Triphenylphosphonium-linked derivative of hecogenin with enhanced antiproliferative activity: Design, synthesis, and biological evaluation.

Hecogenin (HCG), a steroidal sapogenin, possesses good antitumor properties. However, the application of HCG for cancer treatment has been hindered primarily by its moderate potency. In this study, we incorporated triphenylphosphonium cation (TPP+) at the C-3 and C-12 positions through different lengths of alkyl chains to target mitochondria and enhance the efficacy and selectivity of the parent compound. Cytotoxicity screening revealed that most of the target compounds exhibited potent antiproliferative activity against five human cancer cell lines (MKN45, A549, HCT-116, MCF-7, and HepG2). Structure-activity relationship studies indicated that the TPP+ group significantly enhanced the antiproliferative potency of HCG. Among these compounds, 3c demonstrated remarkable potency against MKN45 cells with an IC50 value of 0.48 µM, significantly more effective than its parent compound HCG (IC50 > 100 µM). Further investigations into the mechanism of action revealed that 3c induced apoptosis of MKN45 cells through the mitochondrial pathway. In a zebrafish xenograft model, 3c inhibited the proliferation of MKN45 cells. Overall, these results suggest that 3c, with potent antiproliferative activity, may serve as a valuable scaffold for developing new antitumor agents.

The Graphene Quantum Dots Gated Nanoplatform for Photothermal-Enhanced Synergetic Tumor Therapy.

Currently, the obvious side effects of anti-tumor drugs, premature drug release, and low tumor penetration of nanoparticles have largely reduced the therapeutic effects of chemotherapy. A drug delivery vehicle (MCN-SS-GQDs) was designed innovatively. For this, the mesoporous carbon nanoparticles (MCN) with the capabilities of superior photothermal conversion efficiency and high loading efficiency were used as the skeleton structure, and graphene quantum dots (GQDs) were gated on the mesopores via disulfide bonds. The doxorubicin (DOX) was used to evaluate the pH-, GSH-, and NIR-responsive release performances of DOX/MCN-SS-GQDs. The disulfide bonds of MCN-SS-GQDs can be ruptured under high glutathione concentration in the tumor microenvironment, inducing the responsive release of DOX and the detachment of GQDs. The local temperature of a tumor increases significantly through the photothermal conversion of double carbon materials (MCN and GQDs) under near-infrared light irradiation. Local hyperthermia can promote tumor cell apoptosis, accelerate the release of drugs, and increase the sensitivity of tumor cells to chemotherapy, thus increasing treatment effect. At the same time, the detached GQDs can take advantage of their extremely small size (5-10 nm) to penetrate deeply into tumor tissues, solving the problem of low permeability of traditional nanoparticles. By utilizing the photothermal properties of GQDs, synergistic photothermal conversion between GQDs and MCN was realized for the purpose of synergistic photothermal treatment of superficial and deep tumor tissues.

Design, synthesis and biological evaluation of novel diosgenin-benzoic acid mustard hybrids with potential anti-proliferative activities in human hepatoma HepG2 cells.

To discover new lead compounds with anti-tumour activities, in the present study, natural diosgenin was hybridised with the reported benzoic acid mustard pharmacophore. The in vitro cytotoxicity of the resulting newly synthesised hybrids (8-10, 14a-14f, and 15a-15f) was then evaluated in three tumour cells (HepG2, MCF-7, and HeLa) as well as normal GES-1 cells. Among them, 14f possessed the most potential anti-proliferative activity against HepG2 cells, with an IC50 value of 2.26 µM, which was 14.4-fold higher than that of diosgenin (IC50 = 32.63 µM). Furthermore, it showed weak cytotoxicity against GES-1 cells (IC50 > 100 µM), thus exhibiting good antiproliferative selectivity between normal and tumour cells. Moreover, 14f could induce G0/G1 arrest and apoptosis of HepG2 cells. From a mechanistic perspective, 14f regulated cell cycle-related proteins (CDK2, CDK4, CDK6, cyclin D1 and cyclin E1) as well mitochondrial apoptosis pathway-related proteins (Bax, Bcl-2, caspase 9, and caspase 3). These findings suggested that hybrid 14f serves as a promising anti-hepatoma lead compound that deserves further research.

Glutathione Conjugation and Protein Adduction Derived from Oxidative Debromination of Benzbromarone in Mice.

Benzbromarone (BBR), a uricosuric agent, has been known to induce hepatotoxicity, and its toxicity has a close relation to cytochrome P450-mediated metabolic activation. An oxidative debromination metabolite of BBR has been reported in microsomal incubations. The present study attempted to define the oxidative debromination pathway of BBR in vivo. One urinary mercapturic acid (M1) and one glutathione (GSH) conjugate (M2) derived from the oxidative debromination metabolite were detected in BBR-treated mice after solid phase extraction. M1 and M2 shared the same chromatographic behavior and mass spectral identities as those detected in N-acetylcysteine/GSH- and BBR-fortified microsomal incubations. The structure of M1 was characterized by chemical synthesis, along with mass spectrometry analysis. In addition, hepatic protein modification that occurs at cysteine residues (M'3) was observed in mice given BBR. The observed protein adduction reached its peak 4 hours after administration and occurred in a dose-dependent manner. A GSH conjugate derived from oxidative debromination of BBR was detected in livers of mice treated with BBR, and the formation of the GSH conjugate apparently took place earlier than the protein adduction. In summary, our in vivo work provided strong evidence for the proposed oxidative debromination pathway of BBR, which facilitates the understanding of the mechanisms of BBR-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This study investigated the oxidative debromination pathway of benzbromarone (BBR) in vivo. One urinary mercapturic acid (M1) and one glutathione (GSH) conjugate (M2) derived from the oxidative debromination metabolite were detected in BBR-treated mice. M1 and M2 were also observed in microsomal incubations. The structure of M1 was characterized by chemical synthesis followed by mass spectrometry analyses. More importantly, protein adduction derived from oxidative debromination of BBR (M'3) was observed in mice given BBR, and occurred in dose- and time-dependent manners. The success in detection of GSH conjugate, urinary N-acetylcysteine conjugate, and hepatic protein adduction in mice given BBR provided solid evidence for in vivo oxidative debromination of BBR. The studies allowed a better understanding of the metabolic activation of BBR.

Preparation and Evaluation of mPEG-PLGA Block Copolymer Micelles Loaded with a Sarsasapogenin Derivative.

Sarsasapogenin derivative 5n (SGD 5n) is a new compound with potent antitumor efficacy, but the low solubility severely affects its absorption and bioavailability. Therefore, the SGD 5n-loaded mPEG-PLGA block copolymer micelles were developed to improve the value of SGD 5n in clinical application. The polymeric micelles were prepared by an organic solvent evaporation method, and the encapsulation efficiency (EE), drug loading (DL), critical micelle concentrations (CMC), morphology, particle size, and zeta potential were determined. The cytotoxicity was examined by the MTT assay, and the cellular uptake study was performed by confocal laser scanning microscopy. A model of tumor-bearing mouse was established to study the antitumor activity in vivo. The results demonstrated that the particle size of the prepared micelle was 124.6 ± 9.6 nm, the encapsulation efficiency was 82.0 ± 2.9%, and the drug loading was 8.3 ± 0.4%. The results of cytotoxicity and cellular uptake demonstrated that the SGD 5n-loaded micelles could efficiently enter tumor cells, and the cellular uptake of SGD 5n presented concentration and time dependence. This study demonstrated that the prepared SGD 5n-loaded polymeric micelles had significant antitumor activity and provided a basis for clinical development of new compound SGD 5n.

Metabolic Epoxidation Is a Critical Step for the Development of Benzbromarone-Induced Hepatotoxicity.

Benzbromarone (BBR) is effective in the treatment of gout; however, clinical findings have shown it can also cause fatal hepatic failure. Our early studies demonstrated that CYP3A catalyzed the biotransformation of BBR to epoxide intermediate(s) that reacted with sulfur nucleophiles of protein to form protein covalent binding both in vitro and in vivo. The present study attempted to define the correlation between metabolic epoxidation and hepatotoxicity of BBR by manipulating the structure of BBR. We rationally designed and synthesized three halogenated BBR derivatives, fluorinated BBR (6-F-BBR), chlorinated BBR (6-Cl-BBR), and brominated BBR (6-Br-BBR), to decrease the potential for cytochrome P450-mediated metabolic activation. Both in vitro and in vivo uricosuric activity assays showed that 6-F-BBR achieved favorable uricosuric effect, while 6-Cl-BBR and 6-Br-BBR showed weak uricosuric efficacy. Additionally, 6-F-BBR elicited much lower hepatotoxicity in mice. Fluorination of BBR offered advantage to metabolic stability in liver microsomes, almost completely blocked the formation of epoxide metabolite(s) and protein covalent binding, and attenuated hepatic and plasma glutathione depletion. Moreover, the structural manipulation did not alter the efficacy of BBR. This work provided solid evidence that the formation of the epoxide(s) is a key step in the development of BBR-induced hepatotoxicity.

How do the substrate reaction forces acting on a gecko's limbs respond to inclines?

Locomotion is an essential character of animals, and excellent moving ability results from the delicate sensing of the substrate reaction forces (SRF) acting on body and modulating the behavior to adapt the motion requirement. The inclined substrates present in habitats pose a number of functional challenges to locomotion. In order to effectively overcome these challenges, climbing geckos execute complex and accurate movements that involve both the front and hind limbs. Few studies have examined gecko's SRF on steeper inclines of greater than 90°. To reveal how the SRFs acting on the front and hind limbs respond to angle incline changes, we obtained detailed measurements of the three-dimensional SRFs acting on the individual limbs of the tokay gecko while it climbed on an inclined angle of 0-180°. The fore-aft forces acting on the front and hind limbs show opposite trends on inverted inclines of greater than 120°, indicating propulsion mechanism changes in response to inclines. When the incline angles change, the forces exerted in the normal and fore-aft directions by gecko's front and hind limbs are reassigned to take full advantage of limbs' different roles in overcoming resistance and in propelling locomotion. This also ensures that weight acts in the angle range between the forces generated by the front and hind limbs. The change in the distribution of SRF with a change in the incline angle is directly linked to the favorable trade-off between locomotive maneuverability and stability.

[Effects of temperature and heating time on armco iron spectral emissivity in atmospheric environment].

The spectral emissivity of pure iron at 1.55 µm was investigated systematically by using our self-designed reflective experimental apparatus based on the Kirchhoff's law, and the influences of temperature and heating time on the spectral emissivity of pure iron were also discussed. The experimental data showed that the spectral emissivity of pure iron increased with temperature rising and its peak value and valley value appeared at certain temperatures. By analyzing the emissivity model of metal with oxidation layer, the variation of the spectral emissivity of pure iron was illustrated. The influence of heating time on the spectral emissivity was different at different temperature. The research results will further enrich pure iron spectral emissivity data, and provide the experimental basis for its application in atmospheric environment.

Prediction of the global occurrence of maize diseases and estimation of yield loss under climate change.

BACKGROUND: Climate change significantly impacts global maize production via yield reduction, posing a threat to global food security. Disease-related crop damage reduces quality and yield and results in economic losses. However, the occurrence of diseases caused by climate change, and thus crop yield loss, has not been given much attention. RESULTS: This study aims to investigate the potential impact of six major diseases on maize yield loss over the next 20 to 80 years under climate change. To this end, the Maximum Entropy model was implemented, based on Coupled Model Intercomparison Project 6 data. The results indicated that temperature and precipitation are identified as primary limiting factors for disease onset. Southern corn rust was projected to be the most severe disease in the future; with a few of the combined occurrence of all the selected diseases covered in this study were predicted to progressively worsen over time. Yield losses caused by diseases varied per continent, with North America facing the highest loss, followed by Asia, South America, Europe, Africa, and Oceania. CONCLUSION: This study provides a basis for regional projections and global control of maize diseases under future climate conditions. © 2024 Society of Chemical Industry.

Targeting the Nrf2-dependent mechanism of b-Ecdysterone in attenuating the motor dysfunction in the MPTP/Pro-induced Parkinson's disease mice model.

Oxidative stress is a pivotal stimulating factor in neurocyte apoptosis and has been involved in the pathogenesis of Parkinson's disease (PD). In this study, we have demonstrated that the improvement in the motor disorder of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/Pro-induced mice caused by b-Ecdysterone (b-Ecd) treatment is due to its antioxidant properties. Using open field, rotarod, and pole climbing tests, we have found that b-Ecd alleviates motor disorder in MPTP/Pro-induced mice and ultimately reduces the impairment of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra (SN). Notably, these effects of b-Ecd were not observed in Nrf2-KO mice. In addition, b-Ecd significantly reduced the formation of ROS and the level of MDA, blocked the increase of LPO, and partially reversed the GSH/GSSG ratio in MPTP/Pro-induced WT mice; however, these results were also not observed in MPTP/Pro-induced Nrf2-KO mice. Mechanistically, b-Ecd enhanced the expression levels of heme oxygenase 1 (HO-1) and GCLc, but not NQO1 (NAD(P)H quinone dehydrogenase 1) and GCLm expression. Interestingly, b-Ecd failed to increase the protein and mRNA levels of HO-1 and GCLc in Nrf2-KO mice, suggesting that b-Ecd attenuates oxidative stress through an Nrf2-dependent mechanism. Furthermore, b-Ecd promoted the expressions of PI3K/Akt phosphorylation (activity) and GSK-3b phosphorylation (inactivity). Conversely, administration of b-Ecd markedly decreased Fyn phosphorylation levels. Collectively, our findings suggest that b-Ecd focuses on Nrf2 in reducing MPTP/Pro-induced oxidative stress and subsequent motor deficits by inhibiting its nuclear export through PI3K/Akt/GSK-3b/Fyn pathway regulation. These further indicate that b-Ecd may be an absorbing therapeutic agent for PD.

GPR35-mediated kynurenic acid sensing contributes to maintenance of gut microbiota homeostasis in ulcerative colitis.

Ulcerative colitis (UC) is a recurrent inflammatory disease related to gut microbiota disorder. Metabolites and their sensors play an important role in the communication between gut microbes and their host. Our previous study revealed that G protein-coupled receptor 35 (GPR35) is a key guardian of kynurenic acid (KA) and a core element of the defense responses against gut damage. However, the mechanism remains unknown. In this study, a DSS-induced rat colitis model was established and 16S rRNA sequencing was applied to explore the influence of GPR35-mediated KA sensing on gut microbiota homeostasis. Our results demonstrated that GPR35-mediated KA sensing is a necessary component in maintaining gut barrier integrity against DSS-induced damage. Furthermore, we provide compelling evidence suggesting that GPR35-mediated KA sensing plays a crucial role in maintaining gut microbiota homeostasis, which contributes to alleviation of DSS-induced colitis. In addition, five classes (Actinobacteria, Beta-/Gamma-proteobacteria, Erysipelotrichi, and Coriobacteriia) and six genera (Corynebacterium, Allobaculum, Parabacteroides, Sutterella, Shigella, and Xenorhabdus) were identified as the marked bacterial taxa that characterized the progression and outcome of colitis and are regulated by GPR35-mediated KA sensing. Our findings highlight that GPR35-mediated KA sensing is an essential defense mechanism against disorder of gut microbiota in UC. The results provide insights into the key role of specific metabolites and their monitor in maintaining gut homeostasis.

Does ipsilateral knee pain improve after hip arthroplasty?

BACKGROUND: Intraarticular hip disease is commonly acknowledged as a cause of ipsilateral knee pain. However, this is based primarily on observational rather than high-quality evidence-based studies, and it is unclear whether ipsilateral knee pain improves when hip disease has been treated. QUESTIONS/PURPOSES: We asked whether (1) hip disease was associated with preoperative ipsilateral knee pain and (2) ipsilateral knee pain would improve after hip arthroplasty. PATIENTS AND METHODS: We retrospectively assessed knee pain in 255 patients who underwent hip arthroplasties between 2006 and 2008. The WOMAC pain score of each joint was the primary outcome measure, which was obtained prospectively before surgery and at 3 months and 1 year postoperatively. Of the 255 patients, 245 (96%) had followup data obtained at 3 months or 1 year. RESULTS: Preoperatively, ipsilateral knee pain was observed more frequently than contralateral knee pain (55% versus 18%). Preoperative ipsilateral knee pain scores were worse than contralateral knee pain scores (mean, 80 versus 95). Ipsilateral knee pain improved at 3 months and 1 year. When compared with the scores for contralateral knee pain at 3 months (95) and 1 year (96), there were no differences between knees. CONCLUSIONS: Our observations suggest hip disease is associated with ipsilateral knee pain and that it improves after hip arthroplasty. This should be considered during preoperative evaluation for patients with hip and knee pain. LEVEL OF EVIDENCE: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

Comparison of total hip and knee arthroplasty cohorts and short-term outcomes from a single-center joint registry.

The purpose of this study was to compare short-term clinical outcomes between total hip arthroplasty (THA) and total knee arthroplasty (TKA) patient cohorts, adjusting for confounding variables including age, sex, body mass index, operative time, length of stay, and preoperative Western Ontario and McMaster Universities and 12-Item Short-Form Health Survey. A total of 349 patients who met inclusion and exclusion criteria created 2 cohorts: THA, 194, and TKA, 155, for statistical analysis via multiple regression and analysis of covariance measures. Outcome measures included Western Ontario and McMaster Universities and 12-Item Short-Form Health Survey data, collected prospectively at baseline and 2 years of follow-up. The current study showed that baseline characteristics of TKA patients have more factors with negative effect on postoperative outcome than THA. However, despite controlling for the possible confounding effect of these variables, THA patients experienced a significantly better functional outcome than TKA patients.

Predicting need for allogeneic transfusion after total knee arthroplasty.

Total knee arthroplasty (TKA) can lead to substantial blood loss. To avoid the high costs of autologous blood predonation programs and efficiently allocate limited blood resources, we sought to identify preoperative and intraoperative factors associated with allogeneic blood transfusion (AllTx) after primary TKA and, subsequently, develop a model to predict patients who will require AllTx. We analyzed 31 independent variables in 644 primary unilateral TKAs without autologous blood predonation for requirement of AllTx. Seventy-one procedures (11.0%) required AllTx. Age, comorbid anemia, preoperative hemoglobin concentration, and surgical time were significant predictors for requiring AllTx. When applied to an independent cohort, our model for predicting the need for AllTx after TKA was 90% sensitive and 52.5% specific.

Study on the influence of COVID-19 on the growth of China's small and medium-sized construction enterprises.

The outbreak of COVID-19 at the beginning of 2020 had a significant impact on China's economy, society, and citizens; it also had a negative impact on the development of the construction industry. In particular, small and medium-sized construction enterprises with low ability to withstand risk have been strongly impacted, aggravating a crisis of survival among these firms. The focus of this study is to analyze the impact of COVID-19 on the growth of small and medium-sized construction companies. Based on the characteristics of small and medium-sized construction enterprises, this paper establishes a growth evaluation index and builds a growth evaluation model based on factor analysis. Twenty-three construction enterprises listed on small and medium-sized enterprises board are selected as samples, and the quarterly data of 2019 and 2020 are used for empirical analysis. The results show that the epidemic has had a high short-term impact on construction enterprises, and the total output value of the construction industry in the first quarter of 2020 was 16% lower than that in the same period of last year. In the long run, the impact of the epidemic on the growth of small and medium-sized construction enterprises has been limited. In the first quarter of 2020, the growth score of enterprises decreased by only 1.95% year-over-year, and it was essentially flat in the second and third quarters. The epidemic has had little influence on solvency, tangible resources or intangible resources but a high short term influence on profitability, capital expansion and market expectations. The long-term impact is small; It is conducive to the improvement of enterprise operation ability. Finally, to both address the influence of the COVID-19 on small and medium-sized construction enterprises and to realize their transformation and upgrading, targeted suggestions are offered at the policy and enterprise levels. The results will help to understand the impact of the epidemic on the growth of construction enterprises, and provide decision support for the healthy and orderly development of the follow-up construction industry.

Synthesis and biological evaluation of celastrol derivatives as potential anti-glioma agents by activating RIP1/RIP3/MLKL pathway to induce necroptosis.

Celastrol, a quinone methide triterpenoid, possesses potential anti-glioma activity. However, its relatively low activity limit its application as an effective agent for glioma treatment. In search for effective anti-glioma agents, this work designed and synthesized two series of celastrol C-3 OH and C-20 COOH derivatives 4a-4o and 6a-6o containing 1, 2, 3-triazole moiety. Their anti-glioma activities against four human glioma cell lines (A172, LN229, U87, and U251) were then evaluated using MTT assay in vitro. Results showed that compound 6i (IC50 = 0.94 µM) exhibited substantial antiproliferative activity against U251 cell line, that was 4.7-fold more potent than that of celastrol (IC50 = 4.43 µM). In addition, compound 6i remarkably inhibited the colony formation and migration of U251 cells. Further transmission electron microscopy and mitochondrial depolarization assays in U251 cells indicated that the potent anti-glioma activity of 6i was attributed to necroptosis. Mechanism investigation revealed that compound 6i induced necroptosis mainly by activating the RIP1/RIP3/MLKL pathway. Additionally, compound 6i exerted acceptable BBB permeability in mice and inhibited U251 cell proliferation in an in vivo zebrafish xenograft model, obviously. In summary, compound 6i might be a promising lead compound for potent celastrol derivatives as anti-glioma agents.

Novel diosgenin-amino acid-benzoic acid mustard trihybrids exert antitumor effects via cell cycle arrest and apoptosis.

In discovering new powerful antitumor agents, two series of novel diosgenin-amino acid-benzoic acid mustard trihybrids (7a-7 g and 12a-12 g) were designed and synthesized. The antiproliferative activities were tested against five human tumor cell lines and one normal cell line using CCK-8 assays. Among the trihybrids, 12e was the most promising compound, which inhibited T24 cells with IC50 value of 6.96 µM, and was stronger than its parent compound diosgenin (IC50 = 32.33 µM). In addition, 12e had weak cytotoxicity on the normal GES-1 cell line (IC50 = 213.74 µM). Moreover, 12e could cause G2/M cell cycle arrest, increase the percentage of apoptosis, induce mitochondrial depolarization, and promote reactive oxygen species generation in T24 cells. Further studies on antitumor mechanism demonstrated that 12e triggered the intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways. More importantly, 12e could inhibit T24 cell proliferation in an in vivo zebrafish xenograft model. Therefore, 12e, as a novel trihybrid with potent cytotoxicity, might be applied as a promising skeleton for antitumor agents, which deserved further optimization.

Alkaloids constituents from the roots of Phragmites australis (Cav.) Trin. ex Steud. with their cytotoxic activities.

Two new alkaloids, phranisines A-B (1-2), along with two known compounds, N-p-Coumaroyl serotonin (3) and N-p-coumaroyl-tryptamine (4), were isolated from the roots of Phragmites australis. The structures of 1-4 were established on the basis of extensive spectroscopic. The absolute configuration of compounds 1-2 were identified through quantum-chemical electronic circular dichroism (ECD) calculation compared with their experimental CD. All the isolated compounds were tested for their cytotoxic activities against HeLa and MCF-7 human cancer cell lines, and compounds 2-4 showed moderate cytotoxic activities against HeLa cell lines with IC50 values ranging from 13.2 to 18.6 µM.

The accuracy and reliability of preoperative templating for metal-on-metal hip resurfacing.

The purposes of this study were to evaluate the accuracy and reliability of preoperative templating on conventional radiographs (CRs) for metal-on-metal hip resurfacing and to determine the factors affecting the accuracy. Four observers templated 80 CRs on 2 separate occasions in a blinded fashion. Eight independent variables were evaluated to investigate their effect on the accuracy of templating. The overall accuracy of templating within one size of the actual component was 80.6% for the femoral component and 98.5% for the acetabular component. Overall, the intraobserver and interobserver reliability was fair to substantial (κ = 0.22-0.61). Using multiple regression analysis, surgical time was the only factor that affected the accuracy of predicting the size of the acetabular component (P = .019). We conclude that CR templating for metal-on-metal hip resurfacing is a useful method for preoperative planning of the sizes of the respective implants and that surgeon experience does play a significant role in the accuracy of predicting component size during templating.