Unveil the mechanism for EHMT -- A novel triterpenoid inhibits proliferation and induces apoptosis in colon cancer through ROS-mediated JNK signaling pathway.

Colon cancer ranks among the most prevalent malignancies worldwide, trailing only lung and breast cancer in incidence. Despite the availability of numerous therapeutic strategies, the burden of new cases and fatalities remains high in countries undergoing socioeconomic transitions. Natural products offer promising avenues for developing more effective and less toxic anticancer agents, expanding the clinical arsenal. In this investigation, we isolated a triterpenoid, (21 S,23 R,24 R)-21,23-epoxy-24-hydroxy-21-methoxytirucalla-7,25-dien-3-one (EHMT), from the fruits of Melia azedarach L., which exhibited significant inhibitory activity against colon cancer cells while sparing normal cells. EHMT effectively curtailed colony formation and induced apoptosis and cell cycle arrest in the HCT116 cell line. Furthermore, EHMT prompted the generation of reactive oxygen species (ROS) and the depolarization of mitochondrial membrane potential. Notably, EHMT treatment triggered ROS-mediated cell apoptosis via activation of the JNK signaling pathway in HCT116 cells. Additionally, our findings extended to Caenorhabditis elegans, where EHMT induced ROS accumulation and apoptosis. Collectively, these findings position EHMT as a promising candidate for the development of anticancer agents in the treatment of colon cancer, offering new hope in the battle against this formidable disease.

Molecular mechanisms involved in the destabilization of two types of R3-R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin.

Chronic traumatic encephalopathy is a neurodegenerative tauopathy pathologically characterized by fibrillary tau aggregates in the depth of sulci. Clearing fibrous tau aggregates is considered a promising strategy in the treatment of CTE. Fisetin (FS), a natural polyphenolic small molecule, was confirmed to disassociate the tau filaments in vitro. However, the molecular mechanisms of FS in destabilizing the CTE-related R3-R4 tau fibrils remain largely unknown. In this study, we compared the atomic-level structural differences of the two types of CTE-related R3-R4 tau fibrils and explored the influence and molecular mechanisms of FS on the two types of fibrils by conducting multiple molecular dynamics (MD) simulations. The results reveal that the type 1 fibril displays higher structural stability than the type 2 fibril, with a lower root-mean-square-fluctuation value and higher ß-sheet structure probability. FS can destabilize both types of fibrils by decreasing the ß-sheet structure content, interrupting the mainchain H-bond network, and increasing the solvent accessible surface area and ß7-ß8 angle of the fibrils. H-bonding, π-π stacking and cation-π are the common interactions driving FS molecules binding on the two types of fibrils, while the hydrophobic interaction occurs only in the type 2 fibril. Due to the relatively short simulation time, our study captures the early molecular mechanisms. However, it does provide beneficial information for the design of drugs to prevent or treat CTE.

A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.

A de novo variant in ZBTB18 gene caused autosomal dominant non-syndromic intellectual disability 22 syndrome: A case report and literature review.

RATIONALE: Autosomal dominant non-syndromic intellectual disability 22 is a rare genetic disorder caused by the ZBTB18 gene. This disorder affects various parts of the body, leading to intellectual disability. It is noteworthy that only 31 cases of this disorder have been reported thus far. As the symptom severity may differ, doctors may face challenges in diagnosing it accurately. It is crucial to be familiar with this disorder's symptoms to receive proper diagnosis and essential medical care. PATIENT CONCERNS: There is a case report of a 6-year-old boy who had an unexplained thyroid abnormality, global developmental delay, and an abnormal signal of white matter in brain MRI. However, he did not have growth retardation, microcephaly, corpus callosum hypoplasia, epilepsy, or dysmorphic facial features. Clinical whole exome sequencing revealed a de novo pathogenic variant in the ZBTB18 gene (c.1207delC, p. Arg403Alafs*60), which is a previously unreported site. This variant causes the premature termination of peptide chain synthesis, leading to incomplete polypeptide chains. DIAGNOSES: Autosomal dominant non-syndromic intellectual and disability 22 syndrome and thyroid dysfunction. INTERVENTIONS: Rehabilitation training. OUTCOMES: The individual is experiencing difficulty with their motor skills, appearing clumsier while running. He struggles with expressing themselves and forming complete sentences, relying mostly on gestures and pointing. LESSONS: The clinical presentations of mental retardation, autosomal dominant, type 22 (MRD22) are complicated and varied. Although early diagnosis can be made according to typical clinical symptoms, whole exome sequencing is necessary for diagnosing MRD22, as our study indicates.

Atomic insights into the inhibition of R3 domain of tau protein by epigallocatechin gallate, quercetin and gallic acid.

Inhibiting tau protein aggregation has become a prospective avenue for the therapeutic development of tauopathies. The third microtubule-binding repeat (R3) domain of tau is confirmed as the most aggregation-favorable fragment of the whole protein. As dimerization is the first step of the aggregation of tau into amyloid fibrils, impeding the dimerization of the R3 domain is critical to prevent the full-length tau aggregation. Natural polyphenol small molecules epigallocatechin gallate (EGCG), quercetin (QE) and gallic acid (GA) are proven to inhibit the aggregation of the full-length recombinant tau (For EGCG and QE) or the R3 domain (For GA) of tau in vitro. However, the underlying molecular mechanisms of the inhibitive effects on the R3 domain of tau remain largely unknown. In this study, we conducted numerous all-atom molecular dynamics simulations on R3 dimers with and without EGCG, QE or GA, respectively. The results reveal that all three molecules can effectively decrease the ß structure composition of the R3 dimer, induce the dimer to adopt loosely-packed conformations, and weaken interchain interactions, thus impeding the dimerization of the R3 peptide chains. The specific preferentially binding sites for the three molecules exhibit similarities and differences. Hydrophobic, π-π stacking and hydrogen-bonding interactions collectively drive EGCG, QE and GA respectively binding on the R3 dimer, while QE also binds with the dimer through cation-π interaction. Given the incurable nature of tauopathies hitherto, our research provides helpful knowledge for the development of drugs to treat tauopathies.

2D TiS2-Nanosheet-Coated Concave Gold Arrays with Triple-Coupled Resonances as Sensitive SERS Substrates.

Herein, a hybrid substrate for surface-enhanced Raman scattering (SERS) is fabricated, which couples localized surface plasmon resonance (LSPR), charge transfer (CT) resonance, and molecular resonance. Exfoliated 2D TiS2 nanosheets with semimetallic properties accelerate the CT with the tested analytes, inducing a remarkable chemical mechanism enhancement. In addition, the LSPR effect is coupled with a concave gold array located underneath the thin TiS2 nanosheet, providing a strong electromagnetic enhancement. The concave gold array is prepared by etching silicone nanospheres assembled on larger polystyrene nanospheres, followed by depositing a gold layer. The LSPR intensity near the gold layer can be adjusted by changing the layer thickness to couple the molecular and CT resonances, in order to maximize the SERS enhancement. The best SERS performance is recorded on TiS2-nanosheet-coated plasmonic substrates, with a detectable methylene blue concentration down to 10-13 m and an enhancement factor of 2.1 × 109 and this concentration is several orders of magnitude lower than that of the TiS2 nanosheet (10-11 m) and plasmonic substrates (10-9 m). The present hybrid substrate with triple-coupled resonance further shows significant advantages in the label-free monitoring of curcumin (a widely applied drug for treating multiple cancers and inflammations) in serum and urine.

Mitochondrial complex I inhibition by homoharringtonine: A novel strategy for suppression of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a hematologic malignancy predominantly driven by the BCR-ABL fusion gene. One of the significant challenges in treating CML lies in the emergence of resistance to tyrosine kinase inhibitors (TKIs), especially those associated with the T315I mutation. Homoharringtonine (HHT) is an FDA-approved, naturally-derived drug with known anti-leukemic properties, but its precise mechanisms of action remain incompletely understood. In this study, we rigorously evaluated the anti-CML activity of HHT through both in vitro and in vivo assays, observing substantial anti-CML effects. To elucidate the molecular mechanisms underpinning these effects, we performed proteomic analysis on BCR-ABL T315I mutation-bearing cells treated with HHT. Comprehensive pathway enrichment analysis identified oxidative phosphorylation (OXPHOS) as the most significantly disrupted, suggesting a key role in the mechanism of action of HHT. Further bioinformatics exploration revealed a substantial downregulation of proteins localized within mitochondrial complex I (MCI), a critical OXPHOS component. These results were validated through Western blot analysis and were supplemented by marked reductions in MCI activity, ATP level, and oxygen consumption rate (OCR) upon HHT exposure. Collectively, our results shed light on the potent anti-CML properties of HHT, particularly its effectiveness against T315I mutant cells through MCI inhibition. Our study underscores a novel therapeutic strategy to overcome BCR-ABL T315I mutation resistance, illuminating a previously uncharted mechanism of action for HHT.

Limonoids from the roots of Melia azedarach and their anti-inflammatory activity.

Twelve undescribed limonoids, meliazedarines J-U (1-12), along with a known one, were isolated from the roots of Melia azedarach. Their structures were elucidated by extensive spectroscopic investigations, X-ray diffraction analyses, and ECD calculations. Compounds 1-8 were identified as ring intact limonoids, while compounds 9-12 were established as ring C-seco ones. The anti-inflammatory potential of compounds 1-4, 6, 8, 9, and 11-13 was evaluated on macrophages. Compounds 1, 3, 4, 6, and 9 significantly suppressed nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, among them compound 3 showed the best inhibitory effect with an IC50 value of 7.07 ± 0.48 µΜ. Furthermore, compound 3 effectively reduced interleukin-1ß secretion in LPS plus nigericin-induced THP-1 macrophages by inhibiting NLRP3 inflammasome activation. The results strongly suggested that limonoids from the roots of M. azedarach might be candidates for treating inflammation-related diseases.

Mechanical upside of PAO mainstream fixations: co-simulation based on early postoperative gait characteristics of DDH patients.

Purpose: To investigate the early postoperative gait characteristics of patients who underwent periacetabular osteotomy (PAO) and predict the biomechanical performance of two commonly used PAO fixation methods: iliac screw (IS) and transverse screw (TS). Methods: A total of 12 patients with unilateral developmental dysplasia of the hip (DDH) (mean age 27.81 ± 4.64 years, 42% male) that were scheduled to undergo PAO surgery were included in this study. Their preoperative CT images and pre- and postoperative gait data were used to create subject-specific musculoskeletal models and complete the inverse dynamics analysis (IDA). Two patients with typical gait characteristics were selected using clustering analysis, and their IDA data were incorporated into finite element (FE) models of IS and TS fixations. Failure simulation was performed by applying iterative steps with increasing gait load to predict yield load. Stress results and yield loads were calculated for each FE model at different phases of the gait cycle. Results: Postoperative gait showed improvement compared to preoperative gait but remained inferior to that of healthy individuals. Postoperative gait was characterized by a lower hip range of motion, lower peri-ilium muscle forces, particularly in the abductors, and a sharper initial peak and flatter second peak of hip joint reaction force (HRF). Finite element analysis (FEA) showed a trend of increasing stress during the second-fourth phases of the gait cycle, with lower stress levels in other phases. At high-stress gait phases, the mean stress of maximum p¯100 differed significantly between IS and TS (p < 0.05) and between coupled and uncoupled muscle forces (p < 0.05). Failure analysis predicted a slightly larger yield load for TS configurations (6.21*BW) than that for IS (6.16*BW), but both were well above the gait load. Coupled and uncoupled groups showed similar results, but uncoupled groups had lower yield loads (5.9*BW). Conclusion: PAO early postoperative gait shows a normalized trend, but abnormalities persist. IS and TS are both capable of resisting mechanical strain failure, with no significant mechanical advantage found for transverse screw fixation during PAO early postoperative gait. Additionally, it is important to note that the TS may have a higher risk of cyclic fatigue failure due to the localized greater stress concentration. Furthermore, the most medial screw is crucial for pelvic stability.

Deciphering the Inhibitory Mechanism of Naphthoquinone-Dopamine on the Aggregation of Tau Core Fragments PHF6* and PHF6.

The formation of neurofibrillary tangles by abnormal aggregation of tau protein is considered to be an important pathological characteristic of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. Two hexapeptides 275VQIINK280 and 306VQIVYK311 in the microtubule binding region, named PHF6* and PHF6, are known to be aggregation-prone and responsible for tau fibrillization. Previous experiments reported that naphthoquinone-dopamine (NQDA) could effectively inhibit the aggregation of PHF6* and PHF6 and disrupt the fibrillar aggregates into nontoxic species, displaying a dual effect on the amyloid aggregation. However, the underlying molecular mechanism remains mostly elusive. Herein, we performed all-atom molecular dynamics (MD) simulations for 114 µs in total to systematically investigate the impacts of NQDA on the oligomerization of PHF6* and PHF6. The conformational ensembles of PHF6* and PHF6 peptides generated by replica exchange MD simulations show that NQDA could effectively prevent the hydrogen bond formation, reduce the ability of peptides to self-assemble into long ß-strand and large ß-sheets, and induce peptides to form a loosely packed and coil-rich oligomer. The interaction analysis shows that the binding of NQDA to PHF6* is mainly through hydrophobic interactions with residue I277 and hydrogen bonding interactions with Q276; for the PHF6 peptides, NQDA displays a strong π-π stacking interaction with residue Y310, thus impeding the Y310-Y310 π-π stacking and I308-Y310 CH-π interactions. The DA group of NQDA displays a stronger cation-π interaction than the NQ group, while the NQ group exhibits a stronger π-π stacking interaction. MD simulations demonstrate that NQDA prevents the conformational conversion to ß-sheet-rich aggregates and displays an inhibitory effect on the oligomerization dynamics of PHF6* and PHF6. Our results provide a complete picture of inhibitory mechanisms of NQDA on PHF6* and PHF6 oligomerization, which may pave the way for designing drug candidates for the treatment of tauopathies.

Protective effect of manganese treatment on insulin resistance in HepG2 hepatocytes.

Introduction: Objectives: manganese (Mn) is closely related to type 2 diabetes mellitus and insulin resistance (IR), but the exact mechanism is unclear. This study aimed to explore the regulatory effects and mechanism of Mn on IR using hepatocyte IR model induced by high palmitate (PA), high glucose (HG) or insulin. Methods: HepG2 cells were exposed to PA (200 µM), HG (25 mM) or insulin (100 nM) respectively, alone or with 5 µM Mn for 24 hours. The expression of key proteins in insulin signaling pathway, intracellular glycogen content and glucose accumulation, reactive oxygen species (ROS) level and Mn superoxide dismutase (MnSOD) activity were detected. Results: compared with control group, the expression of phosphorylated protein kinase B (Akt), glycogen synthase kinase-3ß (GSK-3ß) and forkhead box O1 (FOXO1) in the three IR groups was declined, and this decrease was reversed by Mn. The reduction of intracellular glycogen content and increase in glucose accumulation in IR groups were also inhibited by Mn. Additionally, the production of ROS was increased in IR models, compared with normal control group, while Mn reduced the excessive production of ROS induced by PA, HG or insulin. However, Mn did not alter the activity of MnSOD in the three IR models. Conclusion: this study demonstrated that Mn treatment can improve IR in hepatocytes. The mechanism is probably by reducing the level of intracellular oxidative stress, enhancing the activity of Akt/GSK-3ß/FOXO1 signal pathway, promoting glycogen synthesis, and inhibiting gluconeogenesis.

Introducción: Objetivos: el manganeso (Mn) está estrechamente relacionado con la diabetes mellitus tipo 2 y la resistencia a la insulina (RI), pero el mecanismo exacto aún no está claro. Este estudio tuvo como objetivo explorar los efectos reguladores y el mecanismo del Mn sobre la RI utilizando un modelo de RI en hepatocitos inducido por palmitato alto (PA), glucosa alta (HG) o insulina. Métodos: las células HepG2 se expusieron a PA (200 µM), HG (25 mM) o insulina (100 nM), solas o junto con 5 µM de Mn durante 24 horas. Se evaluó la expresión de proteínas clave en la vía de señalización de la insulina, el contenido intracelular de glucógeno y la acumulación de glucosa, el nivel de especies reactivas de oxígeno (ROS) y la actividad superóxido dismutasa del manganeso (MnSOD). Resultados: en comparación con el grupo de control, la expresión de proteína quinasa B fosforilada (Akt), la glucógeno sintasa quinasa-3ß (GSK-3ß) y la proteína forkhead box O1 (FOXO1) en los tres grupos de RI se redujo, y esta disminución fue revertida por el Mn. La reducción del contenido de glucógeno intracelular y el aumento de la acumulación de glucosa en los grupos de RI también fueron inhibidos por el Mn. Además, la producción de ROS aumentó en los modelos de RI en comparación con el grupo de control normal. Mientras que el Mn redujo la producción excesiva de ROS inducida por PA, HG o insulina. Sin embargo, el Mn no alteró la actividad de la MnSOD en los tres modelos de RI. Conclusión: este estudio demostró que el tratamiento con Mn puede mejorar la RI en hepatocitos. El mecanismo probablemente sea mediante la reducción del nivel de estrés oxidativo intracelular, mejorando la actividad de la vía de señalización Akt/GSK-3ß/FOXO1, promoviendo la síntesis de glucógeno e inhibiendo la gluconeogénesis.

Diet, physical activity, and UV protection comprehensively influenced vitamin D status in college students: a cross-section study from China.

BACKGROUND: Vitamin D deficiency is one of the most prevalent health problems worldwide in all age groups, whereas vitamin D status of Chinese college students was seldom studied in China. The purpose of this study was to explore the vitamin D status in Chinese college freshmen and its influencing factors, providing evidence for nutrition strategy application. METHODS: Information including demographic status, diet habit, physical activity, and ultraviolet ray (UV) protection was collected by online questionnaire. Serum 25(OH)D3 concentrations were measured using a liquid chromatograph mass spectrometer. Multivariate linear regression analyses were used to explore the comprehensive influence of diet, physical activity and UV protection on serum 25(OH)D3 levels. RESULTS: Totally 1667 freshmen from 26 provinces, autonomous districts or municipalities, were recruited, with a mean age of 18.6 ± 0.9 years. The mean serum 25(OH)D3 levels were 18.1 ± 6.3 ng/mL and the proportion of vitamin D deficiency and insufficiency was 67.5% and 27.8%, respectively. Multivariate linear regression indicated that higher intake of milk and yogurt, calcium or vitamin D supplementation, and longer time of outdoor activity were positively linked to higher serum 25(OH)D3, while higher intake of candy and higher UV protection index were negatively associated with serum 25(OH)D3, after adjusted for age, gender, region of original residence, latitudes, longitude and BMI. CONCLUSIONS: Vitamin D deficiency is very common in Chinese college students. Milk and yogurt intake and outdoor activity should be encouraged while candy intake should be limited for preventing vitamin D deficiency. Public health policies should focus on these changeable lifestyles and consider well-balanced guidelines on UV protection and vitamin D supplementation.

Inhibitive and Destructive Mechanisms of Chronic Traumatic Encephalopathy-Related R3-R4 Tau Peptide Chains and Protofibril by Epigallocatechin Gallate: Evidence from Molecular Dynamics Simulation.

Chronic traumatic encephalopathy (CTE), a unique tauopathy, is pathologically associated with the aggregation of hyperphosphorylated tau protein into fibrillar aggregates. Inhibiting tau aggregation and disaggregating tau protofibril might be promising strategies to prevent or delay the development of CTE. Newly resolved tau fibril structures from deceased CTE patients' brains show that the R3-R4 fragment of tau forms the core of the fibrils and the structures are distinct from other tauopathies. An in vitro experiment finds that epigallocatechin gallate (EGCG) can effectively inhibit human full-length tau aggregation and disaggregate preformed fibrils. However, its inhibitive and destructive effects on the CTE-related R3-R4 tau and the underlying molecular mechanisms remain elusive. In this study, we performed extensive all-atom molecular dynamics simulations on the CTE-related R3-R4 tau dimer/protofibril with and without EGCG. The results reveal that EGCG could reduce the ß-sheet structure content of the dimer, induce the dimer to form loosely packed conformations, and impede the interchain interactions, thus inhibiting the further aggregation of the two peptide chains. Besides, EGCG could reduce the structural stability, decrease the ß-sheet structure content, reduce the structural compactness, and weaken local residue-residue contacts of the protofibril, hence making the protofibril disaggregated. We also identified the dominant binding sites and pivotal interactions. EGCG preferentially binds with hydrophobic, aromatic, and positively/negatively charged residues of the dimer, while it tends to bind with polar, hydrophobic, aromatic, and positively charged residues of the protofibril. Hydrophobic, hydrogen-bonding, π-π stacking, and cation-π interactions synergistically drive the binding of EGCG on both the dimer and the protofibril, but anion-π interaction only exists in the interaction of EGCG with the dimer. Our work unravels EGCG's inhibitive and destructive effects on the CTE-related R3-R4 tau dimer/protofibril and the underlying molecular mechanisms, which provides useful implications for the design of drugs to prevent or delay the progression of CTE.

Germacrane-type sesquiterpenoids from the flowers of Chrysanthemum indicum with hepatoprotective activity.

Two new germacrane-type sesquiterpenoids, chrysanthemolides A (1) and B (2), and four known germacrane-type sesquiterpenoids, hanphyllin (3), 3ß-hydroxy-11α,13-dihydro-costunolide (4), costunolide (5), and 6,7-dimethylmethylene-4-aldehyde-1ß-hydroxy-10(15)-ene-(4Z)-dicyclodecylene (6), were isolated and identified from the flowers of Chrysanthemum indicum. The structures of the new compounds were elucidated via high resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR) spectra and electronic circular dichroism (ECD). Meanwhile, all the isolates were tested for their hepatoprotective activity in tert-butyl hydroperoxide (t-BHP) injured AML12 cells. Compounds 1, 2, and 4 showed significant protective effects at 40 µM, comparable with the positive control resveratrol at 10 µM. As the most potent one, compound 1 was chosen for further studies. Compound 1 dose-dependently increased the viability of t-BHP-injured AML12 cells. Furthermore, compound 1 decreased reactive oxygen species accumulation, while increased glutathione level, heme oxygenase-1 level and superoxide dismutase activity, through anchoring in the binding site of Kelch domain of the Kelch-like ECH-associated protein 1 (Keap1) to promote the dissociation of nuclear factor erythroid 2-related factor 2 from Keap1 and translocation to nuclei. In summary, germacrane-type sesquiterpenoids from C. indicum might be further developed to protect liver against oxidative damage.

Molecular Mechanism in the Disruption of Chronic Traumatic Encephalopathy-Related R3-R4 Tau Protofibril by Quercetin and Gallic Acid: Similarities and Differences.

Chronic traumatic encephalopathy (CTE) is a unique progressive neurodegenerative tauopathy pathologically related to the aggregation of the tau protein to neurofibrillary tangles. Disrupting tau oligomers (protofibril) is a promising strategy to prevent CTE. Quercetin (QE) and gallic acid (GA), two polyphenol small molecules abundant in natural crops, were proved to inhibit recombinant tau and the R3 fragment of human full-length tau in vitro. However, their disruptive effect on CTE-related protofibril and the underlying molecular mechanism remain elusive. Cryo-electron microscopy resolution reveals that the R3-R4 fragment of tau forms the core of the CTE-related tau protofibril. In this study, we conducted extensive all-atom molecular dynamics simulations on CTE-related R3-R4 tau protofibril with and without QE/GA molecules. The results disclose that both QE and GA can disrupt the global structure of the protofibril, while GA shows a relatively strong effect. The binding sites, exact binding patterns, and disruptive modes for the two molecules show similarities and differences. Strikingly, both QE and GA can insert into the hydrophobic cavity of the protofibril, indicating they have the potential to compete for the space in the cavity with aggregation cofactors unique to CTE-related protofibril and thus impede the further aggregation of the tau protein. Due to relatively short time scale, our study captures the early disruptive mechanism of CTE-related R3-R4 tau protofibril by QE/GA. However, our research does provide valuable knowledge for the design of supplements or drugs to prevent or delay the development of CTE.

Atomistic Insights into the Inhibitory Mechanism of Tyrosine Phosphorylation against the Aggregation of Human Tau Fragment PHF6.

Abnormal aggregation of the microtubule-associated protein tau into intracellular fibrillary inclusions is characterized as the hallmark of tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy. The hexapeptide 306VQIVYK311 (PHF6) of R3 plays an important role in the aggregation of tau. Recent experimental studies reported that phosphorylation of residue tyrosine 310 (Y310) could decrease the propensity of PHF6 to form fibrils and inhibit tau aggregation. However, the underlying inhibitory mechanism is not well understood. In this work, we systematically investigated the influences of phosphorylation on the conformational ensembles and oligomerization dynamics of PHF6 by performing extensive all-atom molecular dynamics (MD) simulations. Our replica exchange MD simulations demonstrate that Y310 phosphorylation could effectively suppress the formation of ß-structure and shift PHF6 oligomers toward coil-rich aggregates. The interaction analyses show that hydrogen bonding and hydrophobic interactions among PHF6 peptides, as well as Y310-Y310 π-π stacking and I308-Y310 CH-π interactions, are weakened by phosphorylation. Additional microsecond MD simulations show that Y310 phosphorylation could inhibit the oligomerization of PHF6 by preventing the formation of large ß-sheet oligomers and multi-layer ß-sheet aggregates. This study provides mechanistic insights into the phosphorylation-inhibited tau aggregation, which may be helpful for the in-depth understanding of the pathogenesis of tauopathies.

Rapid, label-free histopathological diagnosis of liver cancer based on Raman spectroscopy and deep learning.

Biopsy is the recommended standard for pathological diagnosis of liver carcinoma. However, this method usually requires sectioning and staining, and well-trained pathologists to interpret tissue images. Here, we utilize Raman spectroscopy to study human hepatic tissue samples, developing and validating a workflow for in vitro and intraoperative pathological diagnosis of liver cancer. We distinguish carcinoma tissues from adjacent non-tumour tissues in a rapid, non-disruptive, and label-free manner by using Raman spectroscopy combined with deep learning, which is validated by tissue metabolomics. This technique allows for detailed pathological identification of the cancer tissues, including subtype, differentiation grade, and tumour stage. 2D/3D Raman images of unprocessed human tissue slices with submicrometric resolution are also acquired based on visualization of molecular composition, which could assist in tumour boundary recognition and clinicopathologic diagnosis. Lastly, the potential for a portable handheld Raman system is illustrated during surgery for real-time intraoperative human liver cancer diagnosis.

Inhibition of bladder cancer growth with homoharringtonine by inactivating integrin α5/ß1-FAK/Src axis: A novel strategy for drug application.

The application of immune checkpoint inhibitors and FGFR protein tyrosine kinase inhibitors have made a tremendous breakthrough in bladder cancer therapy. However, inadequate drug responses and drug resistance interfere with successful treatment outcomes. For a new drug to enter the market, there is a long development cycle with high costs and low success rates. Repurposing previously Food and Drug Administration (FDA)-approved medications and using novel drug discovery strategies may be an optimal approach. Homoharringtonine (HHT) has been used for hematologic malignancies for over 40 years in China and was approved by the FDA approximately 10 years ago. Many studies have demonstrated that HHT effectively inhibits the development of several types of solid tumors, although the underlying mechanisms of action are unclear. In this study, we investigated the mechanisms underlying HHT activity against bladder cancer growth. We first compared HTT with the drugs currently used clinically for bladder cancer treatment. HHT showed stronger inhibitory activity than cisplatin, carboplatin, and doxorubicin. Our in vitro and in vivo data demonstrated that HHT inhibited proliferation, colony formation, migration, and cell adhesion of bladder cancer cells and induced apoptosis and cell cycle arrest in the nanomolar concentration range. Furthermore, we revealed that HHT treatment could downregulate the MAPK/Erk and PI3k/Akt signaling pathways by inactivating the integrin α5/ß1-FAK/Src axis. HHT-induced activity reduced cell-ECM interactions and cell migration, thus suppressing tumor metastasis progression. Altogether, HHT shows enormous potential as an anticancer agent and may be applied as a combination treatment strategy for bladder cancer.

Erratum to "Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study".

[This corrects the article DOI: 10.1515/med-2022-0506.].

Enantioselective semisynthesis of novel cephalotaxine esters with potent antineoplastic activities against leukemia.

Cephalotaxine-type alkaloids (CTAs), represented by homoharringtonine (HHT, 1), display potent efficacy against different types of leukemia cells. In this study, a method for hydrogenation of ß-substituted itaconic acid monoesters with chiral Ru[DTBM-SegPhos](OAc)2 was developed. This metal-catalyzed asymmetric hydrogenation enabled the convenient semisynthesis of novel cephalotaxine derivatives with chiral 2'-substituted-succinic acid 4-mono-methyl esters as side chains. The preliminary structure-activity relationship (SAR) of the compounds' antineoplastic activities was studied. Eventually, we discovered compound 10b with potent antineoplastic activities against leukemia and broadly anticancer activities against a panel of cancer cells. Our study provided a highly enantioselective process enabling the semisynthesis of cephalotaxine derivatives, which are interesting for further study on a scientific basis.