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Herein, for the first time we have explored the umpolung reactivity of the vinylogous carbon center of diazo arylidene succinimide (DAS) through rhodium catalysis to achieve [2,3]‐Stevens rearrangement of α‐thioether esters. The protocol has successfully demonstrated the distal C−H bond functionalization of the α‐thioether esters. Alongside, the carbenoid reactivity of DAS has also been achieved with Doyle‐Kirmse reaction of allyl/propargyl phenyl sulfides. The protocol proved to be practical to synthesize a wide variety of [2,3]‐Stevens rearrangement products exclusively and the possible side products emanating from Pummerer rearrangement and [1,2]‐Stevens rearrangement were not observed. This catalytic protocol works smoothly in environmentally benign solvent under open air to afford the corresponding desired products with excellent diastereo‐, regio‐ and chemo‐selectivities in good to excellent yields. The protocol also proved to be scalable on gram quantity. [ABSTRACT FROM AUTHOR]

The palladium (II) catalyzed direct C3‐(sp2)−H alkenylation of five membered heterocyclic aldehydes has been developed using 3‐aminobutanoic acid as a catalytic transient directing group. A wide range of heterocyclic aldehydes reacted with various acrylates to afford highly site‐selective C3‐alkenylated products. This method features an exclusive E‐selective alkenylation at the C3‐position of heterocyclic aldehydes with a broad substrate scope. The protocol also proved to be useful to construct the mechanochromic luminogen. [ABSTRACT FROM AUTHOR]

The rearrangement of dithiolanes and dithianes to access disulfide‐linked‐dithioesters under visible‐light photoredox catalysis via controlled C−S bond cleavage has been disclosed. Unlike, the usual deprotection of dithioacetals to corresponding aldehydes under the oxidative conditions, we observed unique regioselective oxidative reactivity of five and six membered cyclic dithioacetals to form disulfide‐linked‐dithioesters by exchanging DMAP and imidazole bases. The generality of the protocol has been demonstrated by exploring a wide range of substrates. As an application, in situ generated thiyl radical has been trapped with disulfides to prepare hetero‐disulfides of potential utility. The protocol proved to be practical on gram scale quantity and relied on clean energy source for the transformation. Based on the series of control experiments, cyclic voltammetry and Stern‐Volmer studies the plausible mechanism has been proposed. [ABSTRACT FROM AUTHOR]

Visible light promoted chemoselective metal free hydrogenation of activated double bond has been achieved via photoredox catalysis. Eosin Y has proved to be an efficient catalyst for the effective reduction of C−C double bonds of alkylidene oxindoles and succinimides under visible light. Commercially viable DIPEA has been employed as a sacrificial electron donor and it's in‐situ generated cationic radical acts as reductant in this transformation. The method proved to be practical as a broad range of substrates containing activated double bond were easily reduced. The method proved to be scalable on a gram quantity and the reduced product has been utilized successfully for the further synthetic application. The systematic and detailed mechanistic studies reveal the oxidative quenching of the photocatalyst by the activated double bond. [ABSTRACT FROM AUTHOR]

A silver triflimide catalyzed one‐pot protocol for the diastereoselective synthesis of dihydrobenzoxepines has been developed. Silver triflimide was found to be an efficient catalyst for the formal (5+2)‐cycloaddition to access dihydrobenzoxepines as a single diastereomer using vinyl diazosuccinimides as 5‐C‐synthons and ketones. An unmet challenge of utilizing the donor‐/acceptor‐type vinyl diazosuccinimides as 5‐C‐synthons under silver‐catalysis is presented. This protocol was found to be highly regio‐, chemo‐ and diastereoselective, and works well with aliphatic as well as aromatic methyl ketones bearing electron deactivating as well as donating groups to afford dihydrobenzo[5,6]oxepino[2,3‐c]pyrroles. The control experiments and time‐dependent NMR studies revealed the plausible mechanism of this transformation. The protocol also proved to be scalable on the gram‐scale synthesis. [ABSTRACT FROM AUTHOR]

A silver(I)‐catalyzed method to access spiro‐pyrrolidinedioneoxiranes has been developed. Silver hexafluoroantimonate was found to be an efficient catalyst for the epoxidation of aldehydes using donor‐/acceptor‐substituted vinyl diazosuccinimides as carbenoid precursors. The protocol has been found to be highly regio‐ and chemoselective, and works well with aromatic aldehydes containing electron‐withdrawing and ‐donating groups to afford spiro‐pyrrolidinedioneoxiranes with a broad substrate scope. [ABSTRACT FROM AUTHOR]

A one‐pot transition‐metal‐free synthesis of styrenyl ethers starting from 2‐aryloxy/alkoxy acetophenones is described. The protocol explores the use of tosyl hydrazide and potassium carbonate as a mild base via Bamford‐Stevens reaction to synthesize the styrenyl ethers. The protocol is very simple, practical and uses mild reaction conditions with simple reaction set‐up. This practical protocol proved to be scalable on gram quantity. [ABSTRACT FROM AUTHOR]

Abstract: An enantioselective organocatalytic multicomponent reaction of aldehydes, ketones, and Meldrum's acid has been developed. A cinchona‐based primary amine (1 mol %) catalyses the multicomponent reaction via the formation of the Knoevenagel product and a chiral enamine to form enantiopure δ‐keto Meldrum's acids in a tandem catalytic pathway. An adverse effect of higher catalyst loading and longer reaction time on enantioselectivity was studied. This mild protocol provides an easy access to enantiopure carboxylic acids, esters and amides and the method is scalable on a gram quantity. DFT calculations were carried out on the proposed reaction mechanism and they were in close agreement with the experimental results. [ABSTRACT FROM AUTHOR]

An expedient and straightforward protocol is developed for the synthesis of highly enantiopure synthesis of γ-butyrolactones. For the first time, one pot enantioselective organocatalytic multicomponent reaction (OMCR) is explored to construct functionalized butyrolactones without the use of pre-functionalized substrates and expensive transition metals. The protocol is proved to be reproducible on a gram scale. Density functional theory (DFT) calculations strongly support the mechanism and were in close agreement with the observed high stereoselectivity. [ABSTRACT FROM AUTHOR]

Background: Effect of anaesthesia and surgery on cell-free DNA (cfDNA) is not known. Given that surgical stress augments inflammation and injury, we hypothesized that levels of cfDNA will fluctuate during perioperative period. Therefore, in this study serial perioperative cfDNA concentration was measured in donors and recipients undergoing living donor liver transplantation (LDLT).Methods: Baseline, post-induction, intraoperative and post-operative plasma cfDNA levels were evaluated in 21 donors and recipients each, by Sytox green method. In addition, qPCR was performed in a subset of samples.Results: Baseline cfDNA levels were higher in recipients (37.62 ng/ml) than in donors (25.49 ng/ml). A decrease in cfDNA was observed following anaesthesia induction in both recipients (11.90 ng/ml) and donors (10.75 ng/ml). When the kinetics of the cfDNA was monitored further, an increase was noted intraoperatively in donors (46.18 ng/ml) and recipients (anhepatic phase: 56.25 ng/ml, reperfusion phase: 54.36 ng/ml). cfDNA levels remained high post-operatively. One recipient who developed post-operative sepsis had the highest cfDNA level (94.72 ng/ml).Conclusion: Plasma cfDNA levels are high in recipients indicative of liver injury. Lower cfDNA levels following induction may be attributed to the subduing effect of anaesthetic agents on cell death. High cfDNA levels seen in intra- and post-operative phases reflect cellular trauma and inflammation. This similar pattern of fluctuation of cfDNA level in donors and recipients is suggestive of its possible utility as a surgical stress marker. In addition, comparable cfDNA levels in anhepatic and reperfusion phase reflect less ischemia reperfusion injury during LDLT. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus ( HBV) infection affects millions of people worldwide and about half a million people die every year. India represents the second largest pool of chronic HBV infections with an estimated 40 million chronically infected patients. Persistence or clearance of HBV infection mainly depends upon host immune responses. Chronically infected individuals remain in immune tolerant phase unless HBV flares and leads to the development of chronic active hepatitis or acute-on-chronic liver failure. Strategies based on inhibition of viral replication (nucleoside analogues) or immune modulation (interferons) as monotherapy, or in combination in sequential therapies, are currently being used globally for reducing HBV viral load and mediating HBsAg clearance. However, the immune status and current therapies for promoting sustained virological responses in HBV-infected patients remain suboptimal. Elimination of ccc DNA is major challenge for future therapies, and new molecules such as NTCP, Toll-like receptor ( TLR)7 agonist ( GS9620) and cyclophilin have emerged as potential targets for preventing HBV entry and replication. Other than these, HBV ccc DNA elimination is the major target for future therapies. [ABSTRACT FROM AUTHOR]

Indian wood apple seed ( Feronia elephantum Correa) constituting 6% (dry weight basis) of the fruit, contains 34% oil and 28% protein. The kernel comprises 62% of the seed. The oil is yellow with an iodine value 131, saponification value 192, unsaponifiable matter 1%. Fatty acid profile of oil by GLC is: palmitic 19.3, stearic 7.3, oleic 27.2, linoleic 19.8 and linolenic 26.4%. [ABSTRACT FROM AUTHOR]

Decarboxylation of cyclic 1,3-diesters, generated from Meldrum′s acid and aldehydes or ketones, provide α,β-unsaturated acids with high E-selectivity. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B surface antigen (HBsAg) seroconversion is sometimes observed in hepatitis B reactivation (rHBV), probably due to immune resetting and differentiation., Aims: To investigate sequential immune differentiation and abrogation of tolerance in patients with rHBV who achieved HBsAg seroconversion., Methods: We included 19 patients with chronic hepatitis B (CHBV; HBV DNA log10 3-8 ), 67 with rHBV (raised ALT [>5XULN], HBV DNAlog10 4-8 ) and 10 healthy controls. Immune differentiation, tolerance and functional status of CD4, CD8, T regulatory cells (Tregs), B cells and follicular T helper (Tfh) cells were assessed at baseline and 24 weeks., Results: At 24 weeks, 81% rHBV (n = 67) lost HBV DNA and HBeAg (41%), and 12 (19%) lost HBsAg and made anti-HBs titers >10 IU/ml. rHBV patients had higher Th1/17, T EM , Tfh, Tfh1/17, plasma and ATM B cells, and lower Tregs, Th2, Th17 and TEMRA expression. rHBV showed lower PD1, TIM3, LAG3, SLAM and TOX compared to CHBV. There was a significant increase in CD8, CD8EM, Tfh, Tfh1/17 and plasma B cells in seroconverters than non-seroconverters. At 24 weeks, we also observed increased plasma B cell frequency in seroconverters. While non-seroconverters showed higher expression of PD1, TIM3, LAG3, SLAM and TOX on CD4/CD8 T cells, blockade of PD1, TIM3, LAG3 and CTLA4 significantly enhanced IFN-γ, TNF-α, IL-4 and IL-21 expression on CD4/CD8 and Tfh cells in non-seroconverters., Conclusions: Non-seroconverters have increased inhibitory markers on CD4/CD8 T cells. There is a critical play of CD8, Tfh and B cells and subsets in seroclearance, along with checkpoint molecules as a potential therapy for non-seroconverters in HBV infection., (© 2022 John Wiley & Sons Ltd.)

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein involved in redox signalling and programmed cell death. The role of AIF has been well recognized in diabetes and obesity. However, the aspect of AIF deficiency in the development of hepatic steatosis and liver injury is unknown. Therefore, in the current study, Harlequin (Hq mutant) mouse with markedly reduced content of AIF was investigated to explore the role of AIF on the initiation of liver injury. The wild type (WT) developed physiological and pathological features of non-alcoholic fatty liver disease (NAFLD) that were not seen in the Hq mice with AIF deficiency, when fed on high fat high fructose (HFHF) diet. Following bile duct ligation (BDL), the liver associated pathological changes were less conspicuous in Hq mice as compared to WT mice. The expression of AIF protein and apoptosis was markedly lesser as compared to their respective control in Hq mice on HFHF diet. Furthermore, the genes involved in fatty acid metabolism were also altered in the group of treated Hq mice. In conclusion, Hq mice failed to develop diet induced hepatic steatosis, suggestive of a role of AIF mediated pathway in the initiation and progression of liver inflammation. Thus, partial loss of AIF appears to be hepatoprotective. SIGNIFICANCE OF THE STUDY: AIF deficiency has multiple roles in altered pathology processes and cellular metabolism, thereby compromising the cellular homeostasis. Considering the molecular functions of AIF in other organ pathology little is known about its role in diet induced liver injury. Hence, the aim of the current study was to investigate the role of AIF deficiency in liver injury and diseases with focus on NAFLD. The study will help to deliniate the mechanisms of NAFLD using Harliquin Mice., (© 2020 John Wiley & Sons Ltd.)

Background: Endothelial progenitor cells (EPCs) help in neovascularization and endothelial repair during injury. Patients with cirrhosis show increased number and function of EPCs in circulation., Methods: Since natural killer (NK) cells regulate EPCs, we investigated the relationship between the 2 in alcoholic cirrhosis (AC, n = 50) and severe alcoholic hepatitis (SAH, n = 18) patients and compared with nonalcoholic cirrhosis (n = 15) and healthy controls (HC, n = 30). Levels of systemic inflammatory cytokines were measured, and coculture assays were performed between EPCs and NK cells in contact-dependent and contact-independent manner. NK cell-mediated killing of EPCs was evaluated, and expression of receptors including fractalkine (FKN) on EPCs and its cognate receptor CX3CR1 on NK cells was studied by RT-PCR assays., Results: Patients with SAH had higher regulated on activation, normal T cell expressed and secreted (RANTES) (p = 0.01), vascular endothelial growth factor (VEGF) (p = 0.04), IL-1β (p = 0.04), and IL-6 (p = 0.00) growth factors and proinflammatory cytokines as compared to AC and HC. Distinct populations of CD31+ CD34+ EPCs with low and high expression of CD45 were significantly lower in SAH than HC (CD45 low , p = 0.03; CD45 hi , p = 0.04) and AC (CD45 low , p = 0.05; CD45 hi , p = 0.02). SAH patients, however, showed increased functional capacity of EPCs including colony formation and LDL uptake. NK cells were reduced in SAH compared with AC (p = 0.002), however with higher granzyme ability (p < 0.001 and p = 0.04, respectively). In SAH, EPC-NK cell interaction assays showed that NK cells lysed the EPCs in both contact-dependent and contact-independent assays. Expression of interaction receptor CX3CR1 was significantly higher on NK cells (p = 0.0005), while its cognate receptor, FKN, was increased on EPCs in SAH patients as compared to HC (p = 0.0055)., Conclusion: We conclude that in SAH, NK cells induce killing of EPCs via CX3CR1/FKN axis that may be one of the key events contributing to disease severity and proinflammatory responses in SAH., (© 2019 by the Research Society on Alcoholism.)

Background: Targeting cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) is difficult because of their similarities with normal stem cells (NSCs). EpCAM can identify CSCs from EpCAM+AFP+HCC cases, but is also expressed on NSCs. We aimed to distinguish the two using integrated protein, mRNA and miRNA profiling., Methods: iTRAQ based protein profiling and Next Generation Sequencing (NGS) was performed on EpCAM+/EpCAM - cells isolated from HCC (Ep+CSC, Ep - HCC) and EpCAM+ cells from non-cancerous/non-cirrhotic control liver tissues (Ep+NSC). Validations were done using qRT-PCR, flowcytometry and western blotting followed by in vitro and in vivo functional studies., Results: 11 proteins were overexpressed (>3 fold) in Ep+CSCs compared to Ep - HCC and Ep+NSC cells. However, RNA-sequencing confirmed the Ep+CSC specific up-regulation of only HSPA8, HNRNPC, MPST and GAPDH mRNAs among these. Database search combined with miRNA profiling revealed Ep + CSC specific down-regulation of 29 miRNAs targeting these four genes. Of these, only miR-26b-5p was found to target both HSPA8 and EpCAM. Validation of HSPA8 overexpression and miR-26b-5p down-regulation followed by linear regression analysis established a negative correlation between the two. Functional studies demonstrated that reduced miR-26b-5p expression increased the spheroid formation, migration, invasion and tumourigenicity of Ep + CSCs. Furthermore, anti-miR-26b-5p increased the number of Ep + CSCs with a concomitant overexpression of stemness genes and reduction of proapoptotic protein BBC3, which is a known substrate of HSPA8., Conclusion: miR-26b-5p imparts metastatic properties and helps in maintenance of Ep + CSCs via HSPA8. Thus, miR-26b-5p and HSPA8 could serve as molecular targets for selectively eliminating the Ep + CSC population in human HCCs., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Asialoglycoprotein receptor expression on hepatocytes has been associated with endocytosis, binding and uptake of hepatitis B virus. The role of asialoglycoprotein receptor in hepatitis B virus vertical transmission and its expression on placenta has not yet been studied., Patients and Methods: Thirty-four HBsAg+ve and 13 healthy pregnant mothers along with their newborns were enrolled. The former were categorized into transmitting and non-transmitting mothers based on their newborns being hepatitis B surface antigen and hepatitis B virus DNA positive. Expression of asialoglycoprotein receptor and hepatitis B surface antigen in placenta and isoform of asialoglycoprotein receptor on dendritic cell in peripheral and cord blood dendritic cells were analysed using flowcytometry, immune histochemistry, immune florescence and qRT-PCR., Results: Twelve HBsAg+ve mothers transmitted hepatitis B virus to their newborns whereas the rest (n = 22) did not. Hepatitis B virus-transmitting mothers showed increased expression of asialoglycoprotein receptor in trophoblasts of placenta. Immunofluorescence microscopy revealed colocalization of hepatitis B surface antigen and asialoglycoprotein receptor in placenta as well as in DCs of transmitting mothers. There was no significant difference in the expression of asialoglycoprotein receptor on peripheral blood mononuclear cells or chord blood mononuclear cells between the 2 groups. However, hepatitis B virus-transmitting mothers and their HBsAg+ve newborns showed increased mRNA levels of isoform of asialoglycoprotein receptor on dendritic cell in peripheral blood mononuclear cells. Hepatitis B virus-transmitting mothers and their HBsAg+ve newborns showed an increased expression of isoform of asialoglycoprotein receptor on dendritic cell on circulating dendritic cells compared to hepatitis B virus non-transmitting mothers and their negative newborns., Conclusions: This study revealed that increased expression of asialoglycoprotein receptor in placenta and colocalization with hepatitis B surface antigen strongly indicates its role in intrauterine transmission of hepatitis B virus. Asialoglycoprotein receptor-blocking strategy can be used for therapeutic intervention of vertical transmission., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Psoriasis Area and Severity Index (PASI) 75 response is currently considered the gold standard for assessing treatment efficacy in moderate-to-severe psoriatic patients. PASI 90 response denotes better clinical improvement compared to PASI 75. Very few studies have assessed if a greater PASI clinical response is associated with greater improvements in Dermatology Life Quality Index (DLQI). A systematic review and meta-analysis was performed to assess the association between PASI response and DLQI. The study was conducted to assess whether greater improvement in PASI scores from PASI 75-89 to PASI 90 is associated with greater Quality of life (QoL) improvements, specifically DLQI scores. Systematic searches were conducted in MEDLINE, EMBASE and Cochrane Library to identify studies evaluating biologic interventions in adult moderate-to-severe psoriasis patients reporting PASI response and their corresponding DLQI change from baseline score. The quality of evidence was assessed through Jadad score for randomized controlled trials and Downs and Black's checklist for observational studies. Meta-analysis estimated change from baseline in DLQI for PASI 75-89 responders to be 78% (95% credible intervals [CrI]: 75-82%) and for PASI 90 responders to be 90% (95% CrI: 88-93%). This implies 12% greater improvement in DLQI score for PASI 90 responders compared with PASI 75-89 responders. In addition, the meta-analysis also showed a statistically significant difference in DLQI score of 0/1 between PASI 75-89 and PASI 90 responders (45% [95% Crl]; 41.0-50.0% and 73% [95% Crl]; 70.0-76.0%), respectively, Bayesian P < 0.0001). In conclusion, substantial improvement in clinical efficacy is associated with improved QoL in patients with moderate-to-severe psoriasis suggesting that PASI 90 responders (clear or almost clear skin) could achieve a superior QoL compared to PASI 75-89 responders., (© 2016 European Academy of Dermatology and Venereology.)

Apical ballooning syndrome is classically described as transient left ventricular (LV) dysfunction, marked LV akinesia, and normal or near-normal coronary arteries. The etiology is unclear and there is limited information based on case reports and small case series. We describe a 35-year-old woman who underwent surgical hepatectomy and developed apical ballooning syndrome in the postoperative period. The novel use of myocardial contrast echocardiography (MCE) in this setting demonstrated intact microvascular perfusion and lack of coronary flow-limiting abnormalities despite apical akinesis. In select patients with similar clinical presentations, performing MCE is safe and may be pursued as an alternative to invasive coronary angiography.