Design of 3D printing osteotomy block for foot based on triply periodic minimal surface.

The ankle joint, which connects the lower limbs and the sole of the foot, is prone to sprain during walking and sports, which leads to ankle arthritis. Supratroleolar osteotomy is an ankle preserving operation for the treatment of ankle arthritis, in which the osteotomy is an important fixing and supporting part. In order to avoid stress shielding effect as much as possible, the osteotomy block is designed as a porous structure. In this study, the osteotomy block was designed based on three-period minimal surface, and the designed structure was manufactured by 3D printing. The mechanical properties of different structures were studied by mechanical test and finite element simulation. In mechanical tests, the Gyroid structure showed a progressive failure mechanism from bottom to bottom, while the Diamond structure showed a shear failure zone at 45° Angle, which was not conducive to energy absorption and was more prone to brittle fracture than the Gyroid structure. Therefore, the Gyroid structure is valuable for further research in the development of porous osteotomy.

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.

Identification of a signature of histone modifiers in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is a cancer that is closely associated with epigenetic alterations, and histone modifiers (HMs) are closely related to epigenetic regulation. Therefore, this study aimed to comprehensively explore the function and prognostic value of HMs-based signature in KIRC. HMs were first obtained from top journal. Then, the mRNA expression profiles and clinical information in KIRC samples were downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Cox regression analysis and least absolute shrinkage and selection operator (Lasso) analysis were implemented to find prognosis-related HMs and construct a risk model related to the prognosis in KIRC. Kaplan-Meier analysis was used to determine prognostic differences between high- and low-risk groups. Immune infiltration and drug sensitivity analysis were also performed between high- and low-risk groups. Eventually, 8 HMs were successfully identified for the construction of a risk model in KIRC. The results of the correlation analysis between risk signature and the prognosis showed HMs-based signature has good prognostic value in KIRC. Results of immune analysis of risk models showed there were significant differences in the level of immune cell infiltration and expression of immune checkpoints between high- and low-risk groups. The results of the drug sensitivity analysis showed that the high-risk group was more sensitive to several chemotherapeutic agents such as Sunitinib, Tipifarnib, Nilotinib and Bosutinib than the low-risk group. In conclusion, we successfully constructed HMs-based prognostic signature that can predict the prognosis of KIRC.

Socioeconomic impact and sufficiency of government financial support during COVID-19 pandemic: A retrospective study.

This study examines the socioeconomic impact of the COVID-19 pandemic and the sufficiency of government support. Based on an online survey with 920 respondents, the cross-tabulation and binary logistic regression results show: firstly, in terms of loss of income, male respondents are more likely to have a loss of income as compared to female counterparts, and secondly, among different categories of employment status, the self-employed respondents are the most vulnerable group, given that more than 20 percent of them experienced loss of income due to the COVID-19 pandemic. Moreover, respondents working in small-and-medium enterprises (SMEs) and the informal sector are more likely to face loss of income as compared to respondents working in other sectors of employment. Likewise, respondents without tertiary education level are more likely to have a loss of income as compared to respondents with university certification. The baseline results highlight the insufficiency of government financial support programs based on the perspective of Malaysians from different demographic backgrounds. As a policy implication, the findings could guide the State in formulating the right policies for target groups who need more assistance than others in the community.

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues.

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

Key role of K+ and Ca2+ in high-yield ethanol production by S. Cerevisiae from concentrated sugarcane molasses.

BACKGROUND: Saccharomyces cerevisiae is an important microorganism in ethanol synthesis, and with sugarcane molasses as the feedstock, ethanol is being synthesized sustainably to meet growing demands. However, high-concentration ethanol fermentation based on high-concentration sugarcane molasses-which is needed for reduced energy consumption of ethanol distillation at industrial scale-is yet to be achieved. RESULTS: In the present study, to identify the main limiting factors of this process, adaptive laboratory evolution and high-throughput screening (Py-Fe3+) based on ARTP (atmospheric and room-temperature plasma) mutagenesis were applied. We identified high osmotic pressure, high temperature, high alcohol levels, and high concentrations of K+, Ca2+, K+ and Ca2+ (K+&Ca2+), and sugarcane molasses as the main limiting factors. The robust S. cerevisiae strains of NGT-F1, NGW-F1, NGC-F1, NGK+, NGCa2+ NGK+&Ca2+-F1, and NGTM-F1 exhibited high tolerance to the respective limiting factor and exhibited increased yield. Subsequently, ethanol synthesis, cell morphology, comparative genomics, and gene ontology (GO) enrichment analysis were performed in a molasses broth containing 250 g/L total fermentable sugars (TFS). Additionally, S. cerevisiae NGTM-F1 was used with 250 g/L (TFS) sugarcane molasses to synthesize ethanol in a 5-L fermenter, giving a yield of 111.65 g/L, the conversion of sugar to alcohol reached 95.53%. It is the highest level of physical mutagenesis yield at present. CONCLUSION: Our results showed that K+ and Ca2+ ions primarily limited the efficient production of ethanol. Then, subsequent comparative transcriptomic GO and pathway analyses showed that the co-presence of K+ and Ca2+ exerted the most prominent limitation on efficient ethanol production. The results of this study might prove useful by promoting the development and utilization of green fuel bio-manufactured from molasses.

Mechanisms of Neuronal Reactivation in Memory Consolidation: A Perspective from Pathological Conditions.

Memory consolidation refers to a process by which labile newly formed memory traces are progressively strengthened into long term memories and become more resistant to interference. Recent work has revealed that spontaneous hippocampal activity during rest, commonly referred to as "offline" activity, plays a critical role in the process of memory consolidation. Hippocampal reactivation occurs during sharp-wave ripples (SWRs), which are events associated with highly synchronous neural firing in the hippocampus and modulation of neural activity in distributed brain regions. Memory consolidation occurs primarily through a coordinated communication between hippocampus and neocortex. Cortical slow oscillations drive the repeated reactivation of hippocampal memory representations together with SWRs and thalamo-cortical spindles, inducing long-lasting cellular and network modifications responsible for memory stabilization.In this review, we aim to comprehensively cover the field of "reactivation and memory consolidation" research by detailing the physiological mechanisms of neuronal reactivation and firing patterns during SWRs and providing a discussion of more recent key findings. Several mechanistic explanations of neuropsychiatric diseases propose that impaired neural replay may underlie some of the symptoms of the disorders. Abnormalities in neuronal reactivation are a common phenomenon and cause pathological impairment in several diseases, such as Alzheimer's disease (AD), epilepsy and schizophrenia. However, the specific pathological changes and mechanisms of reactivation in each disease are different. Recent work has also enlightened some of the underlying pathological mechanisms of neuronal reactivation in these diseases. In this review, we further describe how SWRs, ripples and slow oscillations are affected in Alzheimer's disease, epilepsy, and schizophrenia. We then compare the differences of neuronal reactivation and discuss how different reactivation abnormalities cause pathological changes in these diseases. Aberrant neural reactivation provides insights into disease pathogenesis and may even serve as biomarkers for early disease progression and treatment response.

Preparation and Mechanical Properties of Core-Shell PS&CeO2 Composite Abrasive Particles.

Core-shell composite abrasive particles are a topic of great interest in surface finishing. It is important to explore the preparation technology and performance parameters associated with them. In this paper, a core-shell composite abrasive particle made of polystyrene and cerium oxide (PS&CeO2, CSPC), which is rigid on the outside and flexible on the inside, is proposed. The microstructure, physical phase characteristics, and mechanical properties of the inner core and composite abrasive particles are investigated. PS microspheres and CSPC composite abrasive particles with different structural features were prepared through a series of experiments, morphological observations, and physical and chemical characterization experiments. Their microstructures and physical phase properties were investigated. The indentation load curves of the PS microspheres and CSPC composite abrasive samples were measured by using an atomic force microscope. The analysis focused on the effects of various dimensional and structural parameters on the modulus of elasticity of both PS microspheres and CSPC composite abrasive particles. The analysis shows that the experimentally prepared PS microspheres have good dispersion, a smooth surface, and a uniform particle size distribution. The prepared CSPC composite abrasive particles are regular spheres with rough, rice-like surfaces, low modulus of elasticity, and overall nonrigid and soft elastic properties. The results of this paper can provide a guide for the preparation technology, performance regulation, and application of polymer microspheres and core-shell composite abrasive particles in CMP.

The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Perceptions of risk and coping strategies during the COVID-19 pandemic among women and older adults.

The world's health, economic, and social systems have been adversely impacted by the COVID-19 pandemic. With lockdown measures being a common response strategy in most countries, many individuals were faced with financial and mental health challenges. The current study explored the effect of the COVID-19 pandemic on the psychological well-being, perception of risk factors and coping strategies of two vulnerable groups in Malaysia, namely women and older adults from low-income households (USD592). A purposive sample of 30 women and 30 older adults was interviewed via telephone during Malaysia's Movement Control Order (MCO) regarding the challenges they faced throughout the pandemic. Thematic analysis was subsequently conducted to identify key themes. The themes identified from the thematic analysis indicated a degree of overlap between both groups. For women, seven themes emerged: 1) Psychological challenges due to COVID-19 pandemic, 2) Family violence, 3) Finance and employment related stress and anxiety, 4) Women's inequality and prejudice, 5) Coping strategies, 6) Professional support, and 7) Women's empowerment. Similarly, there were six themes for the older adults: 1) Adverse emotional experiences from COVID-19, 2) Threats to health security, 3) Loss of social connections, 4) Government aid to improve older adults' psychological well-being, 5) Psychological support from family members and pets, and 6) Self-reliance, religion, and spirituality. The findings provide valuable information on the specific burdens faced by these groups, and support psychological interventions and mitigations that would be appropriate to improve well-being during the recovery phase.

[Virtual preoperative planning and 3D-printed templates for pre-contoured plates in treatment of acetabular posterior wall fractures].

OBJECTIVE: To evaluate the feasibility and accuracy of virtual preoperative planning and 3D-printed templates for pre-contoured plates for the treatment of posterior wall fractures of the acetabulum. METHODS: A retrospective analysis of 29 patients with posterior acetabular wall fractures treated between August 2017 and March 2021 were divided into 2 groups based on whether to use preoperative virtual planning and 3D printed template. In 3D-printing group, there were 14 patients, including 10 males and 4 females； aged from 21 to 53 years old；CT-based virtual surgical planning was done using Mimics and 3-Matic software and 3D-printed templates for pre-contoured plates were adopted. In conventional group, there were 15 patients, including 10 males and 5 females；aged from 19 to 55 years old；conventional method of intra-operative contouring to adapt the plate to the fracture region was adopted. Blood loss, surgical time, radiographic quality of reduction, and hip function were compared between groups. RESULTS: The difference in operation time and intraoperative blood loss was significant（P<0.05）. Twenty-three patients were followed up from 12 to 30 months, and the fractures in both groups healed with a healing time of 3 to 6 months. At the last follow-up, the Merle d'Aubign-Postel score of the 3D printed group was lower than that of the conventional group（P<0.05）, with no significant differences in walking ability, hip mobility and total score（P>0.05）. In 3D printing group, 6 cases were excellent, 5 cases were good, 3 cases were fair；in conventional group, 5 cases were excellent, 5 cases were good, 4 cases were fair, 1 case was worse；no significant difference between two groups（P>0.05）. CONCLUSION: Virtual preoperative planning and 3D-printed templates for pre-contoured plates can reduce operative time and the blood loss of surgery, improve the quality of reduction. This method is efficient, accurate and reliable to treat acetabular posterior wall fractures.

Deep learning of heart-sound signals for efficient prediction of obstructive coronary artery disease.

Background: Due to the limitations of current methods for detecting obstructive coronary artery disease (CAD), many individuals are mistakenly or unnecessarily referred for coronary angiography (CAG). Objectives: Our goal is to create a comprehensive database of heart sounds in CAD and develop accurate deep learning algorithms to efficiently detect obstructive CAD based on heart sound signals. This will enable effective screening before undergoing CAG. Methods: We included 320 subjects suspected of CAD who underwent CAG. We employed advanced filtering techniques and state-of-the-art deep learning models (VGG-16, 1D CNN, and ResNet18) to analyze the heart sound signals and identify obstructive CAD (defined as at least one ≥50 % stenosis). To assess the performance of our models, we prospectively recruited an additional 80 subjects for testing. Results: In the test set, VGG-16 exhibited the highest performance with an area under the ROC curve (AUC) of 0.834 (95 % CI, 0.736-0.930), while ResNet-18 and CNN-7 achieved AUCs of only 0.755 (95 % CI, 0.614-0.819) and 0.652 (95 % CI, 0.554-0.770) respectively. VGG-16 demonstrated a sensitivity of 80.4 % and specificity of 86.2 % in the test set. The combined diagnostic model of VGG and DF scores achieved an AUC of 0.915 (95 % CI: 0.855-0.974), and the AUC for VGG combined with PTP scores was 0.908 (95 % CI: 0.845-0.971). The sensitivity and specificity of VGG-16 exceeded 0.85 in patients with coronary artery occlusion and those with 3 vascular lesions. Conclusions: Our deep learning model, based on heart sounds, offers a non-invasive and efficient screening method for obstructive CAD. It is expected to significantly reduce the number of unnecessary referrals for downstream screening.

Gain enhancement of perovskite nanosheets by a patterned waveguide: excitation and temperature dependence of gain saturation.

Optical gain enhancement of two-dimensional CsPbBr3 nanosheets was studied when the amplified spontaneous emission is guided by a patterned structure of polyurethane-acrylate. Given the uncertainties and pitfalls in retrieving a gain coefficient from the variable stripe length method, a gain contour [Formula: see text] was obtained in the plane of spectrum energy (ℏω) and stripe length (x), whereby an average gain was obtained, and gain saturation was analysed. Excitation and temperature dependence of the gain contour show that the waveguide enhances both gain and thermal stability due to the increased optical confinement and heat dissipation, and the gain origins were attributed to the two-dimensional excitons and the localized states.

Synthesis of Naphthalimides through Tandem Pd(II)-Catalyzed C(sp3)-H Oxidation and Diels-Alder Reaction Using a Transient Directing Group Strategy.

Naphthalimides have found extensive applications in materials science and pharmaceuticals. It is still highly desirable to develop efficient methods for the synthesis of naphthalimides with structural diversity. In this work, we developed a new approach for the synthesis of naphthalimides via a tandem reaction of o-methylbenzaldehydes and maleimides. The tandem reaction involves Pd(II)-catalyzed benzylic C(sp3)-H oxidation using an amino acid as the transient directing group and Diels-Alder reaction. The subsequent dehydration forms naphthalimides. The reaction introduces the imide moiety and constructs a benzene ring simultaneously, allowing for easy access to a range of naphthalimides with a variety of substituents.

Right-leaning egalitarians are just as susceptible to social justice-induced product patronage! Evidence from the US and Malaysia.

We investigated the impact of egalitarianism on consumers' inclination to support fair-trade products and examined whether this effect was observed among individuals with different political affiliations. In four experiments featuring a fictional chocolate brand presented in either a social-justice (fair trade) or quality-focused (control) manner, we examined the product purchase intentions of both left- and right-leaning consumers in the United States and Malaysia (Studies 1a, N = 200; 1b, N = 269; & 2, N = 410). Results revealed that participants expressed a greater willingness to support the product when it was framed as contributing to a social justice cause, but this effect was limited to left- and right-leaning consumers who strongly endorsed egalitarian principles. Study 3 (N = 354) employed a mediated-moderation approach and confirmed that an elevated sensitivity to injustice was the underlying mechanism driving increased intentions to support the product among egalitarians exposed to social justice framing. These results demonstrate that right-leaning consumers can be influenced by social justice framing when their commitment to equity is strong.

Optical Gain of Vertically Coupled Cd0.6Zn0.4Te/ZnTe Quantum Dots.

The optical modal gain of Cd0.6Zn0.4Te/ZnTe double quantum dots was measured using a variable stripe length method, where large and small quantum dots are separated with a ZnTe layer. With a large (~18 nm) separation layer thickness of ZnTe, two gain spectra were observed, which correspond to the confined exciton levels of the large and small quantum dots, respectively. With a small (~6 nm) separation layer thickness of ZnTe, a merged single gain spectrum was observed. This can be attributed to a coupled state between large and small quantum dots. Because the density of large quantum dots (4 × 1010 cm-2) is twice the density of small quantum dots (2 × 1010 cm-2), the density of the coupled quantum dots is determined by that of small quantum dots. As a result, we found that the peak gain (123.9 ± 9.2 cm-1) with the 6 nm separation layer is comparable to that (125.2 ± 29.2 cm-1) of the small quantum dots with the 18 nm separation layer.

Versatile functionalization of pectic conjugate: From design to biomedical applications.

Pectin exists extensively in nature and has attracted much attention in biological applications for its unique chemical and physical characteristics. Functionalized pectin, especially pectic conjugates, has given many possibilities for pectin to improve its properties and bioactivity as well as to deliver active molecules. To better exploit this strategy of pectic functionalization, this review presents in detail the structural modifications of pectin, different synthetic methods, and design strategies of pectic conjugates involving both traditional chemical and "green" approaches. Here, the research ideas and applications of pectic prodrugs as well as the development of preparation based on pectic conjugates are reviewed, with emphasis on crosslinking systems of functionalized pectin and nanosystems based on self-assembly techniques. We hope this review will provide comprehensive and valuable information for the functionalization and systematization of the pectic conjugate from synthesis to application.

Methanol-Dependent Carbon Fixation for Irreversible Synthesis of d-Allulose from d-Xylose by Engineered Escherichia coli.

d-Allulose is a rare hexose with great application potential, owing to its moderate sweetness, low energy, and unique physiological functions. The current strategies for d-allulose production, whether industrialized or under development, utilize six-carbon sugars such as d-glucose or d-fructose as a substrate and are usually based on the principle of reversible Izumoring epimerization. In this work, we designed a novel route that coupled the pathways of methanol reduction, pentose phosphate (PP), ribulose monophosphate (RuMP), and allulose monophosphate (AuMP) for Escherichia coli to irreversibly synthesize d-allulose from d-xylose and methanol. After improving the expression of AlsE by SUMO fusion and regulating the carbon fluxes by knockout of FrmRAB, RpiA, PfkA, and PfkB, the titer of d-allulose in fed-batch fermentation reached ≈70.7 mM, with a yield of ≈0.471 mM/mM on d-xylose or ≈0.512 mM/mM on methanol.

Spontaneous healing after conservative treatment of isolated grade IV pancreatic duct disruption caused by trauma: A case report.

BACKGROUND: Trauma is a common cause of pancreatic duct disruption. Surgical treatment is recommended in current clinical guidelines for adult pancreatic injury because non-surgical treatments have higher risks of serious complications or even death compared with surgical treatment. CASE SUMMARY: A 22-year-old woman was admitted to Tiantai People's Hospital of Zhejiang Province after 1-h duration of abdominal pain and distension following trauma. The diagnosis was "traumatic pancreatic rupture". The patient's symptoms were not severe, her vital signs were stable, and signs of peritonitis were not obvious. Therefore, conservative treatment could be considered, with the possibility of emergency surgery if necessary. After 2 mo of conservative treatment with duct drainage, the pancreatic duct healed spontaneously with no significant complications. CONCLUSION: We report a case of pancreatic duct disruption in the head and neck caused by trauma that was treated conservatively and healed spontaneously, providing a new choice for clinical practice. For isolated pancreatic injury with rupture of the pancreatic duct in the head and neck, conservative treatment under close observation is feasible.

The impact of the methyl esters of homogalacturonan on cellular uptake dependent hypoglycemic activity in IR-HepG2 cells.

A homogalacturonan (HG) FPLP obtained from Ficus pumila L. was reported to have anti-diabetic activity but how this is influenced by degree of methyl-esterification (DM) of HG is unknown. To comprehensively analyze the role of DM in hypoglycemic activity in insulin-resistant HepG2 cells, HG derivatives (0 < DM < 100) were prepared from FPLP (DM25) by alkali or methanol acidified with acetyl chloride. Interestingly, a quadratic curve relationship revealed that hypoglycemic effect increased and then decreased with DM, and which was the most pronounced with DM54. DM might regulate activity by altering the intracellular drug concentration through cellular uptake. Furthermore, HG-DMn (0 < n < 100) were dependent on macropinocytosis, while HG-DMn (30 < n < 100) were also dependent on caveolae-mediated endocytosis. For HG, higher lipophilicity, smaller particle size, and more endocytosis mechanisms involved were favorable for cellular uptake, thereby increasing the intracellular drug concentration and enhancing the hypoglycemic activity. This work provides ideas for future investigations on structure-activity relationships.