly inhibited the MV4-11 flank tumor growth and prolonged survival in the bone marrow transplant model via decreasing the expression of Ki67 and inducing apoptosis. Taken together, the present study identified a novel function of ISL as a selective FLT3 inhibitor. ISL could also be a potential natural bioactive compound for treating AML with FLT3-ITD or FLT3-ITD/F691L mutations. Thus, ISL and licorice might possess potential therapeutic effects for treating AML, providing a new strategy for anti-AML.

Iridoids from Valeriana jatamansi induce autophagy-associated cell death via the PDK1/Akt/mTOR pathway in HCT116 human colorectal carcinoma cells.

Chlorovaltrates U-W (1-3), three previously undescribed iridoids, together with four known analogues were isolated from the roots of Valeriana jatamansi. Their structures were elucidated by means of spectroscopic analyses (HRESIMS, NMR). The cytotoxicity of all isolates was evaluated. Compounds 5-7 exhibited selective cytotoxicity against HCT116 cells, with IC50 values of 9.3, 1.7 and 2.2 µM, respectively. The preliminary mechanistic study revealed that, the cytotoxicity effect of 6 was attributed to Akt/mTOR activation blockade via inhibition of PDK1 phosphorylation. Meanwhile, compound 6 could induce autophagosome formation in HCT116 cells via suppressing its downstream Akt/mTOR. These findings show that compound 6 could be of great importance to the development of anti-colon cancer agents.

Clonazepam add-on therapy for refractory epilepsy in adults and children.

BACKGROUND: Epilepsy affects about 50 million people worldwide, nearly a quarter of whom have drug-refractory epilepsy. People with drug-refractory epilepsy have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. OBJECTIVES: To assess the efficacy and tolerability of clonazepam when used as an add-on therapy for adults and children with refractory focal onset or generalised onset epileptic seizures, when compared with placebo or another antiepileptic agent. SEARCH METHODS: We searched the following databases on 14 September 2017: Cochrane Epilepsy Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 14 September 2017), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: Double-blind randomised controlled studies of add-on clonazepam in people with refractory focal or generalised onset seizures, with a minimum treatment period of eight weeks. The studies could be of parallel or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted relevant data, and assessed trial quality. We contacted study authors for additional information. MAIN RESULTS: No double-blind randomised controlled trials met the inclusion criteria. AUTHORS' CONCLUSIONS: There is no evidence from double-blind randomised controlled trials for or against the use of clonazepam as an add-on therapy for adults and children with refractory focal or generalised onset epileptic seizures.

Pharmacokinetics and tissue distribution of crotonoside.

1. Crotonoside is a bioactive ingredient from Croton Herba with a strong antitumour activity. This study aimed to develop a highly sensitive and selective high-performance liquid chromatography (HPLC) method to quantify crotonoside in biological samples for pharmacokinetics and distribution studies. 2. Protein precipitation by perchloric acid was used to separate crotonoside from the biological samples, and the recovery rates for crotonoside and the internal standard (luteoloside) were >80%. All calibration curves examining the crotonoside levels in plasma and tissues were linear (all correlation coefficients > 0.99). 3. The response to crotonoside appeared to be dose disproportional to the maximum plasma concentration and the area under the time-concentration curve in plasma over the range of 12.5-50.0 mg/kg, and crotonoside was highly distributed in tissues after intravenous administration. The highest crotonoside level was detected in the liver (28.79 ± 14.96 µg/g), whereas crotonoside was undetected in the brain.

Preparation, Characterization, Pharmacokinetics and Biodistribution of Baicalin-Loaded Liposome on Cerebral Ischemia-Reperfusion after i.v. Administration in Rats.

The dry root of Scutellaria baicalensis, has traditionally been applied in the treatment of cerebral ischemia in Chinese clinics. Baicalin (BA) is considered the key ingredient in it for the brain protection effects. The bioavailability of BA is very low because of its poor lipid and water solubility, which limits the therapeutic effects and clinical application. The aim of the present study was to develop a novel BA-loaded liposome (BA-LP) formulation to improve the drug lipophilicity and further to enhance the drug-concentration in the brain tissues. This study is also designed to investigate the pharmacokinetics of BA in the pathological conditions of stroke and evaluate the pharmacokinetic differences of BA caused by stroke after intravenous administration with BA and BA-LP. In this study, the novel BA-LP prepared in early stage were characterized by morphology, size, zeta potential, encapsulation rate and the in vitro release. The pharmacokinetics and biodistribution of BA and BA-LP were investigated by intravenous administration in rats with middle cerebral artery occlusion (MCAO) model and normal group respectively. BA-LP had a mean particle size of 160⁻190 nm, zeta potential of -5.7 mV, and encapsulation efficiency of 42 ± 1%. The BA-LP showed a sustained-release behavior, the in vitro drug-release kinetic model of BA-LP fit well with the biphasic dynamic model equation: Q = 1 - (60.12e0.56t - 59.08e0.0014t). Pharmacokinetic behavior in MCAO rats is not consistent with that of normal rats. The middle cerebral artery occlusion rats got higher Cmax and AUC0⁻t, which were about 1.5⁻2 times to normal rats both in BA and liposome groups. In addition, it got especially higher distribution in brain, while BA were not detected in brain tissues on normal rats. The Cmax and AUC0⁻t values were significantly greater with liposome than BA on both normal and MCAO rats. The tissue distribution behavior was significantly altered in the case of liposome administrated in comparison with BA, which the concentrations in the heart, liver, spleen, lungs and brain were all increased after administrated liposome, but decreased in kidneys. The TI values showed that the target of liposome was improved especially to heart, spleen and brain, and the brain's target was higher in striatum and cerebellum. In conclusion, BA-LP might be a potential drug delivery system to improve the therapeutic efficacy of BA. In addition, these results also suggest that the pathological damages of ischemia-reperfusion have a significant impact on the pharmacokinetic traits of BA.

The Influence of Aconitum carmichaelii Debx. on the Pharmacokinetic Characteristics of Main Components in Rheum palmatum L.

Rhei Radix et Rhizoma was one of the commonly used traditional Chinese medicines, and the compatibility of Rhei Radix et Rhizoma and Aconiti Lateralis Radix Praeparata was the basic herb pair applied in many Chinese traditional prescription. Rhubarb anthraquinones were the main bioactive materials of Rhei Radix et Rhizoma. To elucidate the compatibility of Rhei Radix et Rhizoma and Aconiti Lateralis Radix Praeparata, the pharmacokinetics of rhubarb anthraquinones as the main marker constituents were investigated. In the present study, pharmacokinetic differences of rhubarb anthraquinones were detected after oral administration of extract of Rheum palmatum L. and compatibility with Aconitum carmichaelii Debx. After oral administration, no difference of peak time can be found for anthraquinones between rhubarb group and compatibility group. But Cmax and area under the curve of aloe-emodin, emodin and chrysophanol in compatibility group were significantly higher than that in rhubarb group. Although the Cmax of rhein in compatibility group was much lower than that in rhubarb group, the area under the curve value was similar in two groups. The clearance and t1/2 of rhubarb anthraquinone were also changed after compatibility. The change of pharmacokinetics characteristics of rhubarb anthraquinone after compatibility may be caused by the drug-drug interaction medicated by chemical reaction and cytochromes P450.

Development and validation of a UHPLC-qTOF-MS method for quantification of fuziline in rat plasma and its application in a pharmacokinetic study.

A specific and sensitive UHPLC-qTOF-MS method was developed and validated for quantification of fuziline in rat plasma after oral administration of three dosages. The analyte was separated on an Acquity UPLC BEH C18 column with a total running time of 3 min using a mobile phase of 0.1% formic acid aqueous solution and methanol (80:20, v/v) at a flow-rate of 0.25 mL/min. The calibration curves for fuziline showed good linearity in the concentrations ranging from 1 to 200 ng/mL with correlation coefficients >0.997. The precision, accuracy, recovery and stability were deemed acceptable. The method was applied to a pharmacokinetics study of fuziline in rats. The mean half-life was 5.93, 6.13 and 5.12 h for 1, 2 and 4 mg/kg oral administration of fuziline, respectively. The peak concentration and area under the concentration-time curve increased linearly with the doses. The sum of these results indicated that, in the range of the doses examined, the pharmacokinetics of fuziline in rat was based on first-order kinetics.

Prevalence and risk factors for anxiety in patients with early- and middle-stage lung cancer: a cross-sectional study.

Objective: Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide, with patients frequently experiencing significant psychological distress, particularly anxiety. Despite the high prevalence of anxiety in patients with cancer, there is limited comprehensive research focusing on the specific factors influencing anxiety in patients with early- and middle-stage lung cancer within the context of Chinese medicine hospitals. Therefore, we aimed to investigate the epidemiology and factors influencing anxiety disorders in patients with early- and middle-stage primary bronchial lung cancer through a cross-sectional study. Methods: A total of 340 patients with early and middle-stage lung cancer admitted to the outpatient ward of the oncology department at Guang'anmen Hospital from June 2023 to December 2023 were included in this study. Survey data, including the patients' general condition questionnaire, Generalized Anxiety Scale (GAD-7), Hospital Anxiety and Depression Scale (HADS), and Mental Toughness Scale (CD-RISC-10), were collected and recorded in a database using a two-person input format. Data analysis was performed using SPSS 27.0 software. Results: Out of the 340 patients with early- and middle-stage lung cancer included in this study, 133 had anxiety, resulting in an overall anxiety detection rate of 39.12%. The chi-square test showed that statistically significant differences in religion, marital status, surgical treatment, tobacco use, and alcohol history between the anxious and non-anxious groups (p < 0.05). Moreover, statistically significant differences were observed in per capita annual family income, pathological type, VAS score, targeted therapy, treatment stage, and mental toughness level (p < 0.001). Other factors were not significantly correlated with anxiety onset. Multivariate logistic regression analysis showed that higher per capita family income and completed treatment independently acted as protective factors against anxiety onset in patients with early- and middle-stage lung cancer. Conversely, rare pathological types, increased pain severity, and lower levels of mental toughness were identified as independent risk factors for anxiety onset in these patients. Conclusion: Anxiety was prevalent in patients with early- and middle-stage lung cancers. Rare pathological types, increased pain severity, and lower levels of mental toughness were independent risk factors for anxiety. Therefore, clinicians and psychologists should pay more attention to patients with rare types of tumors, actively manage their pain symptoms, and consider implementing mental resilience training to improve patients' mental toughness.

Protective effect of ginsenoside Rb1 against aconitine cardiotoxicity studied by myocardial injury, action potential, and calcium signaling.

Aconitine is the main active component of Aconitum plants. Although aconitine has effects that include strengthening the heart, analgesia, anti-tumor, and immune-regulating effects, aconitine has both efficacy and toxicity, especially cardiotoxicity. Severe effects can include arrhythmia and cardiac arrest, which limits the clinical application of aconitine-containing traditional Chinese medicine. Ginsenoside Rb1(Rb1) is mainly found in plants, such as ginseng and Panax notoginseng, and has cardiovascular-protective and anti-arrhythmia effects. This study aimed to investigate the detoxifying effects of Rb1 on aconitine cardiotoxicity and the electrophysiological effect of Rb1 on aconitine-induced arrhythmia in rats. Pathological analysis, myocardial enzymatic indexes, and Western blotting were used to investigate the ameliorating effect of Rb1 on aconitine cardiotoxicity. Optical mapping was used to evaluate the effect of Rb1 on action potential and calcium signaling after aconitine-induced arrhythmia. Rb1 inhibited pathological damage caused by aconitine, decreased myocardial enzyme levels, and restored the balance of apoptotic protein expression by reducing the expression of Bax and cleaved caspase 3 and increasing the expression of Bcl-2, thereby reducing myocardial damage caused by aconitine. Rb1 also reduced the increase in heart rate caused by aconitine, accelerated action potential conduction and calcium signaling, and reduced the dispersion of action potential and calcium signal conduction. Rb1 reduced the cardiotoxicity of aconitine by attenuating aconitine-induced myocardial injury and inhibiting the aconitine-induced retardation of ventricular action potential and calcium signaling in rats.

Fuzi lizhong pills alter microbial community compositions and metabolite profiles in ulcerative colitis rat with spleen-kidney yang deficiency syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a chronic inflammatory bowel condition that is frequently related with Spleen-Kidney Yang Deficiency Syndrome (SKYD) in Chinese medicine. Fuzi Lizhong Pill (FLZP), a traditional medicine for SKYD, has been utilized in China for generations, although the exact mechanism by which it treats UC is unknown. AIM OF THE STUDY: The goal of this study is to further understand FLZP's therapeutic mechanism in SKYD-associated UC. MATERIALS AND METHODS: To investigate the impact of FLZP on SKYD-associated UC, we used a comprehensive method that included serum metabolomics and gut microbiota profiling. The chemical composition of FLZP was determined using mass spectrometry. UC rats with SKYD were induced and treated with FLZP. Serum metabolomics and 16S rRNA microbial community analysis were used to evaluate FLZP's effects on endogenous metabolites and gut microbiota, respectively. Correlation analysis investigated the association between metabolites and intestinal flora. A metabolic pathway analysis was undertaken to discover putative FLZP action mechanisms. RESULTS: FLZP contains 109 components, including liquiritin (584.8176 µg/g), benzoylaconine (16.3087 µg/g), benzoylhypaconine (31.9583), and hypaconitine (8.1160 µg/g). FLZP predominantly regulated seven metabolites and eight metabolic pathways involved in amino acid and nucleotide metabolism, with an emphasis on energy metabolism and gastrointestinal digestion. FLZP also influenced intestinal flora variety, increasing probiotic abundance while decreasing pathogenic bacteria prevalence. An integrated investigation identified associations between changes in certain gut flora and energy metabolism, specifically the tricarboxylic acid (TCA) cycle. CONCLUSIONS: FLZP successfully cures UC in SKYD rats by regulating amino acid and energy metabolism. Its positive effects may include altering microbiota composition and metabolite profiles in UC rats with SKYD. These findings shed light on FLZP's mode of action and its implications for UC management.

Weakly supervised salient object detection via image category annotation.

The rapid development of deep learning has made a great progress in salient object detection task. Fully supervised methods need a large number of pixel-level annotations. To avoid laborious and consuming annotation, weakly supervised methods consider low-cost annotations such as category, bounding-box, scribble, etc. Due to simple annotation and existing large-scale classification datasets, the category annotation based methods have received more attention while still suffering from inaccurate detection. In this work, we proposed one weakly supervised method with category annotation. First, we proposed one coarse object location network (COLN) to roughly locate the object of an image with category annotation. Second, we refined the coarse object location to generate pixel-level pseudo-labels and proposed one quality check strategy to select high quality pseudo labels. To this end, we studied COLN twice followed by refinement to obtain a pseudo-labels pair and calculated the consistency of pseudo-label pairs to select high quality labels. Third, we proposed one multi-decoder neural network (MDN) for saliency detection supervised by pseudo-label pairs. The loss of each decoder and between decoders are both considered. Last but not least, we proposed one pseudo-labels update strategy to iteratively optimize pseudo-labels and saliency detection models. Performance evaluation on four public datasets shows that our method outperforms other image category annotation based work.

Pancreatic cancer progression and mortality predicted by depression and anxiety: a systematic review and meta-analysis protocol.

Although the relationship between psychological factors and pancreatic cancer outcomes has been widely discussed, controversy remains. We will for the first time systematically summarize the literature to explore the correlation of anxiety and depression to the prognosis of patients with pancreatic cancer. The findings will fill existing research gaps, informing healthcare providers about better psychological care and medical treatment. The following databases will be retrieved from their inception to July 2023: Cochrane Library, MEDLINE (PubMed), Web of Science, EMBASE, and four Chinese databases (Chinese National Knowledge Infrastructure, Wanfang Database, Chinese Biomedical Literature Database, and Chongqing VIP Chinese Science and Technology Periodical Database). The World Health Organization Clinical Trials Registry, Chinese Clinical Registry, and ClinicalTrials.gov will be searched to identify other related studies. A manual search will be performed to identify missing eligible studies based on the reference list of selected articles. The search will focus on studies published in Chinese or English. To assess the risk of bias in the selected articles, Newcastle-Ottawa Quality Assessment Scale (NOS) will be used for the cohort study. Funnel plots and Egger's test will be used to assess whether publication bias exists. Moreover, the Grading of Recommendations Assessment Development and Evaluation (GRADE) will be utilized to analyze the credibility of the results from selected articles. Two independent evaluators will implement the study selection and data extraction, as well as evaluate the risk of bias and evidence quality. Data will be analyzed using Stata 16.0. Trial registration: PROSPERO registration number is CRD42022366232.

Oxaliplatin-induced peripheral neurotoxicity in colorectal cancer patients: mechanisms, pharmacokinetics and strategies.

Oxaliplatin-based chemotherapy is a standard treatment approach for colorectal cancer (CRC). However, oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe dose-limiting clinical problem that might lead to treatment interruption. This neuropathy may be reversible after treatment discontinuation. Its complicated mechanisms are related to DNA damage, dysfunction of voltage-gated ion channels, neuroinflammation, transporters, oxidative stress, and mitochondrial dysfunction, etc. Several strategies have been proposed to diminish OIPN without compromising the efficacy of adjuvant therapy, namely, combination with chemoprotectants (such as glutathione, Ca/Mg, ibudilast, duloxetine, etc.), chronomodulated infusion, dose reduction, reintroduction of oxaliplatin and topical administration [hepatic arterial infusion chemotherapy (HAIC), pressurized intraperitoneal aerosol chemotherapy (PIPAC), and hyperthermic intraperitoneal chemotherapy (HIPEC)]. This article provides recent updates related to the potential mechanisms, therapeutic strategies in treatment of OIPN, and pharmacokinetics of several methods of oxaliplatin administration in clinical trials.

Single-Molecule Force Spectroscopy of Deoxyribonucleic Acid and Deoxyribonucleic Acid Polymerase Activity Impacted by Alkylating Agents.

DNA alkylating agents are widely used in anticancer pharmacology. Although shown to induce cross-linking and/or methylation of DNA, how they affect the mechanical properties of DNA and activity of DNA enzymes remains to be elucidated. Here, we perform single-molecule optical tweezer experiments on DNA treated with alkylating agents, including melphalan, cisplatin, and dacarbazine. While all three drugs induce a significant increase of overstretching force and a reduction of hysteresis, suggesting stabilization of DNA against shearing forces, their effects on elasticity of DNA were quite different, with the largest change in persistence length induced by cisplatin. Furthermore, we find that these alkylating-agent-induced changes on DNA have different effects on processivity of DNA polymerase, with melphalan and cisplatin showing significantly reduced activity and dacarbazine showing little effect. Overall, our results provide new insights into the effects for these alkylating agents, which could potentially facilitate a better design of related drugs.

Assessment and modulation of forsythiaside absorption with MDCKII cells and validation with in situ intestinal experiment.

Forsythiaside was characterized by low intestinal absorption by in situ rat experiment and Caco-2 cells. The mechanisms behind this low absorption had not yet been elucidated. The purpose of this study was to investigate the role of efflux transporters in the intestinal absorption of forsythiaside as a potential mechanism for its low small-intestinal absorption following oral administration. Polarized MDCKII cell lines stably transfected with human or murine complementary DNA encoding for various efflux transporters (P-gp/MDR1, MRP2 and Bcrp1) were used to study transepithelial transport of forsythiaside and compare results with the MDCKII-Wild type cells. The transportation inhibitors GF120918, MK571 and Ko143 were used to investigate the transport mechanism. The active transport of forsythiaside was found in MDCKII-WT cells. The MDCKII-MRP2 and MDCKII-Bcrp1 cells significantly increased forsythiaside efflux ratio compared with the parental cells due to the apically directed transport by MRP2 and Bcrp1, respectively. The efflux ratios in MRP2 and Bcrp1 transfected cell lines were greatly decreased in the presence of MK-571 and Ko143, respectively, which indicated that forsythiaside efflux by MRP2 and Bcrp1 were significantly inhibited by their selective inhibitors. MDCKII-MDR1 cells did not exhibit a significant reduction in the forsythiaside efflux compared with the parental cells, indicating that it was not a good substrate for MDR1. And the results were then validated by the in situ experiment. This study presents direct evidence that forsythiaside is effluxed by both MRP2 and Bcrp1, which may contribute to its poor oral bioavailability.