Glutathione-triggered prodrugs: Design strategies, potential applications, and perspectives.

The burgeoning prodrug strategy offers a promising avenue toward improving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione (GSH) have been regarded as a hallmark of tumor cells and characteristic feature of the tumor microenvironment. Considering the pivotal involvement of elevated GSH in the tumorigenic process, a diverse repertoire of GSH-triggered prodrugs has been developed for cancer therapy, facilitating the attenuation of deleterious side effects associated with conventional chemotherapeutic agents and/or the attainment of more efficacious therapeutic outcomes. These prodrug formulations encompass a spectrum of architectures, spanning from small molecules to polymer-based and organic-inorganic nanomaterial constructs. Although the GSH-triggered prodrugs have been gaining increasing interests, a comprehensive review of the advancements made in the field is still lacking. To fill the existing lacuna, this review undertakes a retrospective analysis of noteworthy research endeavors, based on a categorization of these molecules by their diverse recognition units (i.e., disulfides, diselenides, Michael acceptors, and sulfonamides/sulfonates). This review also focuses on explaining the distinct benefits of employing various chemical architecture strategies in the design of these prodrug agents. Furthermore, we highlight the potential for synergistic functionality by incorporating multiple-targeting conjugates, theranostic entities, and combinational treatment modalities, all of which rely on the GSH-triggering. Overall, an extensive overview of the emerging field is presented in this review, highlighting the obstacles and opportunities that lie ahead. Our overarching goal is to furnish methodological guidance for the development of more efficacious GSH-triggered prodrugs in the future. By assessing the pros and cons of current GSH-triggered prodrugs, we expect that this review will be a handful reference for prodrug design, and would provide a guidance for improving the properties of prodrugs and discovering novel trigger scaffolds for constructing GSH-triggered prodrugs.

Naphthalimide Fluorescent Skeleton for Facile and Accurate Quantification of Glutathione.

Glutathione (GSH), the most prevalent nonprotein thiol in biological systems, acts as both an antioxidant to manipulate intracellular redox homeostasis and a nucleophile to detoxify xenobiotics. The fluctuation of GSH is closely related to the pathogenesis of diverse diseases. This work reports the construction of a nucleophilic aromatic substitution-type probe library based on the naphthalimide skeleton. After an initial evaluation, the compound R13 was identified as a highly efficient GSH fluorescent probe. Further studies demonstrate that R13 could readily quantify GSH in cells and tissues via a straightforward fluorometric assay with a comparable accuracy to the results from the HPLC. We then used R13 to quantify the content of GSH in mouse livers after X-ray irradiation, revealing that irradiation-induced oxidative stress leads to the increase of oxidized GSH (GSSG) and depletion of GSH. In addition, probe R13 was also applied to investigate the alteration of the GSH level in the Parkinson's mouse brains, showing a decrease of GSH and an increase of GSSG in Parkinson's mouse brains. The convenience of the probe in quantifying GSH in biological samples facilitates further understanding of the fluctuation of the GSH/GSSG ratio in diseases.

Imaging of Carbonic Anhydrase Level in Epilepsy with an Environment-Sensitive Fluorescent Probe.

Carbonic anhydrases (CAs) participate in various physiological and pathological activities by catalyzing the interconversion between carbon dioxide and bicarbonate ions. Under normal circumstances, they guarantee that the relevant biological reactions in our body occur within an appropriate time scale. Abnormal expression or activity alteration of CAs is closely related to the pathogenesis of diverse diseases. This work reports an inhibitor-directed fluorescent probe FMRs-CA for the detection of CAs. Excellent selectivity, favorable biocompatibility, and desirable blood-brain barrier (BBB) penetration endow the probe with the ability to image the fluctuation of CAs in cells and mice. We achieved in situ visualization of the increased CAs in hypoxic cells with this probe. Additionally, probe FMRs-CA was mainly enriched within the liver and gradually metabolized by the liver. With the help of FMRs-CA, the increase of CAs in epileptic mouse brains was revealed first from the perspective of imaging, providing the mechanism connection between abnormal CA expressions and epilepsy.

Synthesis and evaluation of Piperine analogs as thioredoxin reductase inhibitors to cause oxidative stress-induced cancer cell apoptosis.

Inhibiting thioredoxin reductase (TrxR) to disrupt the redox equilibrium and induce tumor cell apoptosis is a significant tumor therapeutic strategy. Piperine, a natural product from black pepper, has been demonstrated to suppress tumor cell proliferation by enhancing reactive oxygen species (ROS), subsequently leading to cell death. However, the development of Piperine as an active molecule is hampered by its weak cytotoxicity. To develop a compound with higher activity, we synthesized 22 Piperine analogs and evaluated their pharmacological properties. Ultimately, B5 was screened by the results of cytotoxicity and inhibition of TrxR activity. In contrast to Piperine, B5 had significant cytotoxicity with a 4-fold increase. The structure-activity relationship demonstrated that the introduction of an electron-withdrawing group into the benzene ring adjacent to the amino group, particularly in the meta-position, was positive and that shortening the olefin double bond had no appreciable impact on cytotoxicity. Further investigating the physiological activity of B5 in HeLa cells, we found that B5 selectively inhibits the activity of TrxR by binding to Sec residues on TrxR. B5 then induces cellular oxidative stress and finally leads to apoptosis. As a result, the study of B5 paved the way for further investigation into the modification and function of Piperine analogs as TrxR inhibitors.

(2E)-1-(2,4,6-Trimethoxyphenyl)-3-(4-chlorophenyl)prop-2-en-1-one, a Chalcone Derivative, Promotes Apoptosis by Suppressing RAS-ERK and AKT/FOXO3a Pathways in Hepatocellular Carcinoma Cells.

BACKGROUND: Liver cancer is an extremely common cancer with the highest mortality rate and poor prognosis. Owing to their low systemic toxicity and few side effects, natural compounds may provide better therapeutic effects for patients. (2E)-1-(2,4,6-trimethoxyphenyl)-3-(4-chlorophenyl)prop-2-en-1-one (TMOCC), a chalcone derivative, exhibits cytotoxicity towards many tumor cells. However, the anticancer mechanism of TMOCC has not been elucidated in human hepatocellular carcinoma (HCC). METHODS: Cell Counting Kit-8 and colony formation assays were used to evaluate the effects of TMOCC on viability and proliferation. Mitochondrial transmembrane potential and flow cytometry assays were used to detect apoptosis. The expression levels of proteins related to apoptosis, the RAS-ERK and AKT/FOXO3a signaling pathways were assessed using western blot. Potential targets of TMOCC were detected using molecular docking analysis. RESULTS: TMOCC inhibited viability and proliferation, and induced the loss of mitochondrial transmembrane potential, apoptosis and DNA double-strand breaks in both HCC cells. The RAS-ERK and AKT/FOXO3a signaling pathways were suppressed by TMOCC. Finally, ERK1, PARP-1, and BAX were identified as potential targets of TMOCC. CONCLUSION: Taken together, our results show that TMOCC promotes apoptosis by suppressing the RAS-ERK and AKT/FOXO3a signaling pathways. TMOCC may be a potential multi-target compound that is effective against liver cancer.

Hemin as a General Static Dark Quencher for Constructing Heme Oxygenase-1 Fluorescent Probes.

The development of small-molecule probes suitable for live-cell applications remains challenging yet highly desirable. We report the first fluorescent probe, RBH, for imaging the heme oxygenase-1 (HO-1) activity in live cells after discovering hemin as a universal dark quencher. Hemin works via a static quenching mechanism and shows high quenching efficiency (>97 %) with fluorophores across a broad spectrum (λex =400-700 nm). The favorable properties of RBH (e.g. long excitation/emission wavelengths, fast response rate and high magnitude of signal increase) enable its use for determining HO-1 activity in complex biological samples. As HO-1 is involved in regulating antioxidant defence, iron homeostasis and gasotransmitter carbon monoxide production, we expect RBH to be a powerful tool for dissecting its functions. Also, the discovery of hemin as a general static dark quencher provides a straightforward strategy for constructing novel fluorescent probes for diverse biological species.

Perceptions and attitudes towards elective egg freezing of Chinese college students: a survey from eastern China.

PURPOSE: Few options are available for preserving female fertility to postpone childbirth. Although egg freezing with successful thawing is now possible, women' attitudes towards its use or the circumstances under which this technique may be considered remain unclear. METHODS: This study is a cross-sectional online survey. From November 2020 to January 2021, 848 questionnaires were collected through the Questionnaire Star Network platform, and a total of 750 valid answers were obtained. RESULTS: For more than 40% of the interviewees, the level of knowledge about egg freezing was only 0-25%; 36.9% of the interviewees supported elective egg freezing, and the main factor affecting their approval was major; approximately 60% of interviewees believed that being married should not be a condition for freezing eggs; and 56.7% of the interviewees supported the establishment of an egg bank in China, and the main factor affecting their acceptance was the place of residence. CONCLUSION: College students generally have a high level of recognition regarding elective egg freezing and the establishment of an egg bank, but their level of knowledge about egg freezing is low. Relevant knowledge must be strengthened to help college students achieve a correct understanding of elective egg freezing and egg bank establishment and then guide college students in developing a scientific dialectical attitude towards this technology.

Fusaricide is a Novel Iron Chelator that Induces Apoptosis through Activating Caspase-3.

Nonsmall cell lung cancer (NSCLC) has been a fatal and refractory disease worldwide. Novel therapeutic developments based on fundamental investigations of anticancer mechanisms underlie substantial foundations to win the fight against cancer diseases. In this study, we isolated a natural product fusaricide (FCD) from an endophytic fungus of Lycium barbarum, identified as Epicoccum sp. For the first time, we discovered that FCD potently inhibited proliferation in a variety of human NSCLC cell lines, with relatively less toxicity to normal cells. Our study exhibited that FCD induced apoptosis, caused DNA damage and cell cycle arrest in G0/G1 phase, and activated caspase-3 as well as other apoptosis-related factors in human NSCLC NCI-H460 cells. FCD was proven to be an iron chelator that actively decreased levels of cellular labile iron pool in NCI-H460 cells in our study. FeCl3 supplement reversed FCD-induced apoptosis. The upregulation of transferrin receptor 1 (TfR1) and downregulation of ferritin heavy chain (FTH) expression were observed after FCD treatment. In summary, our study highlighted the potential anticancer effects of FCD against human NSCLCs and demonstrated that the FCD-mediated apoptosis depended on binding to intracellular iron.

The effectiveness and safety of topical ß-receptor blocker in treating superficial infantile haemangiomas: A meta-analysis including 20 studies.

AIMS: To evaluate the effectiveness and safety of topical ß-receptor blocker in treating superficial infantile haemangiomas (SIH) and compare the effectiveness and safety of topical ß-receptor blocker against other therapies. METHODS: A search of the literature using PubMed, Embase, Cochrane Review database, China National Knowledge Infrastructure and Wanfang were performed to identify the studies that estimated the effectiveness and safety of topical ß-receptor blocker in treating SIH, the fixed-effect or random-effects meta-analytical techniques were applied to assess the outcomes. RESULTS: Twenty studies, involving 2098 patients, were included to conduct this analysis. Topical propranolol and topical timolol were discovered to be as effective as oral propranolol in treating SIH (propranolol, odds ratio [OR] = 0.486, 95% confidence interval [CI] 0.165, 1.426, P = .189; timolol, OR = 0.955; 95%CI 0.700, 1.302; P = .769), and topical timolol was more effective than topical imiquimod (OR = 2.561; 95%CI 1.182, 5.550; P = .017), observation (OR = 18.458; 95%CI 5.660, 60.191; P < .001) and topical saline solutions (OR = 19.193; 95%CI 8.837, 41.683; P < .001) in treating SIH. The comparison between topical propranolol and oral propranolol led to no discovery of significant difference in the incidence of adverse effects (OR = 1.258; 95%CI 0.471, 3.358; P = .647). Compared with oral propranolol, topical timolol was associated with fewer incidences of adverse effects (OR = 0.191; 95%CI 0.043, 0.858; P = .031). No significant difference in the incidence of adverse effects was found when topical timolol and topical imiquimod were compared (OR = 0.077; 95%CI 0.005, 1.206; P = .068). CONCLUSION: This meta-analysis provided evidence that topical ß-receptor blockers (propranolol and timolol), especially timolol, may replace oral propranolol as a first-line treatment for SIH.

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update.

Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

An Azo Coupling Strategy for Protein 3-Nitrotyrosine Derivatization.

Herein, a strategy for the selective derivatization of 3-nitrotyrosine-containing proteins using the classic azo coupling reaction as the key step is described. This novel approach featured multiple advantages and was successfully applied to detect picomole levels of protein tyrosine nitration in biological samples.

Meta-analysis of the diagnostic value of contrast-enhanced ultrasound for the detection of vascular complications after liver transplantation.

BACKGROUND: contrast-enhanced ultrasound (CEUS) is increasingly used to identify vascular complications in patients after liver transplantation. The present study aimed to evaluate the diagnostic accuracy of CEUS using all available data. MATERIALS AND METHODS: relevant studies published before February 2018 were retrieved from PubMed, EMBASE, ScienceDirect and Web of Science. Pooled sensitivity and specificity, diagnostic odds ratio (DOR) and summary receiver operating characteristic curve (SROC) were calculated to estimate the diagnostic performance of CEUS for vascular complications. Sensitivity analysis was performed that stratified studies according to age, study design and sample size in order to determine the influence of these factors on the overall effect. Meta-regression analyses were performed to examine the possible sources of heterogeneity. Quality assessment and publication bias of the included studies were also evaluated. RESULTS: thirteen studies which consisted of 2,781 CEUS cases were included in the analysis. The pooled weighted estimates of sensitivity and specificity were 0.90 (95% CI, 0.84 to 0.95) and 1.00 (95% CI, 1.00 to 1.00), the diagnostic odds ratio (DOR) was 431.96 (95% CI, 164.60 to 1,133.59) and the area under the curve (AUC) of SROC was 0.9741. According to the sensitivity analysis, age, study design and sample size had an insignificant influence on the diagnostic performance of CEUS. The meta-regression analyses did not reveal a strong correlation between CEUS accuracy and study design, treatment time of patients and experience of the radiologists. CONCLUSION: the results of our meta-analysis showed a high sensitivity, specificity and accuracy of the CEUS modality for the identification of vascular complications in patients after liver transplantation. Since this is the first meta-analysis investigating in this aspect, more evidence is required to validate the clinical utility of CEUS for the identification of vascular complications in patients with a transplanted liver.

Epigenetically controlled Six3 expression regulates glioblastoma cell proliferation and invasion alongside modulating the activation levels of WNT pathway members.

Glioma is the most common primary brain tumor in adults. Six3 is a human homologue of the highly conserved sine oculis gene family and essential transcription regulatory factor in process of eye and fetal forebrain development. However, little is known about the role of Six3 in human tumorigenesis. The aim of this study is to investigate the methylation/expression of Six3 and reveal its function and action mechanism in glioma. Our results showed that Six3 was down-regulated in human glioma tissues and human glioma SHG-44, U251, SF126 and U373-MG cells compared with the normal tissues. And the down-regulation of Six3 was associated with the methylation of its promoter. Glioma U251 cells lacked endogenous Six3. Treatment with demethylating agent (5-aza-2'-deoxycytidine) or exogenous expression of Six3 restored Six3 production and resulted in suppression of cell cycle G1/S transition, proliferation and invasion and down-regulation of the expression of Wnt1, p-GSK3-ß, ß-catenin and cyclin D1 in glioma U251 cells. However, knockdown of Six3 in SHG-44 cells, which have relative higher baseline level of Six3, resulted in an opposite action. These results demonstrate that Six3 silence or loss in glioma is induced by its promoter hypermethylation and Six3 down-regulation contributes to proliferation and invasion of glioma. And this process is involved in activation of Wnt/ß-catenin pathway. Six3 play a suppressor role in the initiation and progression of human glioma and potentially serve as a target for the diagnosis and treatment of human glioma.

Selective selenol fluorescent probes: design, synthesis, structural determinants, and biological applications.

Selenium (Se) is an essential micronutrient element, and the biological significance of Se is predominantly dependent on its incorporation as selenocysteine (Sec), the genetically encoded 21st amino acid in protein synthesis, into the active site of selenoproteins, which have broad functions, ranging from redox regulation and anti-inflammation to the production of active thyroid hormones. Compared to its counterpart Cys, there are only limited probes for selective recognition of Sec, and such selectivity is strictly restricted at low pH conditions. We reported herein the design, synthesis, and biological evaluations of a series of potential Sec probes based on the mechanism of nucleophilic aromatic substitution. After the initial screening, the structural determinants for selective recognition of Sec were recapitulated. The follow-up studies identified that probe 19 (Sel-green) responds to Sec and other selenols with more than 100-fold increase of emission in neutral aqueous solution (pH 7.4), while there is no significant interference from the biological thiols, amines, or alcohols. Sel-green was successfully applied to quantify the Sec content in the selenoenzyme thioredoxin reductase and image endogenous Sec in live HepG2 cells. With the aid of Sel-green, we further demonstrated that the cytotoxicity of different selenocompounds is correlated to their ability metabolizing to selenols in cells. To the best of our knowledge, Sel-green is the first selenol probe that works under physiological conditions. The elucidation of the structure-activity relationship for selective recognition of selenols paves the way for further design of novel probes to better understand the pivotal role of Sec as well as selenoproteins in vivo.

Intraperitoneal administration of fetuin-A attenuates D-galactosamine/lipopolysaccharide-induced liver failure in mouse.

BACKGROUND: Fulminant hepatic failure (FHF) is a devastating syndrome, which sometimes results in death or liver transplantation, in which inflammation would aggravate the development of fetuin-A which would act as an anti-inflammatory factor and may be an available approach to attenuate FHF. AIMS: The purpose of this study was to investigate the effects of fetuin-A on D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced liver failure in mice. METHODS: A mouse model of FHF induced by D-GalN/LPS was established and fetuin-A was injected intraperitoneally prior to D-GalN/LPS treatment. At different time points after D-GalN/LPS intervention, serum TNF-α and IL-6 levels were measured by ELISA. Fetuin-A mRNA and protein expression in liver tissues was assessed by RT-PCR, Western blotting and immunohistochemical staining. Besides, an observation of liver tissue injury, the apoptosis of hepatocytes, was analyzed by TUNEL assay. RESULTS: Expression of fetuin-A mRNA and protein in liver tissue were significantly and gradually decreased after D-GalN/LPS administration. A pre-intervention of exogenous fetuin-A significantly improved the liver function, decreased TNF-α and IL-6 expression in peripheral blood, and liver tissue inhibited hepatocyte apoptosis responded to D-GalN/LPS induction so as to decrease the mortality rates of FHF mouse. Meanwhile, fetuin-A was negatively correlated with the hepatic pathological score and TNF-α protein staining in FHF mouse. CONCLUSIONS: An intraperitoneal injection of fetuin-A attenuates D-GalN/LPS-induced FHF in mice. Fetuin-A might be a protective agent of liver damage partly through inhibiting liver inflammatory response and hepatocyte apoptosis.

The Difference between Stress Deformation and Adsorption Deformation of Coal Reservoirs and Its Role in Permeability Prediction.

The key to the variation in permeability within coal reservoirs lies in the stress-induced deformation and desorption-induced deformation during the coalbed methane (CBM) production. The differences in sample scale and measurement methods between stress-induced deformation and desorption-induced deformation significantly affect the accuracy of permeability measurements. Therefore, in order to elucidate the relationship between stress-induced deformation and adsorption-induced deformation, as well as the influencing factors, and to assess the accuracy of permeability evolution prediction, this study conducted a series of parallel experiments, including compression deformation experiments under stress loading (stress-induced deformation), methane adsorption-induced deformation experiments (adsorption-induced deformation), µCT scanning, and overburden permeability measurements.The results of the study indicate that stress-induced deformation and adsorption-induced deformation are negatively correlated but exhibit a relatively weak correlation. Stress-induced deformation encompasses deformation of coal matrix, minerals, and fractures, whereas adsorption-induced deformation primarily reflects coal matrix deformation. While there is some overlap between the two, they are not entirely identical. The main influencing factor of stress-induced deformation is the mechanical strength of coal, with minerals in coal increasing the Young's modulus of coal reservoirs. Among them, minerals that are more dispersed and have smaller particles have a more significant impact on stress-induced deformation. The primary influencing factor of adsorption-induced deformation is the deformation capability of the coal matrix, with minerals and fractures having less significant effects. Permeability changes are controlled by fracture deformation, but stress-induced deformation measurements weakly reflect this aspect, leading to an inability to accurately predict the scale of the impact of effective stress changes on permeability during CBM production and CO2-ECBM processes. In contrast, adsorption-induced deformation relatively accurately reflects the deformation capability of the coal matrix and provides a more accurate prediction of permeability rebound under the condition of almost unchanged effective stress in the late stages of mining. Therefore, deformation parameters under stress loading are challenging to directly apply to the prediction of permeability evolution, while adsorption-induced deformation parameters can be effectively utilized.

[Applications of ion chromatography for the analysis of Chinese herbal medicine components].

Ion chromatography (IC) is a novel high performance liquid chromatographic technique that is suitable for the separation and analysis of ionic substances in different matrix samples. Since 1975, it has been widely used in many fields, such as the environment, energy, food, and medicine. IC compensates for the separation limitations of traditional gas chromatography and high performance liquid chromatography and can realize the qualitative analysis and quantitative detection of strongly polar components. This chromatographic technique features not only simple operations but also rapid analysis. The sensors used in IC are characterized by high sensitivity and selectivity, and the technique can simultaneously separate and determine multiple components. Several advances in IC instrumentation and chromatographic theories have been developed in recent years. IC can analyze various types of samples, including ions, sugars, amino acids, and organic acids (bases). Chinese herbal medicines are typically characterized by highly complex chemical compositions and may contain carbohydrates, proteins, alkaloids, and other active components. They also contain toxic residues such as sulfur dioxide, which may be produced during the processing of medicinal materials. Therefore, the analysis and elucidation of the precise chemical constituents of Chinese herbal medicines present key problems that must be resolved in modern Chinese herbal medicine research. In this context, IC has become an important method for analyzing and identifying the complex components of Chinese herbal medicines because this method is suitable for detecting a single active ingredients among complex components. This paper introduces the different types and principles of IC as well as research progress in this technique. As the applications of IC-based methods in pharmaceutical science, cell biology, and microbiology increase, further development is necessary to expand the applications of this technique. The development of innovative techniques has enabled IC technologies to achieve higher analytical sensitivity, better selectivity, and wider application. The components of Chinese herbal medicines can be divided into endogenous and exogenous components according to their source: endogenous components include glycosides, amino acids, and organic acids, while exogenous components include toxic residues such as sulfur dioxide. Next, the applications of IC to the complex components of Chinese herbal medicines in recent decades are summarized. The most commonly used IC technologies and methods include ion exchange chromatography and conductivity detection. The advantages of IC for the analysis of alkaloids have been demonstrated. This method exhibits better characteristics than traditional analytical methods. However, the applications of IC for the speciation analysis of inorganic anions are limited. Moreover, few reports on the direct application of the technique for the determination of the main active substances in Chinese herbal medicines, including flavonoids, phenylpropanoids, and steroids, have been reported. Finally, this paper reviews new IC technologies and their application progress in Chinese herbal medicine, focusing on their prospects for the effective separation and analysis of complex components. In particular, we discuss the available sample (on-line) pretreatment technologies and explore possible technologies for the selective and efficient enrichment and separation of different components. Next, we assess innovative research on solid-phase materials that can improve the separation effect and analytical sensitivity of IC. We also describe the features of multidimensional chromatography, which combines the advantages of various chromatographic techniques. This review provides a theoretical reference for the further development of IC technology for the analysis of the complex chemical components of Chinese herbal medicines.

The Shehata technique for undescended testes that cannot be brought into the scrotum in one operation-a case series and meta-analysis.

Background: Fowler-Stephens orchiopexy is commonly used for testes that cannot be brought into the scrotum in one operation. However, this surgical technique may result in a higher rate of testicular atrophy postoperatively. Methods: During the period between 2019 and 2023, we analyzed the cases of 20 patients in whom the Shehata technique was applied for testes that could not be brought into the scrotum in one operation, and we conducted a meta-analysis to explore the incidence of testicular atrophy vis-à-vis the Shehata technique and Fowler-Stephens orchiopexy. Results: The average age of the 20 patients was 3.78 (0.76-11.42) years. The blood supply to the testes was satisfactory, with the absence of atrophy, and the testes could be brought into the scrotum in stage II surgery. A postoperative reexamination with ultrasound revealed that the testes were securely positioned within the scrotum, with good blood supply and no atrophy, which was in contrast to their condition before the operation. The volume of the testes postoperatively was significantly greater than that of the preoperative testes (p = 0.009). There were no statistically significant differences in the growth rate of volume of the testes between the surgically treated side and the contralateral side (p = 0.25). The meta-analysis showed that the Shehata technique resulted in a lower incidence of testicular atrophy compared with Fowler-Stephens orchiopexy (p = 0.01). Conclusions: The Shehata technique preserves the main vessels of the testes with a lower incidence of testicular atrophy, which may be a valid and safe alternative to the Fowler-Stephens technique.

Hydroxygenkwanin exerts a neuroprotective effect by activating the Nrf2/ARE signaling pathway.

High levels of reactive oxygen species (ROS) have been associated with the progression of neurodegenerative diseases such as Alzheimer's disease. The activation of the NFE2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway may restore the neuron's redox balance and provide a therapeutic impact. Hydroxygenkwanin (HGK), a dominant flavone from Genkwa Flos, has received expanding attention due to its medicinal activities. Our investigation results demonstrated the ability of HGK to protect the PC12 cells from oxidative damage caused by an excessive hydrogen peroxide load. HGK also showed the ability to upregulate a panel of endogenous antioxidant proteins. Further investigations have demonstrated that the neuroprotection mechanism of HGK is dependent on the activation of the Nrf2/ARE signaling pathway. Activating the Nrf2/ARE pathway by HGK reveals a novel mechanism for understanding the pharmacological functions of HGK. These findings suggest that HGK could be considered for further development as an oxidative stress-related neurological pathologies potential therapeutic drug.

3D-printed porous zinc scaffold combined with bioactive serum exosomes promotes bone defect repair in rabbit radius.

Currently, the repair of large bone defects still faces numerous challenges, with the most crucial being the lack of large bone grafts with good osteogenic properties. In this study, a novel bone repair implant (degradable porous zinc scaffold/BF Exo composite implant) was developed by utilizing laser melting rapid prototyping 3D printing technology to fabricate a porous zinc scaffold, combining it under vacuum conditions with highly bioactive serum exosomes (BF EXO) and Poloxamer 407 thermosensitive hydrogel. The electron microscope revealed the presence of tea saucer-shaped exosomes with a double-layered membrane structure, ranging in diameter from 30-150 nm, with an average size of 86.3 nm and a concentration of 3.28E+09 particles/mL. In vitro experiments demonstrated that the zinc scaffold displayed no significant cytotoxicity, and loading exosomes enhanced the zinc scaffold's ability to promote osteogenic cell activity while inhibiting osteoclast activity. In vivo experiments on rabbits indicated that the hepatic and renal toxicity of the zinc scaffold decreased over time, and the loading of exosomes alleviated the hepatic and renal toxic effects of the zinc scaffold. Throughout various stages of repairing radial bone defects in rabbits, loading exosomes reinforced the zinc scaffold's capacity to enhance osteogenic cell activity, suppress osteoclast activity, and promote angiogenesis. This effect may be attributed to BF Exo's regulation of p38/STAT1 signaling. This study signifies that the combined treatment of degradable porous zinc scaffolds and BF Exo is an effective and biocompatible strategy for bone defect repair therapy.