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Background: Diabetic foot ulcers (DFU), characterized by open sores or wounds primarily occurring on the feet of diabetes patients, are a serious and highly morbid complication of long-standing diabetes, accounting for significant morbidity and mortality. These ulcers develop when diabetes damages both nerves and blood vessels, a combination known as neurovascular complications. Neurovascular disease is a well-established risk factor. While studies have extensively examined risk factors for DFU, few have specifically focused on patients with diabetic neurovascular disease. Therefore, we assess the prevalence and risk factors for DFU in diabetic patients with established neurovascular complications. Methods: This study analyzed data from 6722 patients with diabetic neurovascular disease aged over 18 years old from the Southern Medical University Nanfang Hospital (SMUNFH) database (2018–2023) and 2689 patients with the same condition and age range from the National Institutes of Health (NIH) Integrated Surveillance System (NIS) database (2017–2019). The incidence of DFU was determined using information from the NIS database and SMUNFH databases. A binary logistic regression model was employed to explore the risk factors for DFU. Results: The incidence of DFU among neurovascular disease patients was 13.4% at SMUNH and 25.9% in the NIS Asian population. Multiple regression analysis identified several factors associated with DFU in the SMUNH database, including diabetic retinopathy, diabetic nephropathy, osteomyelitis, coronary heart disease, tinea pedis (fungal foot infection), sepsis, ability to sense a 128 Hz tuning fork (both left and right sides), C-reactive protein (CRP) levels, and urinary albumin-to-creatinine ratio (ACR). Analysis of NIS data revealed that in the broader Asian population, peripheral vascular disorders and osteomyelitis were associated with DFU. Conclusion: The prevalence of DFU is higher in Asia than in China. Focusing on peripheral vascular disorders and osteomyelitis can effectively reduce the prevalence of DFU in the Asian population while addressing diabetic retinopathy, diabetic nephropathy, osteomyelitis, coronary heart disease, tinea pedis, ability to sense a 128 Hz tuning fork, CRP levels, and urinary ACR can be effective in China. [ABSTRACT FROM AUTHOR]

The shear band due to strain localization is deemed a strong discontinuous plane in this study, and simulated by the numerical manifold method (NMM). The SMP (Spatially Mobilized Plane) criterion is incorporated into the Drucker-Prager (DP) model by the transformed stress (TS) method. The constitutive integration of plasticity is carried out on the new yielding surface with the tensile part being cut off, leading to a mixed complementarity problem (MiCP). The Gauss-Seidel based projection contraction (GSPC) algorithm is invoked to solve the MiCP. In NMM, the cohesion is a constant when the contact is in slipping state. This study modifies the cohesion so that the decaying of cohesion could be reflected with the growth of the sliding. To accelerate the convergence, the contact stiffness matrix in open state is proposed to be constructed in a new way in this paper. The NMM formulation for solving the strain localization problem is derived in this study. The displacement controlled method is extended to the material nonlinearity accompanied with contact problem. Two examples, including the soil block and soil slope under compression, have been studied to verify the efficiency of the proposed method in simulating the process of shear band evolution. [ABSTRACT FROM AUTHOR]

N -acetylneuraminic acid (Neu5Ac) is a glycan receptor of viruses spread in many eukaryotic cells. The present work aimed to design, synthesis and biological evaluation of a panel of Neu5Ac derivatives based on a cyclodextrin (CD) scaffold for targeting influenza and coronavirus membrane proteins. The multivalent Neu5Ac glycoclusters efficiently inhibited chicken erythrocyte agglutination induced by intact influenza virus in a Neu5Ac density–dependent fashion. Compared with inhibition by Neu5Ac, the multivalent inhibitor with 21 Neu5Ac residues on the primary face of the β -CD scaffold afforded 1788-fold higher binding affinity inhibition for influenza virus hemagglutinin with a dissociation constant (K D) of 3.87 × 10−7 M. It showed moderate binding affinity to influenza virus neuraminidase, but with only about one-thirtieth the potency of that with the HA protein. It also exhibited strong binding affinity to the spike protein of three human coronaviruses (severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus 2), with K D values in the low micromolar range, which is about 10-time weaker than that of HA. Therefore, these multivalent sialylated CD derivatives have possible therapeutic application as broad-spectrum antiviral entry inhibitors for many viruses by targeting the Neu5Ac of host cells. [Display omitted] • A series of mono-, tri-, hepta-, nona-, and 21-valent Neu5Ac glycoclusters were designed and synthesized. • Glycocluster interactions with influenza virus hemagglutinin protein were evaluated using HI and SPR assays. • Binding affinities of 41 with influenza virus neuraminidase and three coronavirus spike glycoproteins were determined using SPR assays. • Cyclodextrin scaffold–based multivalent Neu5Ac glycoclusters may be novel broad-spectrum antiviral entry inhibitors. [ABSTRACT FROM AUTHOR]

Since the influenza viruses can rapidly evolve, it is urgently required to develop novel anti-influenza agents possessing a novel mechanism of action. In our previous study, two pentacyclic triterpene derivatives ( Q8 and Y3 ) have been found to have anti-influenza virus entry activities. Keeping the potential synergy of biological activity of pentacyclic triterpenes and l -ascorbic acid in mind, we synthesized a series of novel l -ascorbic acid-conjugated pentacyclic triterpene derivatives ( 18 – 26 , 29 – 31 , 35 – 40 and 42 – 43 ). Moreover, we evaluated these novel compounds for their anti-influenza activities against A/WSN/33 virus in MDCK cells. Among all evaluated compounds, the 2,3- O , O -dibenzyl-6-deoxy- l -ascorbic acid-betulinic acid conjugate ( 30 ) showed the most significant anti-influenza activity with an EC 50 of 8.7 μM, and no cytotoxic effects on MDCK cells were observed. Time-of-addition assay indicated that compound 30 acted at an early stage of the influenza life cycle. Further analyses revealed that influenza virus-induced hemagglutination of chicken red blood cells was inhibited by treatment of compound 30 , and the interaction between the influenza hemagglutinin (HA) and compound 30 was determined by surface plasmon resonance (SPR) with a dissociation constant of K D = 3.76 μM. Finally, silico docking studies indicated that compound 30 and its derivative 31 were able to occupy the binding pocket of HA for sialic acid receptor. Collectively, these results suggested that l -ascorbic acid-conjugated pentacyclic triterpenes were promising anti-influenza entry inhibitors, and HA protein associated with viral entry was a promising drug target. [ABSTRACT FROM AUTHOR]

Multivalent effect plays an important role in biological processes, particularly in the specific recognition of virus with its host cell during the first step of infection. Here we report the synthesis of multivalent pentacyclic triterpene grafted on cyclodextrin core and potency of against influenza entry activity. Nine star-shaped compounds containing six, seven and eight pentacyclic triterpene pharmacophore on cyclodextrin scaffold were prepared by way of copper-catalyzed azide-alkyl cycloaddition reaction under microwave activation. Some of the multimers exhibited much potent antiviral activity against H1N1 virus (A/WSN/33), even equivalent or superior to oseltamivir. The most active compound 31 , a heptavalent oleanolic acid- β -cyclodextrin conjugate, shows an up to 125-fold potency enhancement by its IC 50 value over the corresponding monovalent conjugate and oleanolic acid, disclosing a clear multivalent effect. Further studies show that three compounds 31 – 33 exhibited broad spectrum inhibitory activity against other two human influenza A/JX/312 (H3N2) and A/HN/1222 (H3N2) viruses with the IC 50 values at 2.47–14.90 μ M. Most importantly, we found that compound 31, one of the best representative conjugate, binds tightly to the viral envelope hemagglutinin with a dissociation constant of K D = 2.08 μ M, disrupting the interaction of hemagglutinin with the sialic acid receptor and thus the attachment of viruses to host cells. Our study might establish a strategy for the design of new pharmaceutical agents based on multivalency so as to block influenza virus entry into host cells. [ABSTRACT FROM AUTHOR]

Echinocystic acid (EA), a naturally occurring oleanane-type triterpene isolated from Dipsacus asperoides , was found to have anti-HCV entry activity in our previous study. Expansion of triterpene structural diversity, including the ring A and/or C expansion and opening, was performed. To elucidate the pharmacophore of EA, seven lactones ( 8 , 16 , 17 , 24 , 26 , 35 and 41 ), three 3,28-dioic acids ( 9 , 36 and 42 ) and two pentols ( 10 and 27 ) were synthesized. The anti-HCV entry activities of those derivatives, along with their parental compound EA and analogs α , β -unsaturated ketone ( 18 ), were evaluated. All the products showed no improvement but detrimental effect on potency of EA. The results demonstrated that ring A and C of EA are highly conserved, indicating the steric effects of the rigid skeleton have a profound effect on the potency. [ABSTRACT FROM AUTHOR]