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Background: Long COVID affects millions of people and results in a substantial decrease in quality of life. Previous primary studies and reviews attempted to study the effect of vaccination against long COVID, but these studies varied in the cut-off time of long COVID. We adhered to the WHO's definition of long COVID and conducted a systematic review and meta-analysis on the effect of pre-COVID and post-COVID vaccination on long COVID., Methods: We obtained data from 13 databases up to 18 February 2024, including peer reviewed and preprint studies. Our inclusion criteria were: (1) long COVID definition as 3 months or beyond, (2) comparing long COVID symptoms between vaccinated and unvaccinated groups, (3) subjects received vaccinations either before or after infected with COVID, (4) the number of doses received by participants was specified. We extracted study characteristics and data and computed the summary odds ratio (OR) with the DerSimonian and Laird random effects model. We then performed subgroup analyses based on the main vaccine brand and long COVID assessment method. ROBINS-I framework was used for assessment of risk of bias and the GRADE approach was used for evaluating the certainty of evidence., Findings: We included data from 25 observational studies (n = 14,128,260) with no randomised controlled trials. One-dose pre-COVID vaccination did not have an effect on long COVID (number of studies = 10, summary OR = 1.01, 95% CI = 0.88-1.15, p-value = 0.896). Two-dose pre-COVID vaccination was associated with a 24% reduced odds of long COVID (number of studies = 15, summary OR = 0.76, 95% CI = 0.65-0.89, p-value = 0.001) and 4 symptoms (fatigue, headache, loss of smell, muscle pain) out of 10 symptoms analysed. The OR of three-dose pre-COVID vaccination against overall long COVID was statistically insignificant but was far away from 1 (number of studies = 3, summary OR = 0.31, 95% CI = 0.05-1.84, p-value = 0.198). One-dose post-COVID vaccination was associated with a 15% reduced odds of long COVID (number of studies = 5, summary OR = 0.85, 95% CI = 0.73-0.98, p-value = 0.024). The OR of two-dose post-COVID vaccination against long COVID was statistically insignificant but was far away from 1 (number of studies = 3, summary OR = 0.63, 95% CI = 0.38-1.03, p-value = 0.066)., Interpretation: Our study suggests that 2-dose pre-COVID vaccination and 1-dose post-COVID vaccination are associated with a lower risk of long COVID. Since long COVID reduces quality of life substantially, vaccination could be a possible measure to maintain quality of life by partially protecting against long COVID., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Feruloyl Sucrose Esters (FSEs) are a class of Phenylpropanoid Sucrose Esters (PSEs) widely distributed in plants. They were investigated as potential selective Alpha Glucosidase Inhibitors (AGIs) to eliminate the side effects associated with the current commercial AGIs. The latter effectively lowers blood glucose levels in diabetic patients but causes severe gastrointestinal side effects., Methods: Systematic structure-activity relationship (SAR) studies using in silico, in vitro and in vivo experiments were used to accomplish this aim. FSEs were evaluated for their in vitro inhibition of starch and oligosaccharide digesting enzymes α-glucosidase and α- amylase followed by in silico docking studies to identify the binding modes. A lead candidate, FSE 12 was investigated in an STZ mouse model., Results: All active FSEs showed desired higher % inhibition of α-glucosidase and desired lower inhibition of α -amylase in comparison to AGI gold standard acarbose. This suggests a greater selectivity of the FSEs towards α -glucosidase than α -amylase, which is proposed to eliminate the gastrointestinal side effects. From the in vitro studies, the position and number of the feruloyl substituents on the sucrose core, the aromatic 'OH' group, and the diisopropylidene bridges were key determinants of the % inhibition of α - glucosidase and α -amylase. In particular, the diisopropylidene bridges are critical for achieving inhibition selectivity. Molecular docking studies of the FSEs corroborates the in vitro results. The molecular docking studies further reveal that the presence of free aromatic 'OH' groups and the substitution at position 3 on the sucrose core are critical for the inhibition of both the enzymes. From the in vitro and molecular docking studies, FSE 12 was selected as a lead candidate for validation in vivo. The oral co-administration of FSE 12 with starch abrogated the increase in post-prandial glucose and significantly reduced blood glucose excursion in STZ-treated mice compared to control (starch only) mice., Conclusion: Our studies reveal the potential of FSEs as selective AGIs for the treatment of diabetes, with a hypothetical reduction of side effects associated with commercial AGIs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cinnamoyl sucrose esters (CSEs) were evaluated as AGIs and their enzyme inhibition activity and potency were compared with gold standard acarbose. The inhibition activity of the CSEs against α-glucosidase and α-amylase depended on their structure including the number of the cinnamoyl moieties, their position, and the presence or absence of the acetyl moieties. The inhibitory values of the CSEs 2 - 9 generally increases in the order of mono-cinnamoyl moieties < di-cinnamoyl ≤ tri-cinnamoyl < tetra-cinnamoyl. This trend was supported from both in vitro and in silico results. Both tetra-cinnamoyl CSEs 5 and 9 showed the highest α-glucosidase inhibitory activities of 77 ± 5%, 74 ± 9%, respectively, against acarbose at 27 ± 4%, and highest α-amylase inhibitory activities of 98 ± 2%, 99 ± 1%, respectively, against acarbose at 93 ± 2%. CSEs 3 , 4 , 6 , 7 , 8 showed desired higher inhibition of α-glucosidase than α-amylase suggesting potential for further development as AGIs with reduced side effects. Molecular docking studies on CSEs 5 and 9 attributed the high inhibition of these compounds to multiple π-π interactions and favorable projection of the cinnamoyl moieties (especially O-3 cinnamoyl) in the enzyme pockets. This work proposes CSEs as new AGIs with potentially reduced side effects.

Reliability of force fields is an essential aspect of protein-folding simulation. In this work, we introduced a newly developed on-the-fly charge-updating scheme called the polarized structure-specific backbone charge (PSBC) model. The PSBC model was designed with the purpose of building the polarizability of backbone hydrogen bonds into the force field by updating the partial charges of backbone hydrogen-bond donor and acceptor atoms during folding simulation. This implementation was intended to mimic the heterogeneity of the protein surrounding during folding. Multiple single-trajectory molecular dynamics simulations were performed to fold a polyalanine peptide, namely ER (Ac-A(EAAAR) 3 A-NH 2 ), using both polarizable (PSBC) and nonpolarizable (Amber03) force fields. Through the PSBC model, ER was folded into a helical peptide with helix content that agrees well with experiments. Comparison between simulations performed using the aforementioned force fields demonstrably showed the importance of electrostatic polarization effect in the folding of the short α-helical peptide. The PSBC model was further validated by folding two other short peptides with different helicities., (Copyright © 2019 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Hexokinase 2 (HK2) binds to Voltage-Dependent Anion Channel 1 (VDAC1) on mitochondrial outer membrane (MOM) to facilitate a preferential access of ATP to HK2 for glycolysis, in order to maintain a constant energy source for cell proliferation in cancer especially. While previous studies have discovered that the VDAC1 N-terminal helix is responsible for regulating molecules from within mitochondria to cytoplasm, the molecular mechanism of how HK2 is able to regulate the ATP access remains elusive. We hereby propose a model for the HK2-VDAC1 association. The model is then subjected to molecular dynamics (MD) simulations, where we probe the effect of HK2 binding on the mobility of the VDAC1 N-terminal helix. Results from the simulations show that HK2 binding restricts the movement of the VDAC1 N-terminal helix. As a result, VDAC1 is kept in the open state most of the time and probably allows a constant supply of ATP to HK2 for glycolysis., (Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Obesity is associated with an increased risk of many chronic diseases. Recently, a growing body of evidence has shown that phytochemicals may inhibit adipogenesis and obesity. In this study, we report for the first time, the ability of Averrhoa carambola L. peel extract commonly known as star fruit (SFP) to effectively suppress adipocyte differentiation in 3T3-L1 preadipocytes and therefore, address it as a potential candidate to treat obesity and its related diseases. (-)-Epicatechin was identified as a bioactive compound likely responsible for this suppression. As the genetic expression studies revealed that the adipogenic activity of SFP extract was due to the simultaneous downregulation of the C/EBPα and PPARγ as well as the upregulation of PPARα receptor genes, a detailed computational docking study was also elucidated to reveal the likely binding mode of (-)-epicatechin to the receptor of interest, accounting for the likely mechanism that results in the overall suppression of adipocyte differentiation.

A high throughput assay was applied to guide the isolation of a new pancreatic α-amylase inhibitor, dracoflavan B, from the dragon's blood resin from Daemonorops draco. Applying C18 column, we successfully isolated both diastereomers and their structures verified by (1)H NMR spectra in comparison with the literature values. Their activity in inhibition of pancreatic α-amylase with comparable IC50 values of 23μM (A type) and 27μM (B type) that are similar to that of acarbose. Dracoflavan B shows much weaker activity in inhibiting bacterial α-amylase and no activity towards fungal α-amylase. Moreover, both isomers show no inhibitory activity towards mammalian α-glucosidase. Kinetic analysis revealed that using starch as the substrate, dracoflavan B was a non-competitive α-amylase inhibitor with a Ki value of 11.7μM. Lack of α-amylase inhibition for proanthocyanidin A2 dimer demonstrated that dracoflavan B hydrophobic nature of the B, A', C' and B' rings are important for its α-amylase inhibition. In addition, selective chemical modification studies revealed that the phenolic group is also vital to dracoflavan B for its pancreatic α-amylase inhibition activity. Without the A ring phenolic hydrogen bond donor, the derivatives of dracoflavan B showed detrimental α-amylase inhibition. On the contrary, galloylation on the A ring phenolic OH group enhanced the activity as shown by the low IC50 (12μM) against α-amylase which is 56% more potent as compared to dracoflavan B., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Clear cell renal cell carcinoma (ccRCC) is characterized by the constitutive up-regulation of the hypoxia inducible factor-1. One of its target enzymes, pyruvate dehydrogenase (PDH) kinase 1 (PDHK1) showed increased protein expression in tumor as compared to patient-matched normal tissues. PDHK1 phosphorylated and inhibited PDH whose enzymatic activity was severely diminished, depriving the TCA cycle of acetylCoA. We and others have shown a decrease in the protein expressions of all respiratory complexes alluding to a compromise in oxidative phosphorylation (OXPHOS). On the contrary, we found that key parameters of OXPHOS, namely ATP biosynthesis and membrane potential were consistently measurable in mitochondria isolated from ccRCC tumor tissues. Interestingly, an endogenous mitochondrial membrane potential (MMP) was evident when ADP was added to mitochondria isolated from ccRCC but not in normal tissues. In addition, the MMP elicited in the presence of ADP by respiratory substrates namely malate/glutamate, succinate, α-ketoglutarate and isocitrate was invariably higher in ccRCC. Two additional hallmarks of ccRCC include a loss of uncoupling protein (UCP)-2 and an increase in UCP-3. Based on our data, we proposed that inhibition of UCP3 by ADP could contribute to the endogenous MMP observed in ccRCC and other cancer cells., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This is a first report of recombinant production of human prepro-Urocortin 2 in Escherichia coli by N-terminal fusion with a triple His₆-SUMO-eXact tag and its subsequent use as an antigen for the production and screening of very high affinity monoclonal antibodies. The rationale for this combinatorial construct is that the His tag allows first step protein purification of insoluble and soluble proteins, the SUMO tag enhances protein expression level and solubility, while the eXact tag facilitates anion-triggered on-column cleavage of the triple tag to recover pure native proteins in a simple two-step protein purification procedure. Compared with an eXact fusion alone, the presence of the SUMO moiety enhanced overall expression levels by 4 to 10 fold but not the solubility of the highly basic prepro-Urocortin 2. Insoluble SUMO-eXact-preproUCN2 was purified in milligram quantities by denaturing IMAC and solubilized in native phosphate buffer by on-column refolding or step-wise dialysis. Only a small fraction of this solubilized protein was able to bind onto the eXact™ affinity column and cleaved by NaF treatment. To test whether binding and cleavage failure was due to improperly refolded SUMO-eXact-preproUCN2 or to the presence of N- and C-terminal sequences flanking the eXact moiety, we created a SUMO-eXact-thioredoxin construct which was overexpressed mainly in the soluble form. This protein bound to and was cleaved efficiently on the eXact™ column to yield native thioredoxin. Solubilized SUMO-eXact-preproUCN2 was used successfully to generate two high affinity mouse monoclonal antibodies (KD~10⁻¹⁰ and 10⁻¹¹ M) specific to the pro-region of Urocortin 2., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Antibodies HK20 and D5 have been shown to target HIV-1 gp41, thereby inhibiting membrane fusion that facilitates viral entry. The binding picture is static, based on the X-ray crystal structures of the Fab regions and gp41 mimetic five-helix bundle. In this study, we carried out molecular dynamics simulation to provide the dynamic binding picture. Calculated binding free energies are within reasonable range of and follow the trend of the experimental values: -15.28 kcal/mol for HK20 Fab (expt. -11.60 kcal/mol) and -17.90 kcal/mol for D5 Fab (expt. -11.70 kcal/mol). Alanine scanning at protein-protein interface reveals that the highest contributors to binding for HK20 Fab are F54 and I56, both of V(H) region, as well as R30' of V(L) region; whereas for D5 Fab, F54 of V(H) region, as well as W32' and Y94' of V(L) region. HK20 F54 and I56, as well as D5 I52, F54, and T56, bind to the gp41 hydrophobic binding pocket, an important region targeted by many other fusion inhibitors. Hydrogen bonding analysis also identifies high-occupancy hydrogen bonds at the periphery of gp41 hydrophobic pocket. Considering that almost all interface residues are turn residues, further work may be directed to turn mimics. Pre-orientation by the hydrogen bonds to poise this particular turn towards the binding pocket may also be a point worth pursuing., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The folding processes of three polyalanine peptides with composition of Ac-(AAXAA)(2)-GY-NH(2) (where X is chosen to be Q, K, and D) are studied by molecular dynamics simulation in solvent of 40% trifluoroethanol using both polarized and unpolarized force fields. The simulations reveal the critical role of polarization effect for quantitative description of helix formation. When polarized force field is used, peptides with distinctive helical propensity are correctly differentiated and the calculated helical contents are in close agreement with experimental measurement, indicating that consideration of polarization effect can correctly predict the effect of sequence variation on helix formation.