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Abstract Background Our ongoing research has revealed that total saponins extracted from the medicinal herb Radix Astragali (AST) exhibits significant growth-inhibitory and proapoptotic effects in human cancer cells. In the present study, the potential of AST in controlling angiogenesis was further investigated with elaboration of the underlying molecular mechanism in human colon cancer cell and tumor xenograft. Results AST decreased the protein level of VEGF and bFGF in HCT 116 colon cancer cells in a time- and dose-dependent manner. Among the Akt/mTOR signal transduction molecules being examined, AST caused PTEN upregulation, reduction in Akt phosphorylation and subsequent activation of mTOR. AST also suppressed the induction of HIF-1α and VEGF under CoCl2-mimicked hypoxia. These effects were intensified by combined treatment of AST with the mTOR inhibitor rapamycin. Despite this, our data also indicate that AST could attenuate cobalt chloride-evoked COX-2 activation, while such effect on COX-2 and its downstream target VEGF was intensified when indomethacin was concurrently treated. The anti-carcinogenic action of AST was further illustrated in HCT 116 xenografted athymic nude mice. AST significantly suppressed tumor growth and reduced serum VEGF level in vivo. In the tumor tissues excised from AST-treated animals, protein level of p-Akt, p-mTOR, VEGF, VEGFR1 and VEGFR2 was down-regulated. Immunohistochemistry has also revealed that AST effectively reduced the level of COX-2 in tumor sections when compared with that in untreated control. Conclusion Taken together, these findings suggest that AST exerts anti-carcinogenic activity in colon cancer cells through modulation of mTOR signaling and downregulation of COX-2, which together reduce VEGF level in tumor cells that could potentially suppress angiogenesis.

Background: Itch is a common symptom that can greatly diminish quality of life. Histamine is a potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic while receiving maximal doses. Mechanisms that drive resistance to antihistamines are poorly defined., Objectives: Signaling of the alarmin cytokine IL-33 in sensory neurons is postulated to drive chronic itch by inducing neuronal sensitization to pruritogens. Thus, we sought to determine if IL-33 can augment histamine-induced (histaminergic) itch., Methods: Itch behavior was assessed in response to histamine after IL-33 or saline administration. Various stimuli and conditional and global knockout mice were utilized to dissect cellular mechanisms. Multiple existing transcriptomic data sets were evaluated, including single-cell RNA sequencing of human and mouse skin, microarrays of isolated mouse mast cells at steady state and after stimulation with IL-33, and microarrays of skin biopsy samples from subjects with CSU and healthy controls., Results: IL-33 amplifies histaminergic itch independent of IL-33 signaling in sensory neurons. Mast cells are the top expressors of the IL-33 receptor in both human and mouse skin. When stimulated by IL-33, mouse mast cells significantly increase IL-13 levels. Enhancement of histaminergic itch by IL-33 relies on a mast cell- and IL-13-dependent mechanism. IL-33 receptor expression is increased in lesional skin of subjects with CSU compared to healthy controls., Conclusions: Our findings suggest that IL-33 signaling may be a key driver of histaminergic itch in mast cell-associated pruritic conditions such as CSU., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1 GoF ) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1 GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future., Competing Interests: Declaration of interests B.S.K. is founder of KliRNA Biotech; he has served as a consultant for 23andMe, ABRAX Japan, AbbVie, Almirall, Amgen, Arcutis Biotherapeutics, Arena Pharmaceuticals, argenx, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Clexio Biosciences, Eli Lilly and Company, Escient Pharmaceuticals, Evommune, Galderma, Genentech, GlaxoSmithKline, Granular Therapeutics, Incyte Corporation, Innovaderm Research, Janssen, Kiniksa, LEO Pharma, Maruho, Novartis, Pfizer, Recens Medical, Regeneron Pharmaceuticals, Sanofi, Septerna, Triveni Bio, Vial, and WebMD; he has stock in ABRAX Japan, KliRNA Biotech, Locus Biosciences, and Recens Medical; he holds a patent for the use of JAK1 inhibitors for chronic pruritus; and he has a patent pending for the use of JAK inhibitors for interstitial cystitis. D.A. has contributed to scientific advisory boards at Pfizer, Takeda, FARE, and the KRF. D.B. is the founder of Lab11 Therapeutics.., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In British Columbia, antiretrovirals are distributed at no cost to patients via a publicly funded program, using generic formulations if available. A generic efavirenz-emtricitabine-tenofovir DF (EFV-FTC-TDF) combination pill became available in April 2018. The authors compared EFV untimed drug levels in subjects switching from brand to generic EFV-FTC-TDF., Methods: Archived plasma HIV viral load samples were identified for consenting participants who switched from brand to generic EFV-FTC-TDF; 3 preswitch and 2-3 postswitch samples, collected ≥1 month apart were assessed for each subject. "Untimed" EFV concentrations with unknown dosing and collection time were assessed using a validated liquid chromatography-tandem mass spectrometry method. Participants' mean, minimum, and maximum EFV levels were compared using the Wilcoxon signed rank test. Participants with EFV levels in the range associated with lower risks of virologic failure and central nervous system toxicity (1000-4000 ng/mL), preswitch and postswitch, were enumerated., Results: EFV levels were assessed in 297 preswitch and 249 postswitch samples from 99 participants, having exposure to brand and generic EFV for a median of 103 (Q1-Q3: 87-116) and 10.3 (Q1-Q3: 8.9-11.7) months, respectively. The final brand sample was collected at a median of 98 days preswitch; the first generic sample was collected at a median of 133 days postswitch. No significant differences were observed in participant mean EFV levels before (median 1968 ng/mL; Q1-Q3: 1534-2878 ng/mL) and after (median 1987 ng/mL; Q1-Q3: 1521-2834 ng/mL) switch (P = 0.85). Eighty participants had mean EFV levels within the 1000-4000 ng/mL range on the brand drug, of which 74 remained within this range postswitch., Conclusions: There were no statistically significant differences between untimed EFV levels in patients switching from the brand to generic EFV combination pill. Given the long elimination half-life of EFV, untimed drug levels may be a convenient way to estimate product bioequivalence., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although there is increased understanding of the alopecia areata (AA) pathogenesis based on studies in scalp tissues, little is known about its systemic profile., Objective: To evaluate the blood proteomic signature of AA and determine biomarkers associated with increased disease severity., Methods: In a cross-sectional study, we assessed 350 inflammatory and cardiovascular proteins using OLINK high-throughput proteomics in patients with moderate to severe AA (n = 35), as compared with healthy individuals (n = 36), patients with moderate to severe psoriasis (n = 19), and those with atopic dermatitis (n = 49)., Results: Seventy-four proteins were significantly differentially expressed between AA and control individuals (false discovery rate, <.05) including innate immunity (interleukin [IL] 6/IL-8), T helper (Th) type 1 (interferon [IFN] γ/CXCL9/CXCL10/CXCL11), Th2 (CCL13/CCL17/CCL7), Th17 (CCL20/PI3/S100A12), and cardiovascular-risk proteins (OLR1/OSM/MPO/PRTN3). Eighty-six biomarkers correlated with AA clinical severity (P < .05), including Th1/Th2, and cardiovascular/atherosclerosis-related proteins, including SELP/PGLYRP1/MPO/IL-18/OSM (P < .05). Patients with AA totalis/universalis showed the highest systemic inflammatory tone, including cardiovascular risk biomarkers, compared to control individuals and even to patients with atopic dermatitis and those with psoriasis. The AA profile showed some Th1/Th2 differences in the setting of concomitant atopy., Limitations: Our analysis was limited to 350 proteins., Conclusion: This study defined the abnormalities of moderate to severe AA and associated circulatory biomarkers. It shows that AA has systemic immune, cardiovascular, and atherosclerosis biomarker dysregulation, suggesting the need for systemic treatment approaches., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Although the precise pathophysiology of irritable bowel syndrome (IBS) remains unknown, it is generally considered to be a disorder of the brain-gut axis, representing the disruption of communication between the brain and the digestive system. The present review describes advances in understanding the pathophysiology and experimental approaches in studying IBS, as well as providing an update of the therapies targeting brain-gut axis in the treatment of the disease., Methods: Causal factors of IBS are reviewed. Following this, the preclinical experimental models of IBS will be introduced. Besides, both current and future therapeutic approaches of IBS will be discussed., Results: When signal of the brain-gut axis becomes misinterpreted, it may lead to dysregulation of both central and enteric nervous systems, altered intestinal motility, increased visceral sensitivity and consequently contributing to the development of IBS. Interference of the brain-gut axis can be modulated by various psychological and environmental factors. Although there is no existing animal experiment that can represent this complex multifactorial disease, these in vivo models are clinically relevant readouts of gastrointestinal functions being essential to the identification of effective treatments of IBS symptoms as well as their molecular targets. Understanding the brain-gut axis is essential in developing the effective therapy for IBS. Therapies include improvement of GI motor functions, relief of visceral hypersensitivity and pain, attenuation of autonomic dysfunctions and suppression of mucosal immune activation., Conclusion: Target-oriented therapies that provide symptomatic, psychological and physiological benefits could surely help to improve the quality of life of IBS patients.

Dissecting antibody specificities in the plasma of HIV-1 infected individuals that develop broadly neutralizing antibodies (bNAbs) is likely to provide useful information for refining target epitopes for vaccine design. Several studies have reported CD4-binding site (CD4bs) antibodies as neutralization determinants in the plasma of subtype B-infected individuals; however there is little information on the prevalence of CD4bs specificities in HIV-infected individuals in India. Here, we report on the presence of CD4bs antibodies and their contribution to virus neutralization in the plasma from a cohort of HIV-1 infected Indian individuals. Plasma from 11 of the 140 HIV-1 infected individuals (7.9%) studied here exhibited cross-neutralization activity against a panel of subtype B and C viruses. Analyses of these 11 plasma samples for the presence of CD4bs antibodies using two CD4bs-selective probes (antigenically resurfaced HXB2gp120 core protein RSC3 and hyperglycosylated JRFLgp120 mutant ΔN2mCHO) revealed that five (AIIMS 617, 619, 627, 642, 660) contained RSC3-reactive plasma antibodies and only one (AIIMS 660) contained ΔN2mCHO-reactive antibodies. Plasma antibody depletion and competition experiments confirmed that the neutralizing activity in the AIIMS 660 plasma was dependent on CD4bs antibodies. To the best of our knowledge, this is the first study to report specifically on the presence of CD4bs antibodies in the plasma of a cohort of HIV-1 infected Indian donors. The identification of CD4bs dependent neutralizing antibodies in an HIV-1 infected Indian donor is a salient finding of this study and is supportive of ongoing efforts to induce similar antibodies by immunization.

Antibody B4e8 exhibits modest cross-neutralizing activity, with preference for HIV subtype B. This preference might be explained by B4e8׳s extensive interaction with Arg315, which occurs at the center of most subtype B V3 sequences but is replaced by Gln in subtype C. The extent to which B4e8׳s ability to neutralize subtype C strains is hindered by Gln315 and/or other factors, e.g. epitope masking, is unclear. We confirmed here that an Arg315-to-Gln substitution in a subtype B virus abrogates B4e8 neutralizing activity. Conversely, B4e8-resistant subtype C viruses were rendered sensitive upon Gln 315-to-Arg substitution. V2 region swapping between B4e8-sensitive and- resistant subtype C strains revealed a role for V2 in limiting B4e8 access, but this was less significant than the absence of Arg315. Our findings, while illustrating the importance of Arg315 for B4e8, suggest that some subtype C strains may be vulnerable to B4e8 derivatives capable of binding stronger to Gln315-containing sequences., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim of the Study: We had reported that Astragalus saponins (AST) exert promising anti-tumorigenic effects by suppressing the growth of HT-29 human colon cancer cells and tumor xenograft. In the present study, we further investigated the anti-angiogenic property of AST in human gastric adenocarcinoma cells (AGS) and attempted to elucidate the underlying mechanism., Materials and Methods: Viability of AGS cells was measured by using the MTT reduction method. Western blotting was performed to examine the effect of AST on apoptotic- and cell growth-related protein expression. Effect of AST on cell cycle progression was also evaluated using PI staining. A Matrigel invasion assay was then employed to demonstrate the effect of AST on the invasiveness of gastric cancer cells. The expression of invasion-associated proteins (VEGF and MMPs) was also investigated., Results: AST could induce apoptosis in AGS cells by activating caspase 3 with subsequent cleavage of poly(ADP-ribose) polymerase. Besides, cell cycle arrest at the G2/M phase had been observed in AST-treated cells, leading to substantial growth inhibition. The anti-proliferative effect of AST was associated with the regulation of cyclin B1, p21 and c-myc. Results indicate that the number of AGS cells invaded through the Matrigel membrane was significantly reduced upon AST treatment, with concomitant down-regulation of the pro-angiogenic protein vascular endothelial growth factor (VEGF) as well as the metastatic proteins metalloproteinase (MMP)-2 and MMP-9., Conclusion: AST derived from the medicinal plant Astragalus membranaceus could modulate the invasiveness and angiogenesis of AGS cells besides its pro-apoptotic and anti-proliferative activities. These findings also suggest that AST has the potential to be further developed into an effective chemotherapeutic agent in treating advanced and metastatic gastric cancers., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The broadly neutralizing antibody 2G12 binds a fairly conserved cluster of oligomannose sugars on the HIV surface glycoprotein gp120, which has led to the hypothesis that these sugars pose potential vaccine targets. Here, we present the chemical analysis, antigenicity, and immunogenicity of a bacterial lipooligosaccharide (LOS) comprised of a manno-oligosaccharide sequence analogous to the 2G12 epitope. Antigenic similarity of the LOS to oligomannose was evidenced by 2G12 binding to the LOS and the inability of sera elicited against synthetic oligomannosides, but incapable of binding natural oligomannose, to bind the LOS. Immunization with heat-killed bacteria yielded epitope-specific serum antibodies with the capacity to bind soluble gp120. Although these sera did not exhibit specific anti-HIV activity, our data suggest that this LOS may find utility as a template for the design of glycoconjugates to target HIV., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: To report the clinicopathologic features of a solitary superficial angiomyxoma arising in the eyelid., Design: Case report., Methods: A retrospective review of the clinical and pathologic features of a patient with solitary superficial angiomyxoma in the eyelid., Results: A 47-year-old male presented with a right upper lid mass for 6 months. Excisional biopsy was performed, and microscopic examination revealed a tumor comprising loose spindle or stellate-shaped cells in myxoid stroma sprinkled with small numbers of neutrophils. The tumor cells were negative for smooth muscle actin, desmin, S-100 protein, and CD34 on immunostaining., Conclusions: Ophthalmologists should be aware of superficial angiomyxoma as a rare cutaneous tumor with a tendency for local recurrence. Multiple lesions and occurrence in the external ear can be associated with the Carney's complex.

Summary: Cerebral arteriovenous malformations (CAVMs) are rarely diagnosed in utero. Most prenatal imaging of intracranial vascular malformations relates to Vein of Galen aneurysmal malformations (VGAMs) or Dural Arteriovenous Malformations (D-AVMs). We report a case of a fetal pial AVF with multiple fistulae and venous pouches, which appeared as an anechoic lesion on the prenatal ultrasound scan. The patient was asymptomatic with normal postnatal growth. No haemodynmaic disturbance was evident. Postnatal Computed tomography (CT), Magnetic Resonance Imaging (MRI) and catheter Digital Subtraction Angiography (DSA) confirmed the presence of a pial AVF. The angiographic findings and family history of nose bleeds suggests the diagnosis of Hereditary Hemorrhagic Telangiectasia. The largest AVF was embolized with tissue adhesive; the residual AVF subsequently removed by surgical excision.

Malignant peritoneal mesothelioma (MPM) is a rare condition with an overall incidence of one to two cases per million [Arch. Surg. 123 (1988) 765.]. It is a tumour that arises from the mesothelium of a serosal cavity. While simultaneous peritoneal and pleural involvement is found in 30-45% of cases of mesothelioma, solitary peritoneal involvement is found only in 10-20%. The disease usually presents late. As a result, most reported cases in the radiological literature describe features of the advanced disease only. We report the radiological findings in early stage of MPM in a patient who was successfully treated by surgery. The diagnostic pitfalls in early stage disease are discussed and the radiological literature of MPM is reviewed.

Biliary papillomatosis is a rare disease characterized by multiple papillary proliferation of the epithelial cell of the bile duct. Because it has a tendency to be recurrent, the treatment strategy is choledochoscopic laser therapy. A patient with biliary papillomatosis treated by choledochoscopic laser therapy, which was complicated by massive haemobilia and shock, is presented. An intrahepatic artery pseudoaneurysm was diagnosed on angiography. A coexisting occlusion necessitated a superselective embolization of the pseudoaneurysm in order to avoid devascularization of the left lobe of the liver.