Irreversible Effects Research Articles

Pediatric Cardio-Oncology: Screening, Risk Stratification, and Prevention of Cardiotoxicity Associated with Anthracyclines.

Anthracyclines have significantly improved the survival of children with malignant tumors, but the associated cardiotoxicity, an effect now under the purview of pediatric cardio-oncology, due to its cumulative and irreversible effects on the heart, limits their clinical application. A systematic screening and risk stratification approach provides the opportunity for early identification and intervention to mitigate, reverse, or prevent myocardial injury, remodeling, and dysfunction associated with anthracyclines. This review summarizes the risk factors, surveillance indexes, and preventive strategies of anthracycline-related cardiotoxicity to improve the safety and efficacy of anthracyclines.

Study on the Performance Degradation of Membrane Electrode Assembly in Proton Exchange Membrane Fuel Cell Caused by Freeze–Thaw Cycles

ABSTRACTDurability of membrane electrode assembly (MEA) is a serious problem to be overcome in the commercial development of proton exchange membrane fuel cell (PEMFC). The change in volume due to water–ice conversion has an irreversible effect on the MEA, which affects the performance of PEMFC. For investigating the optimal initial water content of MEA that minimizes the impact on PEMFC performance after freeze–thaw (F/T) cycles, this study first measured the high‐frequency resistance to determine the water content of MEA, and then subjected five MEAs with different water contents to 60 F/T cycles at −20°C to 30°C. The fuel cell output performance of five MEAs was found to be inconsistently degraded by polarization curve tests, with the cells of the two MEAs with the lowest and highest water contents exhibiting the worst output performance. Electrochemical impedance spectroscopy curves proved that the difference in resistance change after F/T cycles is one reason why the cell output performance is degraded differently. Finally, the degradation of cell performance was further explained by cyclic voltammetry. These results indicate that MEA has the best output performance for F/T cycles at an initial water content of 3.0.

Editorial for Clean Energy Science and Technology (Volume 2, Issue 2)

All human activities are nothing more than the conversion and flow of energy, and energy flow processes that have irreversible effects on the Earth’s environment are of particular concern. Energy flow processes of interest are less often purely physical, and more often include complex chemical processes involving light, electricity, heat, and force, which are inevitably distributed in almost all human activities. Therefore, the optimization of these processes towards maximizing energy efficiency is inevitably the result of multi-physical and interdisciplinary collaborations, which will ultimately have a significant impact on the likelihood and schedule of achieving the goal of energy conservation and emission reduction. The authors of the articles in this issue, with creative thinking, rigorous arguments, and abundant data, have superbly illustrated the need for multiphysics and interdisciplinary synergy in clean energy science and technology from a wide range of perspectives.

Intrinsic performance loss rate: Decoupling reversible and irreversible losses for an improved assessment of photovoltaic system performance

AbstractSolar electricity is set to play a pivotal role in future energy systems. In view of a market that may soon reach the terawatt (TW) scale, a careful assessment of the performance of photovoltaic (PV) systems becomes critical. Research on PV fault detection and diagnosis (FDD) focuses on the automated identification of faults within PV systems through production data, and long‐term performance evaluations aim to determine the performance loss rate (PLR). However, these two approaches are often handled separately, resulting in a notable gap in the field of reliability. Within PV system faults, one can distinguish between permanent, irreversible effects (e.g. bypass diode breakage, delamination and cell cracks) and transient, reversible losses (e.g. shading, snow and soiling). Reversible faults can significantly impact (and bias) PLR estimates, leading to wrong judgements about system or component performance and misallocation of responsibilities in legal claims. In this work, the PLR is evaluated by applying a fault detection procedure that allows the filtering of shading, snow and downtime. Compared with standard filtering methods, the addition of an integrated FDD analysis within PLR pipelines offers a solution to avoid the influence of reversible effects, enabling the determination of what we call the intrinsic PLR (i‐PLR). Applying this method to a fleet of PV systems in the built environment reveals four main PLR bias scenarios resulting from shading losses. For instance, a system with increasing shading over time exhibits a PLR of −1.7%/year, which is reduced to −0.3%/year when reversible losses are filtered out.

(128) ABORTION AND THE MYTH OF THE HARM-FREE PREGNANCY

Abstract Introduction A comprehensive description of the impact of pregnancy and childbirth on the human body has never been published. All pregnancies pose an unquantifiable threat to one's health and childbirth has permanent, irreversible effects that are cumulative and often late-manifesting. This reality refutes the anti-abortion, pro-natalist claim that there is any such thing as an elective abortion. Objective Abortion access supports the fundamental human right to bodily autonomy and sexual self-determination, hence every abortion is performed in the service of the pregnant person's health. The neglect of these principles has allowed politically-motivated legislatures to introduce imprecise health exception language that does not acknowledge the actual impact of pregnancy and childbirth. Affirming that abortion is life-saving healthcare refutes the health exception fallacy. Methods Maternal mortality and morbidity statistics are flawed and incomplete. None of the standard measures adequately captures the effects of pregnancy, whether voluntary or forced, upon the health of the parturient or her community. This report elucidates the unpredictable and often unattributed morbidity associated with pregnancy and childbirth, and argues for a human rights approach to abortion policy. Results Abortion bans have downstream effects that negatively impact the care of all pregnancy-capable people and their communities. Allowing non-experts to legislate against evidence-based care creates confusion and leads to mistrust of the healthcare system. Gendered disinformation, gag rules, and criminalization of pregnancy all result in stigma and harm. Conclusions The cultural reluctance to seriously study the effects of pregnancy on health is linked to gender inequality and is correlated with restrictive abortion laws that violate ethical principles of beneficence and patient autonomy. Involuntary pregnancy is a major and preventable cause of human suffering that can be relieved with permissive abortion policies based on ethical and scientific standards of care. Disclosure No.

Design and preparation of a multi-responsive Cd-based fluorescent coordination polymer for smart sensing of nitrobenzene and ornidazole

The improper utilization of nitrobenzene (NB) and ornidazole (ORN) has resulted in irreversible effects on the environment. By combining experimental investigation, density functional theory (DFT) calculations, and machine learning, an effective green strategy for detecting NB and ORN in aqueous solutions can be developed. In this study, a one-dimensional Cd-based coordination polymer (Cd-HCIA-3) was designed and synthesized using 5-((4-carboxybenzyl)oxy)isophthalic acid and rigid 2,2′-bipyridine under solvothermal reaction conditions. Cd-HCIA-3 exhibits excellent fluorescence properties and stability in aqueous solutions. DFT calculations were performed to predict the fluorescence sensing performance of Cd-HCIA-3, revealing that photoinduced electron transfer is the key mechanism for inducing fluorescence quenching in the presence of NB and ORN, with weak molecular interactions promoting electron transfer. Fluorescence sensing experiments were conducted to verify the DFT results, showing that Cd-HCIA-3 can selectively detect NB and ORN in aqueous solutions with limits of detection of 7.22 × 10−8 and 1.31 × 10−7 mol/L, respectively. This study’s findings provide valuable insights into the design and synthesis of fluorescent coordination polymers for target analytes.

Effects of steady-state fluid-structure interactions on air-supported membrane structures subjected to wind actions

With the perspective of static aeroelasticity, steady-state influences of fluid-structure interaction (FSI) on wind loads and responses of rectangular-planed air-supported membrane structure (ASMS) are investigated in this study. Steady-state FSI simulations are performed by coupling Reynolds-averaged computational fluid dynamics solving wind loads and static finite element analysis solving structural deformations. The feasibility of these simulations is validated with wind tunnel tests concerning time-averaged results. In contrast to analysis without static aeroelasticity, significant variations in wind pressure distributions and amplifications on structural wind responses due to steady-state FSI effects are observed. Subsequently, influencing factors and mechanisms of steady-state FSI effects are analyzed. These time-averaged effects are more significant with the increasing magnitude of structural wind actions, lower internal pressures and less membrane tensile stiffness. Though unlikely to induce irreversible effects as shell structures, the buckling of ASMS can make steady-state FSI more pronounced because of the coupling between stronger flow separation and larger membrane deformations. Accompanied with steady-state FSI, such buckling effect usually contributes to varying locations of the structural maximum responses and noticeable increases in response amplification factors, which deserves attentions in practice. Practically, it is realizable to evaluate these steady-state FSI effects above with simulations because of the much lower computational cost and reliable accuracy.

Toxicity mechanism of acrolein on energy metabolism disorder and apoptosis in human ovarian granulosa cells

Acrolein (ACR), an unsaturated, highly reactive aldehyde, is a widespread environmental toxin. ACR exerts permanent and irreversible side effects on ovarian functions. Granulosa cells play a crucial role in supporting ovarian function. Thus, in this study, we investigated the toxicity effects of granulosa cells induced by ACR. Following treatment with varying ACR concentrations (0, 12.5, 25, 50, and 100 μM), we observed that ACR exposure induced reactive oxygen species accumulation, mitochondrial energy metabolism disorder, and apoptosis in KGN cells (a human ovarian granulosa cell line) in a dose-dependent manner. In addition, mitochondrial biogenesis in KGN cells displayed biphasic changes after ACR exposure, with activation at a low ACR dose (12.5 μM), but inhibition at higher ACR doses (≥50 μM). SIRT1/PGC-1α-mediated mitochondrial biogenesis is crucial for maintaining intracellular mitochondrial homeostasis and cellular function. The inhibition/activation of the SIRT1/PGC-1α pathway in KGN cells validated its role in ACR-induced damage. The results indicated that the inhibition of the SIRT1/PGC-1α pathway aggravated ACR-induced cell damage, whereas its activation partially counteracted ACR-induced cell damage. This study attempted to uncover a novel mechanism of ACR-induced ovarian toxicity so as to provide an effective treatment option for safeguarding female reproductive health from the adverse effects of ACR.

Ionic Modulation of Ferromagnetic and Proximity‐Induced Magnetization in Co/Pd Heterostructures

AbstractDespite the rampant discovery of tunable magnetic properties using magneto‐ionic gating, e.g., magnetic anisotropy, exchange bias, and exchange interactions, there are few studies that give a quantitative understanding of the reversible and irreversible effects of ionic infiltration. In this study, in situ vibrating sample magnetometry, superconducting quantum interference device magnetometry, and X‐ray magnetic circular dichroism (XMCD) reveal the reversible and irreversible control of magnetization, anisotropy, proximity‐effects, spin, and orbital angular momenta. Pd/Co/Pd trilayers, loaded using solid‐state hydrogen‐ion gating, show a decrease in the saturation magnetization of Co, and an increase in the proximity‐induced moment of Pd. This results in little to no change in the net effective magnetization, yet, allows for the effective anisotropy to be reversibly controlled by 270 kJ m−3. The reversible control of the effective anisotropy is dominated by a reversible change in surface anisotropy, however, under repeated cycling, irreversible evolution occurs in the heterostructure. XMCD measurements indicate this is partly due to hydrogen‐induced modification of the spin and orbital angular momenta. Together, these measurements indicate that the origin of the reversible and irreversible effects of magneto‐ionic gating is interfacial and provides crucial insight to scale and optimize thin film heterostructures for enhanced longevity and faster response time.

Severity of effect considerations regarding the use of mutation as a toxicological endpoint for risk assessment: A report from the 8th International Workshop on Genotoxicity Testing (IWGT).

Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose-response curve (e.g., benchmark dose) by a composite adjustment factor (AF). An "effect severity" AF (ESAF) is employed in some regulatory contexts. An ESAF of 10 may be incorporated in the derivation of a health-based guidance value (HBGV) when a "severe" toxicological endpoint, such as teratogenicity, irreversible reproductive effects, neurotoxicity, or cancer was observed in the reference study. Although mutation data have been used historically for hazard identification, this endpoint is suitable for quantitative dose-response modeling and risk assessment. As part of the 8th International Workshops on Genotoxicity Testing, a sub-group of the Quantitative Analysis Work Group (WG) explored how the concept of effect severity could be applied to mutation. To approach this question, the WG reviewed the prevailing regulatory guidance on how an ESAF is incorporated into risk assessments, evaluated current knowledge of associations between germline or somatic mutation and severe disease risk, and mined available data on the fraction of human germline mutations expected to cause severe disease. Based on this review and given that mutations are irreversible and some cause severe human disease, in regulatory settings where an ESAF is used, a majority of the WG recommends applying an ESAF value between 2 and 10 when deriving a HBGV from mutation data. This recommendation may need to be revisited in the future if direct measurement of disease-causing mutations by error-corrected next generation sequencing clarifies selection of ESAF values.

Harnessing External Irradiation for Precise Activation of Metal-Based Agents in Cancer Therapy.

Cancer is a significant global health issue. Platinum-based chemotherapy drugs, including cisplatin, are crucial in clinical anti-cancer treatment. However, these drugs have limitations such as drug resistance, non-specific distribution, and irreversible toxic and side effects. In recent years, the development of metal-based agents has led to the discovery of other anti-cancer effects beyond chemotherapy. Precise spatiotemporal controlled external irradiation can activate metal-based agents at specific sites and play a different role from traditional chemotherapy. These strategies can not only enhance the anti-cancer efficiency, but also show fewer side effects and non-cross-drug resistance, which are ideal approaches to solve the problems caused by traditional platinum-based chemotherapy drugs. In this review, we focus on various metal-based agent-mediated cancer therapies that are activated by three types of external irradiation: near-infrared (NIR) light, ultrasound (US), and X-ray, and give some prospects. We hope that this review will promote the generation of new kinds of metal-based anti-cancer agents.

Carbene-Mediated Polymer Modification Using Diazo Compounds under Photo or Thermal Activation Conditions.

Based on the characteristics of commodity polymers in large quantities and low costs, modification of existing commodity polymers emerges as the most effective approach for exploring novel materials. Nevertheless, conventional modification methods typically involve high-energy processes (e.g., high temperature, high-energy radiation), which may lead to irreversible detrimental effects on the polymers, contradicting the desired performance enhancement through modification. In this work, we propose a carbene-mediated postpolymerization modification (PPM) strategy utilizing diazo compounds. Under photochemical or thermal activation conditions, insertion of the C-H bond can be achieved without compromising the performance of polymers. These diazo compounds can be easily synthesized in just two steps and applied to all C-H-containing polymers. This practical and effective modification strategy offers new opportunities and possibilities for enhancing the value and expanding the applications of polymers.

Assessment of multispecies biofilm growth on root canal dentin under different radiation therapy regimens.

To assess the growth of a multispecies biofilm on root canal dentin under different radiotherapy regimens. Sixty-three human root dentin cylinders were distributed into six groups. In three groups, no biofilm was formed (n = 3): NoRT) non-irradiated dentin; RT55) 55Gy; and RT70) 70Gy. In the other three groups (n = 18), a 21-day multispecies biofilm (Enterococcus faecalis, Streptococcus mutans, and Candida albicans) was formed in the canal: NoRT + Bio) non-irradiated + biofilm; RT55 + Bio) 55Gy + biofilm; and RT70 + Bio) 70Gy + biofilm. The biofilm was quantified (CFUs/mL). Biofilm microstructure was assessed under SEM. Microbial penetration into dentinal tubules was assessed under CLSM. For the biofilm biomass and dentin microhardness pre- and after biofilm growth assessments, 45 bovine dentin specimens were distributed into three groups (n = 15): NoRT) non-irradiated + biofilm; RT55 + Bio) 55Gy + biofilm; and RT70 + Bio) 70Gy + biofilm. Irradiated specimens (70Gy) had higher quantity of microorganisms than non-irradiated (p = .010). There was gradual increase in biofilm biomass from non-irradiated to 55Gy and 70Gy (p < .001). Irradiated specimens had greater reduction in microhardness after biofilm growth. Irradiated dentin led to the growth of a more complex and irregular biofilm. There was microbial penetration into the dentinal tubules, regardless of the radiation regimen. Radiotherapy increased the number of microorganisms and biofilm biomass and reduced dentin microhardness. Microbial penetration into dentinal tubules was noticeable. Cumulative and potentially irreversible side effects of radiotherapy affect biofilm growth on root dentin. These changes could compromise the success of endodontic treatment in oncological patients undergoing head and neck radiotherapy.

Measurement of lead, mercury, and cadmium in blood donors in Canada.

Fetal and neonatal exposure to lead is associated with irreversible adverse effects on neural development. There is no reliable threshold for lead effect, so limiting exposure is recommended. A significant correlation has been reported between post-transfusion blood lead level (BLL) in infants and lead levels in transfused RBC units. We measured levels of lead, mercury, and cadmium, in Canadian donor blood to investigate if concerning levels for neonatal transfusion exist. Whole blood samples from blood donors (n = 2529) were shipped cold within 7 days of donation. All permanent blood donation clinics across Canada were sampled. Twelve of these permanent clinics and 8 mobile clinics with a greater potential for having higher lead or mercury levels were oversampled. Heavy metals were measured by inductively coupled plasma mass spectrometry. Of all donations, 2.2% (lead) and 0.4% (mercury) had levels higher than the recommended thresholds for safe neonatal transfusion. BLLs were higher in males but there was no significant difference in the blood mercury levels of males versus females. Cadmium levels were higher in females. There was a positive correlation between donor age and levels of heavy metals, with lead having the strongest correlation (r = 0.47, p < .0001). Three clinics in close proximity to two lead-producing mines were among the clinics with the highest BLLs. Significantly higher blood mercury levels were observed in coastal clinics. Our data on donor blood heavy metal levels supports considering blood transfusion as an exposure source to heavy metals and encourages informed selection of blood units for transfusion to vulnerable groups.

The Helix Ring Peptide U11 from the Venom of the Ant, Tetramorium bicarinatum, Acts as a Putative Pore-Forming Toxin.

An insect neuroactive helix ring peptide called U11-MYRTX-Tb1a (abbreviated as U11) from the venom of the ant, Tetramorium bicarinatum. U11 is a 34-amino-acid peptide that is claimed to be one of the most paralytic peptides ever reported from ant venoms acting against blowflies and honeybees. The peptide features a compact triangular ring helix structure stabilized by a single disulfide bond, which is a unique three-dimensional scaffold among animal venoms. Pharmacological assays using Drosophila S2 cells have demonstrated that U11 is not cytotoxic but instead suggest that it may modulate potassium channels via the presence of a functional dyad. In our work described here, we have tested this hypothesis by investigating the action of synthetically made U11 on a wide array of voltage-gated K and Na channels since it is well known that these channels play a crucial role in the phenomenon of paralysis. Using the Xenopus laevis oocyte heterologous expression system and voltage clamp, our results have not shown any modulatory effect of 1 μM U11 on the activity of Kv1.1, Kv1.3, Kv1.4, Kv1.5, Shaker IR, Kv4.2, Kv7.1, Kv10.1, Kv11.1 and KQT1, nor on DmNav and BgNav. Instead, 10 μM U11 caused a quick and irreversible cytolytic effect, identical to the cytotoxic effect caused by Apis mellifera venom, which indicates that U11 can act as a pore-forming peptide. Interestingly, the paralytic dose (PD50) on blowflies and honeybees corresponds with the concentration at which U11 displays clear pore-forming activity. In conclusion, our results indicate that the insecticidal and paralytic effects caused by U11 may be explained by the putative pore formation of the peptide.

Exploring the structural characteristics and dye removal capabilities of powder-, granule- and film- shaped magnetic activated carbon derived from Oleaster seed.

Dye pollution in water caused by excessive discharge of industrial effluent has become a major environmental problem in recent decades because of its irreversible effects on human health. In this study, low-cost carbon-based adsorbents synthesized from Oleaster seed (OS) were prepared in three forms of powder (PAC), film (FAC), and granule (GAC) and used for the removal of methylene blue dye. The properties of the synthesized adsorbents were characterized by SEM-EDX, BET, XPS and FTIR analyses. The maximum adsorption capacity (qmax) of PAC, FAC, and GAC adsorbents were obtained as 68.49, 32.25, and 15.10 mg/g, respectively at the optimum experimental conditions of pH = 10, adsorbent dosages of 0.5, 1, and 2 g/l, contact times of 60, 90, and 120 min, dye concentration of 10 mg/L, and temperature of 25°C. The Langmuir isotherm well described the equilibrium data for all three adsorbents. The pseudo-second-order kinetic model provided the best fit with the adsorption data obtained from all three adsorbents. Adsorption occurred spontaneously through a combination of chemical and physical mechanisms, with a thermodynamically exothermic process. The desorption experiments demonstrated that all the adsorbents have substantial potential for recovery. The novel activated carbon/alginate composite films are proposed as more promising biosorbents to remove MB dye from the aquatic environment compared to GAC adsorbents.

Inhibition of TBL1 cleavage alleviates doxorubicin-induced cardiomyocytes death by regulating the Wnt/β-catenin signal pathway.

Doxorubicin (DOX) is a widely used anthracycline anticancer agent; however, its irreversible effects on the heart can result in DOX-induced cardiotoxicity (DICT) after cancer treatment. Unfortunately, the pathophysiology of DICT has not yet been fully elucidated, and there are no effective strategies for its prevention or treatment. In this investigation, the novel role of transducin beta-like protein 1 (TBL1) in developing and regulating DICT was explored. We observed a reduction in TBL1 protein expression levels as well as cleavage events in the transplanted cardiac tissues of patients diagnosed with Dilated Cardiomyopathy and DICT. It was revealed that DOX selectively induces TBL1 cleavage at caspase-3 preferred sites-D125, D136, and D215. Interestingly, overexpression of the uncleaved TBL1 mutant (TBL1uclv) variant reduced apoptosis, effectively preventing DOX-induced cell death. We confirmed that cleaved TBL1 cannot form a complex with β-catenin. As a result, Wnt reporter activity and Wnt target gene expression collectively indicate a decrease in Wnt/β-catenin signalling, leading to DICT progression. Furthermore, the cleaved TBL1 triggered DOX-induced abnormal electrophysiological features and disrupted calcium homeostasis. However, these effects were improved in TBL1uclv-overexpressing human-induced pluripotent stem cell-derived cardiomyocytes. Finally, in a DICT mouse model, TBL1uclv overexpression inhibited the DICT-induced reduction of cardiac contractility and collagen accumulation, ultimately protecting cardiomyocytes from cell death. Our findings reveal that the inhibition of TBL1 cleavage not only mitigates apoptosis but also enhances cardiomyocyte function, even in the context of DOX administration. Consequently, this study's results suggest that inhibiting TBL1 cleavage may be a novel strategy to ameliorate DICT.

A low dose of curcumin-PDA nanoparticles improves viability and proliferation in endoneurial fibroblasts and Schwann cell cultures

Curcumin is a polyphenol extracted from Curcuma longa’s roots. Low doses of curcumin are related to anti-inflammatory, antioxidant, and neuroprotective effects, while high doses are used for their lethality. This diversity of behaviors allows us to understand curcumin as a compound with hormetic action. Due to its strongly hydrophobic character, curcumin is often solubilized in organic compounds. In this way, we have recently reported the undesirable and occasionally irreversible effects of alcohol and DMSO on the viability of primary Schwann cell cultures. In this scenario, the use of nanoparticles as delivery systems has become a successful alternative strategy for these compounds. In the present work, we describe the structure of Polydopamine (PDA) nanoparticles, loaded with a low dose of curcumin (Curc-PDA) without the use of additional organic solvents. We analyzed the curcumin released, and we found two different forms of curcumin. Small increased cell viability and proliferation were observed in endoneurial fibroblast and Schwann cell primary cultures when Curc-PDA was steadily supplied for 5 days. The increased bioavailability of this natural compound and the impact on cells in culture not only confirm the properties of curcumin at very low doses but also provide a glimpse of a possible therapeutic alternative for PNS conditions in which SCs are involved.

Morphology evolution of bacterial cellulose carbon and loaded with MnO2 microspheres for high performance supercapacitors

The rapid development of economy and technology caused numerous irreversible effects on the environment, and the rational use and storage of existing resources have became an indispensable process in modern development. Energy storage through supercapacitors can effectively alleviate part of the energy crisis. Here, the effects of heating rates on the morphology of carbonized bacterial cellulose (CBC) carbon and its electrochemical properties were studied and CBC-5 (heating rate of 5 ℃/min) with porous structure was confirmed to be supporting material for loading MnO2. The specific capacitance of CBC-5@MnO2 composites was high up to 190 F g−1 at 1 A g−1, and its capacitance retention rate was up to 96.6% after 8000 cycles. The superior electrochemical performance cannot be achieved without the cooperative effect among the metal oxides and carbon materials, which also benefits from the fast transport of ions and electrons in solution. The assembled CBC-5//CBC-5@MnO2-6 h hybrid supercapacitors exhibited largest energy density and power density values of 44.5 Wh kg−1 (at 0.2 A g−1) and 11111.1 W kg−1 (at 10 A g−1), respectively. The assembled button cells can light up small LED bulbs for at least 10 min. The porous bacterial cellulose carbon can provided possibilities for high electrode design.

Study on β-glucosidase activators by 3D-QSAR, molecular docking and molecular dynamics simulation

To investigate the conformational relationship and mechanism of action of β-glucosidase (BGL) activators, a theoretical study of three-dimensional quantitative structure activity relationship, molecular docking, molecular dynamics (MD) simulations, and binding free energy analysis were performed. The results indicate that comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models had good stability and predictive ability, with r2cv/ r2pred values of 0.540/0.998 and 0.654/0.993, respectively. The derived contour maps of steric, electrostatic, and hydrogen bond donor field further displayed the modified information of these activators. Molecular docking and MD were performed on calcium diascorbate (CaAS) and L-Ascorbyl 2,6-Dipalmitate (L-ADP), which have good activating ability. The study indicates a positive interaction between the activators and the enzyme, and this interaction does not cause irreversible negative effects on the conformation of BGL. The MD results show that the total binding free energies of CaAS and L-ADP with BGL were −19.837 kJ/mol and −37.798 kJ/mol, respectively, and the binding force of the activators with BGL was mainly derived from hydrophobic interaction and hydrogen bonding. This study offers important guidance for the efficient use of BGL and for the research and development of effective activators.