Rhizosphere microbial markers (micro-markers): A new physical examination indicator for traditional Chinese medicines.

Rhizosphere microorganisms, as one of the most important components of the soil microbiota and plant holobiont, play a key role in the medicinal plant-soil ecosystem, which are closely related to the growth, adaptability, nutrient absorption, stress tolerance and pathogen resistance of host plants. In recent years, with the wide application of molecular biology and omics technologies, the outcomes of rhizosphere microorganisms on the health, biomass production and secondary metabolite biosynthesis of medicinal plants have received extensive attention. However, whether or to what extent rhizosphere microorganisms can contribute to the construction of the quality evaluation system of Chinese medicinal materials is still elusive. Based on the significant role of rhizosphere microbes in the survival and quality formation of medicinal plants, this paper proposed a new concept of rhizosphere microbial markers (micro-markers), expounded the relevant research methods and ideas of applying the new concept, highlighted the importance of micro-markers in the quality evaluation and control system of traditional Chinese medicines (TCMs), and introduced the potential value in soil environmental assessment, plant pest control and quality assessment of TCMs. It provides reference for developing ecological planting of TCMs and ensuring the production of high quality TCMs by regulating rhizosphere microbial communities.

Deep Learning Bridged Bioactivity, Structure, and GC-HRMS-Readable Evidence to Decipher Nontarget Toxicants in Sediments.

Identifying causative toxicants in mixtures is critical, but this task is challenging when mixtures contain multiple chemical classes. Effect-based methods are used to complement chemical analyses to identify toxicants, yet conventional bioassays typically rely on an apical and/or single endpoint, providing limited diagnostic potential to guide chemical prioritization. We proposed an event-driven taxonomy framework for mixture risk assessment that relied on high-throughput screening bioassays and toxicant identification integrated by deep learning. In this work, the framework was evaluated using chemical mixtures in sediments eliciting aryl-hydrocarbon receptor activation and oxidative stress response. Mixture prediction using target analysis explained <10% of observed sediment bioactivity. To identify additional contaminants, two deep learning models were developed to predict fingerprints of a pool of bioactive substances (event driver fingerprint, EDFP) and convert these candidates to MS-readable information (event driver ion, EDION) for nontarget analysis. Two libraries with 121 and 118 fingerprints were established, and 247 bioactive compounds were identified at confidence level 2 or 3 in sediment extract using GC-qToF-MS. Among them, 12 toxicants were analytically confirmed using reference standards. Collectively, we present a "bioactivity-signature-toxicant" strategy to deconvolute mixtures and to connect patchy data sets and guide nontarget analysis for diverse chemicals that elicit the same bioactivity.

Neural correlates of individual differences in moral identity and its positive moral function.

Moral identity is an important moral variable which has positive moral functions, such as contributing to prosocial behaviours, reducing antisocial behaviours, and resisting the risk factors of antisocial behaviours. However, little is known about the neural correlates of moral identity and the neural basis of the effect of moral identity on the risk factors of antisocial behaviours, including moral disengagement. In this study, we explored these issues in 142 college students by estimating the regional homogeneity (ReHo) through resting-state functional magnetic resonance imaging (fMRI). The whole-brain correlation analyses found that higher internalized moral identity was correlated with higher ReHo in the precuneus. Furthermore, the ReHo in the precuneus was negatively correlated with moral disengagement, suggesting positive moral functions of the neural mechanisms of moral identity. These findings deepen our understanding of individual differences in moral identity and provide inspiration for the education of moral identity and the intervention for moral disengagement from the perspective of the brain.

Network evolution of core symptoms after lung cancer thoracoscopic surgery:A dynamic network analysis.

OBJECTIVES: To investigate relationships between various symptoms occurring 1-2 and 5-6 days following days after thoracoscopic surgery, to identify core symptoms, and to monitor changes in core symptoms over time following lung cancer thoracoscopic surgery. METHODS: We evaluated symptoms using the Anderson Symptom Scale (Chinese version) and the Lung Cancer-Specific Symptoms Template in 214 lung cancer patients hospitalized in the Department of Thoracic Surgery of a provincial hospital in Jiangsu Province from March 2023 to September 2023. Data was collected at 1-2 days and 5-6 days postoperatively. Symptom networks were constructed for each time point, and centrality indicators were analyzed to identify core symptoms while controlling for influencing factors. RESULTS: According to the network analysis, fatigue (rs = 26.00、rc = 0.05、rb = 1.02) had the highest strength, closeness, and betweenness in the symptom network 1-2 days after lung cancer surgery. At 5-6 days after surgery, shortness of breath (rs = 27.00) emerged as the symptom with the highest strength, fatigue (rc = 0.04) had the highest closeness, and cough (rb = 1.08) ranked highest in betweenness within the symptom network. CONCLUSION: Fatigue stands out as the most core symptom in the network 1-2 days after lung cancer surgery. Shortness of breath, fatigue and cough are the most core symptoms in the symptom network 5-6 days after surgery. Therefore, clinical staff can improve the postoperative symptom experience of lung cancer patients by developing symptom management programmes tailored to these core symptoms.

AMPK inhibition sensitizes acute leukemia cells to BH3 mimetic-induced cell death.

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms. Because of toxicities, including thrombocytopenia after BCLXL inhibition as well as hematopoietic, hepatic and possible cardiac toxicities after MCL1 inhibition, there is substantial interest in finding agents that can safely sensitize neoplastic cells to these BH3 mimetics. Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors. Cell fractionation and phosphoproteomic analyses suggest that sensitization by dorsomorphin involves dephosphorylation of the proapoptotic BCL2 family member BAD at Ser75 and Ser99, leading BAD to translocate to mitochondria and inhibit BCLXL. Consistent with these results, BAD knockout or mutation to BAD S75E/S99E abolishes the sensitizing effects of dorsomorphin. Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.

Efficacy and Safety Assessment of Intrathoracic Perfusion Chemotherapy Combined with immunological factor Interleukin-2 in the Treatment of Advanced Non-Small Cell Lung Cancer: A Retrospective Cohort Study.

Objective: This study evaluated the efficacy and safety of the gemcitabine and oxaliplatin intrathoracic perfusion chemotherapy (IPCGOR) regimen combined with interleukin-2 (IL-2) for advanced non-small cell lung cancer (NSCLC). Methods: We conducted a retrospective analysis of 460 advanced NSCLC patients from the Yunnan Province Early Cancer Diagnosis and Treatment Project (June 2020-October 2022), assessing the IPCGOR and IL-2 combination. Outcomes were measured based on RECIST 1.1 criteria, focusing on objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (MOS), and treatment safety. Results: The treatment demonstrated an ORR of 67.4%, a DCR of 97.4%, an mPFS of 8.5 months, and an MOS of 12.5 months. 14 patients underwent successful surgery post-treatment. Common adverse reactions were manageable, with no treatment-related deaths reported. Conclusion: The IPCGOR combined with IL-2 regimen shows promising efficacy and a tolerable safety profile for advanced NSCLC. These findings suggest its potential as a reference for treating advanced NSCLC. However, the study's retrospective nature and single-center design pose limitations. Future research should focus on prospective studies, randomized controlled trials, and long-term outcome assessments, particularly in diverse patient subgroups, to further validate and refine the clinical application of this regimen.

TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic ß1-integrin.

BACKGROUND: Astrocytes regulate blood-brain barrier (BBB) integrity, whereas subarachnoid haemorrhage (SAH) results in astrocyte dysregulation and BBB disruption. Here, we explored the involvement of tissue inhibitor of matrix metalloprotease-1 (TIMP1) in astrocyte-mediated BBB protection during SAH, along with its underlying mechanisms. METHODS: C57BL/6J mice were used to establish a model of SAH. The effects of TIMP1 on SAH outcomes were analysed by intraperitoneal injection of recombinant mouse TIMP1 protein (rm-TIMP1; 250 µg/kg). The roles of TIMP1 and its effector ß1-integrin on astrocytes were observed by in vivo transduction with astrocyte-targeted adeno-associated virus carrying TIMP1 overexpression plasmid or ß1-integrin RNAi. The molecular mechanisms underlying TIMP1 and ß1-integrin interactions were explored in primary cultured astrocytes stimulated with red blood cells (RBCs). RESULTS: TIMP1 was upregulated after SAH. Administration of rm-TIMP1 mitigated SAH-induced early brain injury (EBI) in male and female mice. TIMP1 was primarily expressed in astrocytes; its overexpression in astrocytes led to increased ß1-integrin expression in astrocytes, along with the preservation of astrocytic endfoot attachment to the endothelium and subsequent recovery of endothelial tight junctions. All of these effects were reversed by the knockdown of ß1-integrin in astrocytes. Molecular analysis showed that TIMP1 overexpression decreased the RBC-induced ubiquitination of ß1-integrin; this effect was partially achieved by inhibiting the interaction between ß1-integrin and the E3 ubiquitin ligase Trim21. CONCLUSION: TIMP1 inhibits the interaction between ß1-integrin and Trim21 in astrocytes, thereby rescuing the ubiquitination of astrocytic ß1-integrin. It subsequently restores interactions between astrocytic endfeet and the endothelium, as well as BBB integrity, eventually mitigating SAH-induced EBI.

Mono- and bis-Pd(ii) complexes of N-confused dithiahexaphyrin(1.1.1.1.1.0) with the absorption and aromaticity modulated by Pd(ii) coordination, macrocycle contraction and ancillary ligands.

To further enrich the coordination chemistry of hexaphyrins and probe the underlying property-structural correlations, N-confused dithiahexaphyrin(1.1.1.1.1.0) (1) with 26 π-electron Hückel aromaticity was synthesized. Based on its unprecedented two unsymmetrical cavities, five palladium complexes 2, 3, 4-Ph, 4-Cl and 5 have been successfully synthesized under various coordinations. Thus, two mono-Pd(ii) complexes 2 and 3 with the Pd(ii) atom coordinated in the two different cavities were obtained by treating 1 with palladium reagents PdCl2, and (PPh3)2PdCl2 respectively. On this basis, bis-Pd(ii) complexes 4-Ph and 4-Cl were synthesized by treating 2 and 3 with (PPh3)2PdCl2 and PdCl2, respectively. As a result, both 4-Ph and 4-Cl contain two Pd(ii) atoms coordinated within the two cavities, with one of the Pd(ii) atoms further coordinated to a triphenylphosphine ligand in addition to an anionic ancillary ligand of Ph- and Cl-, respectively. Notably, a further contracted mono-Pd(ii) complex 5 was synthesized by treating 1 with Pd(PPh3)4 by eliminating one of the meso-carbon atoms together with the corresponding C6F5 moiety. These complexes present tunable 26 π aromaticity and NIR absorption up to 1060 nm. This work provides an effective approach for developing distinctive porphyrinoid Pd(ii) complexes from a single porphyrinoid, without resorting to tedious syntheses of a series of porphyrinoid ligands.

High Tribocatalytic Performance of FeOOH Nanorods for Degrading Organic Dyes and Antibiotics.

Tribocatalysis is vitally important for electrochemistry, energy conservation, and water treatment. Exploring eco-friendly and low-cost tribocatalysts with high performance is crucial for practical applications. Here, the highly efficient tribocatalytic performance of FeOOH nanorods is reported. The factors related to the tribocatalytic activity such as nanorod diameter, surface area, and surface roughness are investigated, and the diameter of the FeOOH nanorods is found to have a significant effect on their tribocatalytic performance. As a result, under ultrasonic excitation, the optimized FeOOH nanorods exhibit superior tribocatalytic degradation toward rhodamine B (RhB), acid orange 7, methylene blue, methyl orange dyes, and their mixture. The RhB and mixed dyes are effectively degraded within 20 min (k = 0.179 min-1 ) and 35 min (k = 0.089 min-1 ), respectively, with the FeOOH nanorods showing excellent reusability. Moreover, antibiotics, such as tetracycline hydrochloride, phenol, and bisphenol A are efficiently degraded. Investigation of the catalytic mechanism reveals that the friction-generated h+ as well as these yielded •OH and •O2 - active radicals participate in the catalytic reaction. This work not only shed light on the design of high-performance tribocatalyst but also demonstrates that by harvesting mechanical energy, the FeOOH nanorods are promising materials for removing organic contaminants in wastewater.

Neutrophil-like pH-responsive pro-efferocytic nanoparticles improve neurological recovery by promoting erythrophagocytosis after intracerebral hemorrhage.

Rationale: Intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease resulting from blood extravasating into the brain parenchyma. Escalation of erythrophagocytosis (a form of efferocytosis), avoiding the consequent release of the detrimental erythrocyte lysates, may be a promising target of ICH management. The ADAM17 inhibitor and liver X receptor (LXR) agonist could promote efficient efferocytosis and injury repair. Nevertheless, the poor bioavailability and restriction of the blood-brain barrier (BBB) hinder their application. Therefore, it is needed that biocompatible and smart nanoplatforms were designed and synthesized to realize effective therapy targeting erythrophagocytosis. Methods: We first assessed the synergistic effect of therapeutic GW280264X (an ADAM17 inhibitor) and desmosterol (an LXR agonist) on erythrophagocytosis in vitro. Then a pH-responsive neutrophil membrane-based nanoplatform (NPEOz) served as a carrier to accurately deliver therapeutic GW280264X and desmosterol to the damaged brain was prepared via co-extrusion. Afterwards, their pH-responsive performance was valued in vitro and targeting ability was assessed through fluorescence image in vivo. Finally, the pro-erythrophagocytic and anti-neuroinflammatory ability of the nanomedicine and related mechanisms were investigated. Results: After the synergistical effect of the above two drugs on erythrophagocytosis was confirmed, we successfully developed neutrophil-disguised pH-responsive nanoparticles to efficiently co-deliver them. The nanoparticles could responsively release therapeutic agents under acidic environments, and elicit favorable biocompatibility and ability of targeting injury sites. D&G@NPEOz nanoparticles enhanced erythrophagocytosis through inhibiting shedding of the efferocytotic receptors MERTK/AXL mediated by ADAM17 and accelerating ABCA-1/ABCG-1-mediated cholesterol efflux regulated by LXR respectively. In addition, the nano-formulation was able to modulate the inflammatory microenvironment by transforming efferocytes towards a therapeutic phenotype with reducing the release of proinflammatory cytokines while increasing the secretion of anti-inflammatory factors, and improve neurological function. Conclusions: This biomimetic nanomedicine is envisaged to offer an encouraging strategy to effectively promote hematoma and inflammation resolution, consequently alleviate ICH progression.

Cu-Catalyzed Direct Enantioselective Vinylogous Mannich Reaction between ß,γ-Unsaturated Pyrazoleamides and Ketimines.

A catalytic asymmetric vinylogous Mannich-type reaction between ß,γ-unsaturated amides and ketimines has been developed in excellent regio-, diastereo-, and enantioselectivities. The methodology provides an efficient approach to construct chiral homoallylic amines with a 3-amino-2-oxindole scaffold. Moreover, the transformations of the chiral products, including the removal of the pyrazole group or Boc group, the reduction of the C-C double bond, and Suzuki coupling, have been investigated.

Syntheses of Thiophene-Thiophene-Linked Corrorin Dimers with Tunable Near-Infrared Absorption and Distinctive Reactivity.

Thiahexaphyrinone 1 and thia-dipyrrin-appended corrorin 2 have been synthesized. Surprisingly, further oxidation of compound 2 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dichloromethane afforded dimer 3 with two molecules of compound 2 linked at the α-carbon atoms of the thienyl units. Treatment of compound 3 with DDQ in MeOH and SnCl2 in tetrahydrofuran/H2O afforded the dimethoxy-attached dimer 4 and hydrogenated dihydroxy-attached dimer 5, respectively. These results provide the first examples for synthesizing thiophene-linked porphyrinoid dimers with tunable near-infrared absorption and chirality.

A survey of nurses' knowledge, attitudes, and practice of sarcopenia: A cross-sectional study.

AIM: This paper aims to assess the current knowledge, attitudes, and behaviors of nursing staff regarding sarcopenia and explore associating factors that influence them. BACKGROUND: Sarcopenia has an insidious onset and is easily overlooked. However, it is has become very common in older people, seriously jeopardizing the quality of life in patients. The present situation of nurses in China is inadequate, even though they are the primary professionals tasked with screening for sarcopenia, the ability to recognize and effectively manage the disease, and the critical role they play in preventing and controlling sarcopenia in patients. DESIGN: We conducted a cross-sectional design of nurses. METHODS: Facilitated sampling was used in seven hospitals in Jiangsu Province, China. A total of 409 hospital nursing staff participated in the survey from December 2022 to March 2023. The main survey instruments were the nursing staff about the knowledge of sarcopenia, beliefs, a behavior questionnaire, and a self-designed general information questionnaire. Descriptive of general data, t-test, and ANOVA for influencing factors of three dimensions, whereas multiple linear regression analyses were performed using SPSS23.0 software. RESULTS: Questionnaires were distributed to 460 nurses, and of the 426 (92.6%) questionnaires returned, 409 (96.0%) were valid. The total mean score of nurses' knowledge, beliefs, and behavior about sarcopenia was 125.42 (SD 18.97), the mean score of knowledge latitude was 29.09 (SD 7.80), the mean score of attitude dimension was 57.53 (SD 7.63), and the mean score of behavior latitude was 38.80 (SD 10.71). Multiple linear regression analysis revealed that the nurse's position, Knowledge of sarcopenia, whether or not they were specialist nurses and years of experience in the workplace were the most significant factors correlated with the level of knowledge, belief, and practice (P < 0.05). CONCLUSIONS: In China, nurses have little knowledge about sarcopenia, but their attitude towards sarcopenia care is positive. However, there is potential for improvement in nursing behavior toward sarcopenia management. RELEVANCE TO CLINICAL PRACTICE: Managers are advised to develop targeted training programs for nurses. Further, it improves their screening and diagnosing abilities, allowing them to prevent and control sarcopenia more effectively.

Performative credibility: How opioid researchers sustain public trust during the opioid epidemic.

Experts often face credibility challenges during times of crisis. However, opioid use disorder (OUD) researchers preserved their scientific credibility despite the increasing public scrutiny of medical knowledge during the opioid epidemic. Building on 30 in-depth interviews with OUD researchers, this article examines how researchers conduct scientific research, collaborate with non-expert stakeholders, and communicate research outcomes to the public. It distinguishes between performative credibility - a discourse enacted through languages, meanings, and symbols in constructing the reality of credibility, and descriptive credibility - the description, perception, and measurements of credibility under a given credibility discourse. It argues that the crisis of expertise is situational - it depends on whether and how performative credibility is sustained. This article finds that OUD researchers enact at least three credibility discourses: professional, data-driven, and community-centered. While researchers can have multiple discourses in mind, their choices of enacting a specific credibility discourse when interacting with non-experts and the public are contingent upon their rankings in the profession, medical training backgrounds, forms of patient interactions, and access to OUD medications. This case recenters sociological studies of expertise and trust on the enacting power of experts' statements and actions. It also reveals the relevance of social locations in understanding the formation of the credibility crisis. Finally, it provides a conceptual framework for understanding public (mis)trust in science and medicine.

Aromatic Ring-Fused Dipyrrins: Programmed [4 + 2]-Cycloaddition Pathway with Regio-selectivity upon Alkylamino-Substitution.

Sulfolenodipyrrins are employed as building blocks to concisely and efficiently construct aromatic rings (e.g., naphthoquinone, anthraquinone, fullerenes, and phthalimide) from fused dipyrrins by programmed [4 + 2]-cycloaddition reactions. Notably, alkylamino-substitution at the α-position not only enhances the reactivity of sulfolenodipyrrins but also results in the regio-selectivity of the cycloaddition reactions. Theoretical calculations in terms of frontier orbitals of dienes, energy of dienes, steric hindrance, and aromaticity have been conducted to understand the reason in depth. Additionally, the fusion of aromatic groups enables bathochromic absorption with up to ∼130 nm for the monoadducts and to ∼200 nm for the bis-adducts. The phthalimide annulation dipyrrin displays red emission, while the other mono- or bis-adducts do not, owing to the presence of typical acceptors such as quinone analogs or fullerene.

[Prediction of quality markers and medicinal value of sea buckthorn leaves based on network pharmacology, content determination, and activity evaluation].

The leaves of sea buckthorn(Hippophae rhamnoides), considered as common food raw materials, have records of medicinal use and diverse pharmacological activities, showing a potential medicinal value. However, the active substances in the sea buckthorn leaves and their mechanisms of action remain unclear. In addition, due to the extensive source and large variety variations, the quality evaluation criteria of sea buckthorn leaves remain to be developed. To solve the problems, this study predicted the main active components, core targets, key pathways, and potential pharmacological effects of sea buckthorn leaves by network pharmacology and molecular docking. Furthermore, ultra-performance liquid chromatography with diode-array detection(UPLC-DAD) was employed to determine the content of active components and establish the chemical fingerprint, on the basis of which the quality markers of sea buckthorn leaves were predicted and then verified by the enzyme activity inhibition method. The results indicated that sea buckthorn leaves had potential therapeutic effects on a variety of digestive tract diseases, metabolic diseases, tumors, and autoimmune diseases, which were consistent with the ancient records and the results of modern pharmacological studies. The core targets of sea buckthorn leaves included PTPN11, AKT1, PIK3R1, ESR1, and SRC, which were mainly involved in the PI3K-AKT, MAPK, and HIF-1 signaling pathways. In conclusion, the active components of sea buckthorn leaves are associated with the rich flavonoids and tannins, among which quercitrin, narcissoside, and ellagic acid can be used as the quality markers of sea buckthorn leaves. The findings provide a reference for the quality control and further development and utilization of sea buckthorn leaves as medicinal materials.

Valsartan Attenuated Homocysteine-Induced Impaired Autophagy and ER Stress in Human Umbilical Vein Endothelial Cells.

Hyperhomocysteinemia is a risk factor for various cardiovascular diseases. However, the mechanism underlying homocysteine- (Hcy-) induced vascular injury remains unclear. The purpose of the present study was to examine a potential mechanism by which Hcy induced injury in human umbilical vascular endothelial cells (HUVEC). The protein abundance of autophagy-related markers was markedly decreased after Hcy treatment, which was associated with endoplasmic reticulum (ER) stress and apoptosis in HUVECs. Protein expression level of angiotensin II type 1 receptor (AT1 receptor) was dramatically increased in response to Hcy. Valsartan, an AT1 receptor blocker, improved autophagy and prevented ER stress and apoptosis in HUVECs treated with Hcy. Consistent with this, silence of AT1 receptor with siRNA decreased the protein abundance of ER stress markers, prevented apoptosis, and promoted autophagy in HUVECs. Inhibition or knockdown of AT1 receptor was shown to be associated with suppression of p-GSK3ß/GSK3ß-p-mTOR/mTOR signaling pathway. Additionally, inhibition of autophagy by 3-MA aggravated Hcy-induced apoptosis, while amelioration of ER stress by 4-PBA prevented Hcy-induced injury in HUVECs. Hcy-induced HUVEC injury was likely attributed to AT1 receptor activation, leading to impaired autophagy, ER stress, and apoptosis.

Endoxifen downregulates AKT phosphorylation through protein kinase C beta 1 inhibition in ERα+ breast cancer.

Endoxifen, a secondary tamoxifen metabolite, is a potent antiestrogen exhibiting estrogen receptor alpha (ERα) binding at nanomolar concentrations. Phase I/II clinical trials identified clinical activity of Z-endoxifen (ENDX), in endocrine-refractory metastatic breast cancer as well as ERα+ solid tumors, raising the possibility that ENDX may have a second, ERα-independent, mechanism of action. An unbiased mass spectrometry approach revealed that ENDX concentrations achieved clinically with direct ENDX administration (5 µM), but not low concentrations observed during tamoxifen treatment (<0.1 µM), profoundly altered the phosphoproteome of the aromatase expressing MCF7AC1 cells with limited impact on the total proteome. Computational analysis revealed protein kinase C beta (PKCß) and protein kinase B alpha or AKT1 as potential kinases responsible for mediating ENDX effects on protein phosphorylation. ENDX more potently inhibited PKCß1 kinase activity compared to other PKC isoforms, and ENDX binding to PKCß1 was confirmed using Surface Plasma Resonance. Under conditions that activated PKC/AKT signaling, ENDX induced PKCß1 degradation, attenuated PKCß1-activated AKTSer473 phosphorylation, diminished AKT substrate phosphorylation, and induced apoptosis. ENDX's effects on AKT were phenocopied by siRNA-mediated PKCß1 knockdown or treatment with the pan-AKT inhibitor, MK-2206, while overexpression of constitutively active AKT diminished ENDX-induced apoptosis. These findings, which identify PKCß1 as an ENDX target, indicate that PKCß1/ENDX interactions suppress AKT signaling and induce apoptosis in breast cancer.

Mechanisms of action of the BCL-2 inhibitor venetoclax in multiple myeloma: a literature review.

Abnormal cellular apoptosis plays a pivotal role in the pathogenesis of Multiple Myeloma (MM). Over the years, BCL-2, a crucial anti-apoptotic protein, has garnered significant attention in MM therapeutic research. Venetoclax (VTC), a small-molecule targeted agent, effectively inhibits BCL-2, promoting the programmed death of cancerous cells. While VTC has been employed to treat various hematological malignancies, its particular efficacy in MM has showcased its potential for broader clinical applications. In this review, we delve into the intricacies of how VTC modulates apoptosis in MM cells by targeting BCL-2 and the overarching influence of the BCL-2 protein family in MM apoptosis regulation. Our findings highlight the nuanced interplay between VTC, BCL-2, and MM, offering insights that may pave the way for optimizing therapeutic strategies. Through this comprehensive analysis, we aim to lay a solid groundwork for future explorations into VTC's clinical applications and the profound effects of BCL-2 on cellular apoptosis.