Search

The study assessed histological, biochemical, oxidative stress, and molecular parameters to evaluate the consequences of Chlorpyrifos and Dimethoate exposure on uterine health in female rats. Despite showing no obvious signs of toxicity apart from minor clinical symptoms in DM-exposed rats, both pesticides caused degenerative changes in uterine tissue. This study demonstrates that pesticides induce inflammatory responses and oxidative stress in rats, by NF-κB activation and altering antioxidant enzyme levels. Besides, CPF and DM exposure disrupted gene expression of HOXA10, HOXA11, and WNT and reduced activation of β-catenin in the uterus, which is crucial for implantation and reproductive function. These findings suggest that pesticide exposure may impair reproductive health and fertility in females, highlighting potential implications for human health., 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 article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background : Pyroptosis, an inflammatory cell death, is involved in the progression of atherosclerosis. Pyroptosis in endothelial cells (ECs) and its underlying mechanisms in atherosclerosis are poorly understood. Here, we investigated the role of a caspase-4/5-NF-κB pathway in pyroptosis in palmitic acid (PA)-stimulated ECs and EVs as players in pyroptosis. Methods : Human umbilical vein endothelial cells (HUVECs) were cultured in an endothelial cell medium, treated with Ox-LDL, PA, caspase-4/5 inhibitor, NF-κB inhibitor, and sEV release inhibitor for 24 h, respectively. The cytotoxicity of PA was determined using an MTT assay, cell migration using a scratch-wound-healing assay, cell morphology using bright field microscopy, and lipid deposition using oil red O staining. The mRNA and protein expression of GSDM-D, CASP4, CASP5, NF-κB, NLRP3, IL-1β, and IL-18 were determined with RT-PCR and Western blot. Immunofluorescence was used to determine NLRP3 and ICAM-1 expressions. Extracellular vesicles (EVs) were isolated using an exosome isolation kit and were characterized by Western blot and scanning electron microscopy. Results: PA stimulation significantly changed the morphology of the HUVECs characterized by cell swelling, plasma membrane rupture, and increased LDH release, which are features of pyroptosis. PA significantly increased lipid accumulation and reduced cell migration. PA also triggered inflammation and endothelial dysfunction, as evidenced by NLRP3 activation, upregulation of ICAM-1 (endothelial activation marker), and pyroptotic markers (NLRP3, GSDM-D, IL-1β, IL-18). Inhibition of caspase-4/5 (Ac-FLTD-CMK) and NF-κB (trifluoroacetate salt (TFA)) resulted in a significant reduction in LDH release and expression of caspase-4/5, NF-κB, and gasdermin D (GSDM-D) in PA-treated HUVECs. Furthermore, GW4869, an exosome release inhibitor, markedly reduced LDH release in PA-stimulated HUVECs. EVs derived from PA-treated HUVECs exacerbated pyroptosis, as indicated by significantly increased LDH release and augmented expression of GSDM-D, NF-κB. Conclusions: The present study revealed that inflammatory, non-canonical caspase-4/5-NF-κB signaling may be one of the crucial mechanistic pathways associated with pyroptosis in ECs, and pyroptotic EVs facilitated pyroptosis in normal ECs during atherosclerosis.

Senescence represents a developmentally orchestrated and precisely regulated cascade of events, culminating in the abscission of plant organs and ultimately leading to the demise of the plant or its constituent parts. In this study, we observed that senescence in cut Lilium tigrinum flowers is induced by elevated ABA levels and the hyperactivation of lipoxygenase (LOX) activity. This cascade increased ROS concentrations, heightened oxidative damage, and disrupted cellular redox equilibrium. This was evidenced by elevated lipid peroxidation, attenuated antioxidant machinery, and reduced membrane stability index (MSI). Despite its known role in delaying flower senescence, the specific biochemical and molecular mechanisms by which nitric oxide (NO) regulates senescence in cut L. tigrinum flowers are not fully elucidated. Specifically, the interactions between NO signaling and ABA metabolism, the regulation of protease activity, and the influence of NO-mediated ROS scavenging, senescence-associated gene expression requires further exploration. Exogenous application of sodium nitroprusside (SNP), a source of NO, mitigated senescence in L. tigrinum cut flowers by upregulating the activity of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and reducing the LOX activity, an indicator of lipid peroxidation. SNP treatment also downregulated the relative expression of senescence-associated gene (SAG12 ),lipoxygenase 1 (LOX1 ), and abscisic aldehyde oxidase 3 (AAO3 ). NO also upregulated defender against apoptotic death 1 (DAD1 ) expression correlated with minimized protease activity and reduced α-amino acid content in SNP-treated tepals. This regulation was accompanied by increased contents of sugars, proteins and phenols and reduced abscisic acid content, which collectively delayed the senesecence and enhanced the longevity of L. tigrinum cut flowers. This study demonstrates that exogenous SNP application can effectively mitigate senescence in cut L. tigrinum flowers by modulating antioxidant enzyme activities, reducing oxidative stress, and regulating the expression of key senescence-associated genes. This study unravels the complex molecular networks involved in NO-mediated senescence delay, which may lead to the development of innovative approaches for improving flower longevity.

Background: Popliteal artery pseudoaneurysm is a state of vascular wall rupture in the popliteal artery. It is generally a rare situation and the most common etiologic factor is iatrogenic causes., Case Presentation: This case report presents a successful diagnosis and management of a 31-year-old patient who was presented with a mass behind the knee, three months after femoropopliteal bypass for the treatment of a gunshot to the knee. An endovascular approach using coils was utilized for the patient, which led to complete remission for the patient., Discussion: The current patient had two primary therapeutic challenges: bleeding and hematoma growth, clot development causing blood flow restriction, and limb ischemia. Pseudoaneurysm also caused internal inflammation, which increased the risk of thrombosis and bypass graft damage during open surgery. Due to the risk of recurrence and graft damage, ultrasound-guided compression was not possible. Thus, endovascular therapy was preferred., Conclusion: The endovascular approach using coils is an option for the management of PAP. However, the endovascular approach should be considered carefully according to the patient's status., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Sphingolipids are eighteen carbon alcohol lipids synthesized from non-sphingolipid precursors in the endoplasmic reticulum (ER). The sphingolipids serve as precursors for a vast range of moieties found in our cells that play a critical role in various cellular processes, including cell division, senescence, migration, differentiation, apoptosis, pyroptosis, autophagy, nutrition intake, metabolism, and protein synthesis. In CVDs, different subclasses of sphingolipids and other derived molecules such as sphingomyelin (SM), ceramides (CERs), and sphingosine-1-phosphate (S1P) are directly related to diabetic cardiomyopathy, dilated cardiomyopathy, myocarditis, ischemic heart disease (IHD), hypertension, and atherogenesis. Several genome-wide association studies showed an association between genetic variations in sphingolipid pathway genes and the risk of CVDs. The sphingolipid pathway plays an important role in the biogenesis and secretion of exosomes. Small extracellular vesicles (sEVs)/ exosomes have recently been found as possible indicators for the onset of CVDs, linking various cellular signaling pathways that contribute to the disease progression. Important features of EVs like biocompatibility, and crossing of biological barriers can improve the pharmacokinetics of drugs and will be exploited to develop next-generation drug delivery systems. In this review, we have comprehensively discussed the role of sphingolipids, and sphingolipid metabolites in the development of CVDs. In addition, concise deliberations were laid to discuss the role of sEVs/exosomes in regulating the pathophysiological processes of CVDs and the exosomes as therapeutic targets., Competing Interests: 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., (© 2024 Published by Elsevier B.V.)

The present study aimed to investigate the morphological features, phytochemicals, phenolic content, and antioxidant activity in different parts of Lagotis cashmeriana . The morphological features depicted that the plant is 7.9 ± 1.699 cm tall with flowers arranged into an inflorescence. The length of inflorescence was 2.597 ± 0.796 cm. Basal leaves were measuring 2.99 ± 0.58 cm. Besides, the number of basal leaves and inflorescence ranged from 4-9 and 0-4 respectively. Methanolic extract of leaves displayed the highest phenolic content (169.5 µg/mL of GAE), followed by inflorescences (157 µg/mL of GAE). Among aqueous extracts, leaves displayed the highest phenolic content (88.38 µg/mL of GAE), followed by inflorescences (76.95 µg/mL of GAE). The results of antioxidant study revealed that the methanolic extracts of leaves possessed the highest antioxidant potential (180.76 µg/mL of AAE). Interestingly, for each extract, there was a positive correlation between the phenolic content and the antioxidant activity.

Introduction: Transplant renal artery stenosis (TRAS) is one of the major vascular complications and is mostly reported within six months following kidney transplant., Case Presentation: The present case was a 16-year-old female whose blood urea nitrogen (BUN) and creatinine rose seven days after a kidney transplant. Ultrasound investigation revealed well-prefusion with a 90-degree angle anastomosis, apparent narrowing, and peak systolic velocity of 300 cm/s. Fourteen days after the transplant, with pre-and post-intervention hemodialysis and well hydration, an angiography with diluted iodinated contrast was done for the patient, which revealed >80 % narrowing at the anastomosis site. Percutaneous transluminal angioplasty (PTAS) with stenting was carried out for the patient, resulting in normal levels of BUN, creatinine, and urinary output., Clinical Discussion: While the patient did not have any risk factors for TRAS and was young, an early stenosis occurred in her left internal iliac artery one week after the kidney transplant. Due to the lower accuracy of CO2 angiography, diluted iodinated contrast angiography with well hydration and pre- and post-intervention dialysis was preferred. Endovascular treatment was preferred by the patient and attending physician due to possible adhesion and complications of open surgery and the possibility of arterial rupture., Conclusion: Performing PTAS two weeks after the renal transplantation at the anastomosis site can be a treatment in patients with early TRAS. However, due to the higher risk of rupture at the anastomosis site, it should be carried out carefully and with consideration of the need for open surgery., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Polycystic ovary syndrome (PCOS) is a complex disorder with diverse metabolic implications. Diagnosis typically relies on oligo-amenorrhoea (OA), hyperandrogenism (HA), and polycystic ovarian morphology (PCOM). However, the role of polymenorrhoea in PCOS remains understudied. Additionally, limited information exists regarding metabolic disturbances in women with partial PCOS phenotypes that do not meet diagnostic criteria. This extensive database aims to provide substantial evidence on the metabolic implications of polymenorrhoea and partial PCOS phenotypes., Design: Prospective observational study., Patients and Measurements: In this single-centre study, 6463 women with PCOS-like characteristics and 3142 age-matched healthy women were included. The study compared clinical (anthropometry, modified Ferriman Gallwey [mFG] score), hormonal (serum testosterone), and metabolic (plasma glucose, serum lipids, insulin) characteristics between women diagnosed with PCOS, those with partial PCOS phenotypes, and the healthy control group RESULTS: In all, 5174 women met Rotterdam criteria for PCOS diagnosis, while 737 were classified as Pre-PCOS, including HA (n = 538), OA (n = 121), or PCOM (n = 78). Common clinical features included oligomenorrhoea (75.5%), hirsutism (82.9%), obesity (27.2%), hypertension (1.6%), metabolic syndrome (19.6%), and diabetes mellitus (5.6%). Women diagnosed with PCOS, HA only, and OA only exhibited higher average body mass index, plasma glucose levels (both fasting and 2 h after the oral glucose tolerance test), and lipid fractions in comparison to those with PCOM and the healthy controls. However, indices of insulin resistance were similar among women with PCOS, HA, PCOM, and OA, albeit higher than in the healthy controls. The polymenorrhoea subgroup (5.9%) had lower BMI and serum testosterone, but similar mFG score, plasma glucose, insulin, and lipid levels as the oligomenorrhoea subgroup., Conclusion: The metabolic disturbances observed in Pre-PCOS women highlight the need to reassess diagnostic criteria. Including the polymenorrhoea subcategory in PCOS criteria is recommended due to similar metabolic dysfunctions as the oligomenorrhoea group., (© 2023 John Wiley & Sons Ltd.)

Cell division is driven by nucleic acid metabolism, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in nucleotide synthesis. As a result, thymidylate synthase has emerged as a critical target in chemotherapy. 5-Fluorouracil (5-FU) is currently being used to treat a wide range of cancers, including breast, pancreatic, head and neck, colorectal, ovarian, and gastric cancers The objective of this study was to establish a new methodology for the low-cost, one-pot synthesis of uracil derivatives (UD-1 to UD-5) and to evaluate their therapeutic potential in BC cells. One-pot organic synthesis processes using a single solvent were used for the synthesis of drug analogues of Uracil. Integrated bioinformatics using GEPIA2, UALCAN, and KM plotter were utilized to study the expression pattern and prognostic significance of TYMS, the key target gene of 5-fluorouracil in breast cancer patients. Cell viability, cell proliferation, and colony formation assays were used as in vitro methods to validate the in silico lead obtained. BC patients showed high levels of thymidylate synthase, and high expression of thymidylate synthase was found associated with poor prognosis. In silico studies indicated that synthesized uracil derivatives have a high affinity for thymidylate synthase. Notably, the uracil derivatives dramatically inhibited the proliferation and colonization potential of BC cells in vitro. In conclusion, our study identified novel uracil derivatives as promising therapeutic options for breast cancer patients expressing the augmented levels of thymidylate synthase., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Arteriovenous malformation (AVM) leads to a direct connection between arterial and venous networks, in which capillary branches are not involved. Pelvic AVM is a benign and rare condition causing severe pain, hematuria, and rectal or vaginal bleeding., Case Presentation: A 36-year-old woman presented with five months history of hematuria. Her medical history was unremarkable, and laboratory findings were all within normal ranges. Abdominopelvic computed tomography (CT) scan revealed a vascular mass in the left lateral pelvis that extended to the bladder neck and was suggestive of an AVM. The patient underwent a laparotomy for the resection of AVM. The first angiography revealed an AVM in the left internal iliac artery. The patient underwent embolization with coil and gel foam. The second angiography revealed complete obstruction of the left internal iliac artery due to multiple coils and AVM of the right internal iliac artery (RIIA), embolized with glue and lipiodol. A week later, venography revealed another left iliac vein malformation embolized with foam sclerotherapy. Forty days later, the third angiography revealed another AVM in the right iliac artery, embolized with three vials of polyvinyl alcohol (PVA). Following two months of follow-up, the symptoms did not return., Discussion: The present study reported a rare case of recurrent pelvic AVM causing painless hematuria in a female patient. The lesion was treated with several angioembolization sessions., Conclusion: Angioembolization is one of the main therapeutic options for AVM. Appropriate material should be precisely chosen for AVM embolization regarding the AVM's location, size, and condition., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The study describes the successful treatment of a rare type of arteriovenous malformation (AVM) in the sole using hybrid surgery, which consists of open resection and embolization. Moreover, the possibility of utilizing ultrasound during examination in addition to angiography for the diagnosing of AVM of the sole is proposed., Competing Interests: The authors have no conflict of interest to declare., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Polycystic ovary syndrome (PCOS) presents clinical symptoms of menstrual abnormalities, excessive hair growth (hirsutism), scalp hair loss, acne and infertility. Metabolic abnormalities such as obesity, insulin resistance, glucose intolerance and cardiovascular problems constitute an essential part of PCOS, all of which can have significant long-term health consequences. Low-grade chronic inflammation demonstrated by persistent moderately elevated serum levels of inflammatory and coagulatory markers plays a critical role in the pathogenesis of PCOS. Oral contraceptive pills (OCPs) constitute the mainstay of pharmacologic therapy for women with PCOS to regularize cyclicity and ameliorate androgen excess. On the other hand, OCP use is associated with various venous thromboembolic and proinflammatory events in the general population. PCOS women always carriers the increased lifetime risk of these events. The studies on the effect of OCPs on inflammatory, coagulation and metabolic parameters in PCOS are less robust. Therefore in this study, we investigated and compared the messenger RNA (mRNA) expression profiles of genes implicated in inflammatory and coagulation pathways between drug-naive and OCP-treated PCOS women. The selected genes include intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1). Furthermore, the correlation between the selected markers and various metabolic indices in the OCP group has also been explored., Method: The relative amounts of ICAM-1, TNF-α, MCP-1 and PAI-1 mRNA in peripheral blood mononuclear cells from 25 drug-naive PCOS subjects (controls) and 25 PCOS subjects who received OCPs containing 0.03 mg-ethinyl-estradiol and 0.15 mg-levonorgestrel for at least six months (cases) were estimated using real-time qPCR. The statistical interpretation was conducted using SPSS version 20.0 (SPSS, Inc, Chicago, IL), Epi Info version 2002 (Disease Control and Prevention Centres, Atlanta, GA) and GraphPad Prism 5 (GraphPad Software, La Jolla, CA) software., Result: Six months of OCP therapy enhanced the expression of inflammatory genes viz ICAM-1, TNF-α and MCP-1 mRNA in PCOS women by 2.54, 2.05 and 1.74 folds, respectively, in this study. However, PAI-1 mRNA in the OCP group showed no significant increase. Furthermore, in cases, ICAM-1 mRNA expression positively correlated with body mass index (BMI) (p = 0.01), fasting insulin (p = 0.01), insulin 2 h p = 0.02), glucose 2 h (p = 0.01) and triglycerides (p = 0.01). TNF-α mRNA expression positively correlated with fasting insulin (p = 0.0007). MCP-1 mRNA expression positively correlated with (BMI) (p = 0.002)., Conclusion: OCPs helped reduce clinical hyperandrogenism and regularise menstrual cycles in women with PCOS. However, OCP use was associated with increased fold expression of inflammatory markers which positively correlated with metabolic abnormalities., (© 2023. The Author(s).)

Tumor heterogeneity is a hallmark of cancer and one of the primary causes of resistance to therapies. Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers and is the most aggressive subtype, is very diverse, connected to metastatic potential and response to therapy. It is a very diverse disease at the molecular, pathologic, and clinical levels. TNBC is substantially more likely to recur and has a worse overall survival rate following diagnosis than other breast cancer subtypes. Chemokines, low molecular weight proteins that stimulate chemotaxis, have been shown to control the cues responsible for TNBC heterogeneity. In this review, we have focused on tumor heterogeneity and the role of chemokines in modulating tumor heterogeneity, since this is the most critical issue in treating TNBC. Additionally, we examined numerous cues mediated by chemokine networks that contribute to the heterogeneity of TNBC. Recent developments in our knowledge of the chemokine networks that regulate TNBC heterogeneity may pave the way for developing effective therapeutic modalities for effective treatment of TNBC., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in this research., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Polycystic ovarian syndrome (PCOS) is a highly prevalent endocrine disorder among females of fertile age. It has been speculated to be associated with low-grade chronic inflammation like other inflammatory response-driven multifactorial illnesses such as diabetes mellitus (DM) and cancer. Monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) are biomarkers of inflammation and endothelial dysfunction, respectively. These have been found to be elevated in PCOS patients. The current research reveals that single nucleotide polymorphisms (SNPs) in their genes are strongly associated with the elevation of these biomarkers. The goal of this study was to see if there was a link between PAI-1 -675 4G/5G and MCP-1 -2518 A/G polymorphisms with the occurrence of PCOS., Material and Method: This study included 220 PCOS participants and 220 healthy controls. The allele-specific polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods were used to investigate PAI-1-675 4G/5G and MCP-1 -2518A/G SNPs, respectively., Results: The -675 4G/5G SNP in the PAI-1 gene was strongly linked to PCOS. The odds ratio (OR) for the 4G/4G genotype was (OR = 3.2; P = 0.001), whereas the OR for the 4G/5G genotype was (OR = 2.39; P = 0.001). The carriers with the 4G/4G and 4G/5G genotypes showed significantly increasing trends in the triglyceride levels ( P < 0.05). The genotypic frequency of the -2518 A/G MCP-1 SNP differed significantly between the PCOS patients and healthy controls; the GG genotype remained a strong predictor of PCOS (OR = 8.7; P = 0.01) and the AG genotype (OR = 2.40; P = 0.01), indicating an elevated risk of predisposing women to PCOS. There was a significant variation in the glucose 2-h levels between -2518A/G MCP-1 genotypes with AG heterozygous and GG mutant genotype showing increasing trends of glucose 2-h levels ( P < 0.05)., Conclusion: Both PAI-1 -675 4G/5G and MCP-1 -2518A/G polymorphisms are associated with predisposition to PCOS and its complications in Kashmiri women., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Maize is a low-temperature (LT)-sensitive plant and its physiological responses towards LT of temperate regions developed is an adaptive trait. To further our understanding about the response of maize to LT at the physiological and photosynthesis level, we conducted Infrared Gas Analysis (IRGA using LICOR6400-XT in 45-day-old grown two maize genotypes, one from temperate region (Gurez-Kashmir Himalayas), viz., Gurez local (Gz local), and another from tropics (Gujarat), viz., GM6. This study was carried out to evaluate the underlying physiological mechanisms in the two differentially temperature-tolerant maize genotypes. Net photosynthetic rate (A/P N ), 18.253 in Gz local and 25.587 (µmol CO 2 m -2  s -1 ) in GM6; leaf conductance (gs), 0.0102 in Gz local and 0.0566 (mmol H 2 O m -2  s -1 ) in GM6; transpiration rate (E), 0.5371 in Gz local and 2.9409 (mmol H 2 O m -2  s -1 ) in GM6; and water use efficiency (WUE), 33.9852 in Gz local and 8.7224 (µmol CO 2 mmol H 2 O -1 ) in GM6, were recorded under ambient conditions. Also, photochemical efficiency of photosystem II (PSII) (F v /F m ), 0.675 in Gz local and 0.705 in GM6; maximum photochemical efficiency (F v '/F m '), 0.310234 in Gz local and 0.401391 in GM6; photochemical quenching (qP), 0.2375 in Gz local and 0.2609 in GM6; non-photochemical quenching (NPQ), 2.0036 in Gz local and 1.1686 in GM6; effective yield of PSII (ФPSII), 0.0789 in Gz local and 0.099 in GM6; and electron transport rate (ETR), 55.3152 in Gz local and 68.112 in GM6, were also evaluated in addition to various response curves, like light intensities and temperature. We observed that light response curves show the saturation light intensity requirement of 1600 µmol for both the genotypes, whereas temperature response curves showed the optimum temperature requirement for Gz local as 20 °C and for GM6 it was found to be 35 °C. The results obtained for each individual parameter and other correlational studies indicate that IRGA forms a promising route for quick and reliable screening of various stress-tolerant valuable genotypes, forming the first study of its kind., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Breast cancer (BC), the second most common cause of cancer-related deaths, remains a significant threat to the health and wellness of women worldwide. The tumor microenvironment (TME), comprising cellular components, such as cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and adipocytes, and noncellular components such as extracellular matrix (ECM), has been recognized as a critical contributor to the development and progression of BC. The interplay between TME components and cancer cells promotes phenotypic heterogeneity, cell plasticity and cancer cell stemness that impart tumor dormancy, enhanced invasion and metastasis, and the development of therapeutic resistance. While most previous studies have focused on targeting cancer cells with a dismal prognosis, novel therapies targeting stromal components are currently being evaluated in preclinical and clinical studies, and are already showing improved efficacies. As such, they may offer better means to eliminate the disease effectively., Conclusions: In this review, we focus on the evolving concept of the TME as a key player regulating tumor growth, metastasis, stemness, and the development of therapeutic resistance. Despite significant advances over the last decade, several clinical trials focusing on the TME have failed to demonstrate promising effectiveness in cancer patients. To expedite clinical efficacy of TME-directed therapies, a deeper understanding of the TME is of utmost importance. Secondly, the efficacy of TME-directed therapies when used alone or in combination with chemo- or radiotherapy, and the tumor stage needs to be studied. Likewise, identifying molecular signatures and biomarkers indicating the type of TME will help in determining precise TME-directed therapies., (© 2021. Springer Nature Switzerland AG.)

Eukaryotic translation initiation factor 4E was recently shown to be a substrate of mTORC1, suggesting it may be a mediator of mTORC1 signaling. Here, we present evidence that eIF4E phosphorylated at S209 interacts with TOS motif of S6 Kinase1 (S6K1). We also show that this interaction is sufficient to overcome rapamycin sensitivity and mTORC1 dependence of S6K1. Furthermore, we show that eIF4E-TOS interaction relieves S6K1 from auto-inhibition due to carboxy terminal domain (CTD) and primes it for hydrophobic motif (HM) phosphorylation and activation in mTORC1 independent manner. We conclude that the role of mTORC1 is restricted to engaging eIF4E with S6K1-TOS motif to influence its state of HM phosphorylation and inducing its activation.

Background: Trichomoniasis, caused by Trichomonas vaginalis protozoan, may lead to clinical or subclinical urethritis or prostatitis in men. Despite the importance of men in the epidemiology of trichomoniasis, there is little information about this topic. This epidemiological study was performed on men in Hamedan, western Iran., Methods: During Oct 2018 to Mar 2019, 214 male individuals, presenting to the Urology Clinic of Shahid Beheshti Hospital in Hamadan, were enrolled and evaluated for trichomoniasis. First-voided urine specimen was used for detection of T. vaginalis infection using molecular and parasitological methods., Results: Trichomoniasis was detected in 10 of 214 male participants (4.7%, 95% CI: 7.5-1.8%) using PCR assay. Culture and wet mount preparation of urine sediment were unable to isolates any T. vaginalis parasite. Nine of the 10 infected men were married, and six of them were ≥49 yr of age. Urinary frequency and dysuria were the most complaints (80%) among infected individuals., Conclusion: Given the notable prevalence of the infection, the prevalence of male trichomoniasis will be underestimated if only conventional diagnostic methods are used. Therefore, the risk of infection as well as the molecular survey of T. vaginalis infection should be considered in men with or without clinical symptoms., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright © 2021 Yarizadeh et al. Published by Tehran University of Medical Sciences.)

Neurodegeneration entails progressive loss of neuronal structure as well as function leading to cognitive failure, apathy, anxiety, irregular body movements, mood swing and ageing. Proteomic dysregulation is considered the key factor for neurodegeneration. Mechanisms involving deregulated processing of proteins such as amyloid beta (Aβ) oligomerization; tau hyperphosphorylation, prion misfolding; α-synuclein accumulation/lewy body formation, chaperone deregulation, acetylcholine depletion, adenosine 2A (A2A) receptor hyperactivation, secretase deregulation, leucine-rich repeat kinase 2 (LRRK2) mutation and mitochondrial proteinopathies have deeper implications in neurodegenerative disorders. Better understanding of such pathological mechanisms is pivotal for exploring crucial drug targets. Herein, we provide a comprehensive outlook about the diverse proteomic irregularities in Alzheimer's, Parkinson's and Creutzfeldt Jakob disease (CJD). We explicate the role of key neuroproteomic drug targets notably Aβ, tau, alpha synuclein, prions, secretases, acetylcholinesterase (AchE), LRRK2, molecular chaperones, A2A receptors, muscarinic acetylcholine receptors (mAchR), N-methyl-D-aspartate receptor (NMDAR), glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and mitochondrial/oxidative stress-related proteins for combating neurodegeneration and associated cognitive and motor impairment. Cross talk between amyloidopathy, synucleinopathy, tauopathy and several other proteinopathies pinpoints the need to develop safe therapeutics with ability to strike multiple targets in the aetiology of the neurodegenerative disorders. Therapeutics like microtubule stabilisers, chaperones, kinase inhibitors, anti-aggregation agents and antibodies could serve promising regimens for treating neurodegeneration. However, drugs should be target specific, safe and able to penetrate blood-brain barrier.

Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets.

Head and neck squamous cell carcinomas (HNSCCs) are a group of heterogeneous aggressive tumors affecting more than half a million patients worldwide annually. While the tobacco- and alcohol-associated HNSCC tumors are declining, human papillomavirus (HPV)-induced tumors are on rise. Despite recent advances in multimodality therapeutic interventions including surgery in combination with chemoradiation therapy (CRT), the overall 5-year survival has not improved more than 50%. The underlying reasons for this dismal prognosis is the intrinsic or acquired resistance to CRT. While previous studies were focused to target tumor cells, recent findings have implicated the involvement of tumor microenvironment (TME) on tumor progression and response to therapy. HNSCC TME includes cancer-associated fibroblasts (CAFs), endothelial cells, immune cells, endocrine cells, and the extracellular matrix (ECM) proteins including collagen and fibronectin. Understanding the crosstalk between TME and cancer cells is important to formulate more effective novel therapies and to overcome resistance mechanisms. Here, we summarized the current literature on recent advances on HNSCC TME with special emphasis on novel cell-cell interactions and therapies currently under development.

This study evaluates the ameliorative potential of Rheum spiciformis methanolic (RS-MeOH) extract in reducing oxidative stress and hyperglycemia in albino rats along with characterization of possible therapeutic compound(s). Groups treated with 50 and 100 mg/kg bw plant extract (RS-MeOH ) decrease blood glucose levels from 359.9±8.2 to 209.5±8.5 mg/dl (50 mg/kg bw) and 354.7±13.3 to 162.5±7.4 mg/dl (100 mg/kg bw) on the 0 th and 14 th day (P<0.001) respectively. This reduction in blood glucose was significant as compared to glibenclamide (20 mg/dl) which reduced glucose levels from 297.7±11.39 to 132.9±8.74 mg/dl on 0 th and 14 th day respectively. Biochemical parameters triglycerdies, cholesterol, low density lipoprotein (LDL) and creatinine were also reduced in a dose dependent manner. Liver marker enzymes were positively modulated by administration of RS-MeOH (P<0.001). Antioxidant enzyme profile showed an enhanced/better pattern after the administration of RS-MeOH extracts for reduced glutathione, reduced glutathione (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and superoxide dismutase (SOD) in both liver and pancreas. Moreover pancreatic histopathology reports revealed β-cell restorative effects with RS-MeOH, thereby potentiating its role in improving blood glucose levels. RS-MeOH purification and isolation studies involving GC-MS and NMR techniques revealed presence of emodin type compounds in RS-MeOH. Overall Rheum spiciformis showed ameliorative action on oxidative stress and hyperglycemia, however further studies to explore the mechanism of action of possible therapeutic compound in invivo clinical trials will prove beneficial for the advancement of new oral antidiabetic drug., Competing Interests: There is none to declare., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aims: Death-associated protein kinase-1 (DAPK1) is a pro-apoptotic Ser/Thr kinase that participates in cell apoptosis and tumor suppression. DAPK1 is frequently lost in many different tumor types including breast cancer. The aim of this study was to evaluate the promoter methylation status of DAPK1 and a possible correlation with the expression of DAPK1 and standard clinicopathological features in invasive ductal breast carcinoma patients (IDC). Methods: Methylation Specific PCR (MSP) was carried out to investigate the promoter methylation status of DAPK1 from 128 breast cancer patients. The effect of promoter methylation on protein expression was evaluated by immunohistochemistry (n=128) and western blotting (n=56). Results: We found significant difference in DAPK1 promoter methylation frequency among breast tumors when compared with the corresponding normal tissues. Hypermethylation of DAPK1 is significantly correlated with the loss of DAPK1 protein expression (P < .001, rs= -0.361). The loss of DAPK1 protein was significantly associated with estrogen receptor (ER) negativity (p= 0.003), triple negative breast cancer (TNB) (p= 0.024) and advanced tumor stages (P = 0.001). Moreover, age at diagnosis (p= 0.041), tumor stage (p= 0.034), ER negativity (p= 0.004) and TNB cancers (p=0.003) correlated significantly with the hypermethylation of the DAPK1 promoter. Coclusion: This study indicates that DAPK1 is methylated in IDC and promoter hypermethylation could be attributed to silencing of DAPK1 gene expression in breast cancer. Thus, we consider DAPK1 inactivation by promoter hypermethylation likely plays a role in the development and progression of breast cancer., (Creative Commons Attribution License)

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background & Objectives: Polycystic ovary syndrome (PCOS) is an endocrinopathy warranting lifelong individualized management by lifestyle and pharmacological agents mainly oral contraceptive pills (OCPs). This study was aimed to report the impact of six-month OCP use on plasminogen activator inhibitor-1 (PAI-1) and factor VIII (FVIII) in women with PCOS., Methods: PCOS women diagnosed on the basis of Rotterdam 2003 criteria, either treated with OCPs (ethinyl estradiol-0.03 mg, levonorgestrel-0.15 mg) for a period of six months (n=40) or drug-naïve (n=42), were enrolled in this study. Blood was drawn to estimate glucose, insulin levels and lipid profile. Chemiluminescence immunoassays were used to measure hormones (LH, FSH, PRL, T 4 ). Plasma levels of PAI-I and FVIII were measured by commercially available kits., Results: Menstrual regularity, Ferriman-Gallwey score and serum total testosterone significantly improved in the OCP group compared to drug-naïve group (P<0.01). No significant difference was observed in PAI-1 levels of the two groups; however, significant decrease in FVIII levels was observed in OCP group as compared to drug-naïve group. PAI-1 levels of OCP group correlated positively with blood glucose two hours, triglycerides and insulin two hours, while FVIII levels of OCP group correlated negatively with fasting insulin and homoeostatic model assessment-insulin resistance., Interpretation & Conclusions: OCPs use has differential effect on pro-coagulant markers among women with PCOS. Well-designed, long-term, prospective, large-scale studies are prerequisite to elucidate the efficacy and safety of OCP in the treatment of PCOS., Competing Interests: None

The aim of the present study was to evaluate the hepatoprotective activity of methanolic extract of Elsholtzia densa against experimentally induced acute (CCl 4 ) and chronic (paracetamol) liver injury in albino wistar rats. Activity was measured by monitoring the serum levels of ALT, ALP AST and LDH, total protein levels, bilirubin and albumin. The results of the CCl 4 and paracetamol-induced liver toxicity experiments showed that the rats treated with the methanolic extract of Elsholtzia densa exhibited a significant decrease in biochemical parameters as well as the proteins, which were all elevated in the CCl 4 and paracetamol group. The extract at a concentration of 300 mg/kg body wt. showed a significant decline (P≤0.05) in the levels of AST, ALT, ALP and LDH to 69.50±2.23IU/L, 60.01±2.25IU/L,46.20±2.24 IU/L and 150.21±5.68IU/L in CCl 4 injected animals and 51.12±2.20 IU/L,49.15±3.25 IU/L, 44.12±2.56 IU/L and 125.15±4.45 IU/L in paracetamol-treated animals when compared to the control group. The activities of tissue antioxidants GSH, GPx, GR, GST and CAT was significantly (P≤0.05) restored in dose dependent manner in animals treated with extracts as with acute and chronic hepatotoxic models. The current study confirmed the hepatoprotective effect of methanolic extract of Elsholtzia densa against the model hepatotoxicant CCl 4 and paracetamol., Competing Interests: The authors do not have any conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Drug discovery is an exhaustive and time-consuming process involving numerous stages like target identification, validation, lead optimization, preclinical trials, clinical trials and finally postmarketing vigilance for drug safety. The application of computer-aided drug designing (CADD) is an indispensable approach for developing safe and effective drugs. Previous methods based on combinatorial chemistry (CC) and high throughput screening (HTS) consumed a lot of time as well as expenditure. CADD based approaches including pharmacophore modeling (PM), molecular docking (MD), inverse docking, chemical similarity (CS), quantitative structure-activity relationship (QSAR), virtual screening (VS) and molecular dynamics simulations have been quite productive in predicting the therapeutic outcome of candidate drugs/compounds besides saving precious time. CADD tools exploit structural and other information available regarding the target (enzyme/receptor) and the ligands to identify the compounds with the ability to treat diseases notably cancer, neurodegenerative disorders, malaria, Ebola, HIV-AIDS and many more. Computational approaches have led to the discovery of many drugs that have passed preclinical and clinical trials and become novel therapeutics in the treatment of a variety of diseases. Some notable examples of CADD derived novel drugs include dorzolamide, saquinavir, ritonavir, indinavir, captopril and tirofiban. CADD plays important role in predicting absorption, distribution, metabolism, excretion and toxicity (ADME/T) of candidate drugs. Overall, CADD represents an effective and much-needed strategy for designing therapeutically effective drugs to combat human diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

MicroRNAs (miRNAs) are a large family of small, approximately 20-22 nucleotide, noncoding RNAs that regulate the expression of target genes, at the post-transcriptional level. miRNAs are involved in virtually diverse biological processes and play crucial roles in cellular processes, such as cell differentiation, proliferation, and apoptosis. Accumulating lines of evidence have indicated that miRNAs play important roles in the maintenance of biological homeostasis and that aberrant expression levels of miRNAs are associated with the onset of many diseases, including cancer. It is possible that the diverse roles that miRNAs play, have potential to provide valuable information in a clinical setting, demonstrating the potential to act as both screening tools for the stratification of high-risk patients, while informing the treatment decision-making process. Increasing evidence suggests that some miRNAs may even provide assistance in the diagnosis of patients with breast cancer. In addition, miRNAs may themselves be considered therapeutic targets, with inhibition or reintroduction of a particular miRNA capable of inducing a response in-vivo. This chapter discusses the role of miRNAs as oncogenes and tumor suppressors in breast cancer development and metastasis . It focuses on miRNAs that have prognostic, diagnostic, or predictive potential in breast cancer as well as the possible challenges in the translation of such observations to the clinic.

Background: Polycystic ovary syndrome (PCOS), associated with a state of low grade chronic inflammation, depends on multiple genetic and environmental factors. Elevated levels of inflammatory markers including intercellular adhesion molecule-1 (ICAM-1) have been demonstrated in affected women. Recent evidence indicates a significant linkage between chromosome 19p13 loci and multifactorial diseases that have an inflammatory component. The aim of this study was to assess the possible association of the lys469glu (K469E) polymorphism of the ICAM-1 gene located on chromosome 19p13 with risk of PCOS in Kashmiri women. Material and Methods: The K469E single nucleotide polymorphism (SNP) was analysed with DNA from peripheral blood leukocytes of 220 PCOS cases and 220 age matched non-PCOS healthy controls using PCR-RFLP. Results: Genotypic frequencies in cases were found to be 32 (14.5%) for EE, 98 (44.5%) for KE, and 90 (40.9%) for KK, with 130 (59.1%) for the KE+EE genotypes compared to healthy control values of 29 (13.2%) for EE, 113 (51.4%) for KE, 78 (35. 5%) for KK and 142 (64.5%) for KE+EE combined.The odds ratios for the EE, KE and KE:EE genotypes were 0.95(95% CI= 0.53-1.71)[p= 0.88], 0.75(95% CI= 0.50-1.12)[p =0.168] and 0.79 (95% CI =0.53-1.16) [p = 0.23], no statistically significant differences being found between cases and controls (χ2 =2.07; p=0.35). Conclusion: In conclusion, there was no apparent significant influence of the K469E polymorphism on risk of PCOS, or any clinical or laboratory parameters., (Creative Commons Attribution License)

l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.

Study Objective: Polycystic ovary syndrome (PCOS), the most common endocrinopathy of women, is a state of chronic low-grade inflammation and is closely linked to type 2 diabetes mellitus and cardiovascular disease. Oral contraceptive pills (OCPs), is the usual first choice of treatment in women with PCOS. Because OCP use has been linked to the risk of venous thrombosis and there are limited data on the effect of OCP use on the inflammatory state of women with PCOS, our objective was to compare the levels of intercellular adhesion molecule (ICAM)-1, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1 between drug-naive and OCP-treated women with PCOS. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Consequent to women diagnosed with PCOS on the basis of Rotterdam 2003 criteria, either treated with OCPs (ethinylestradiol 0.03 mg, levonogestrel-0.15 mg) for a period of 6 months (n = 50) or drug-naive (n = 51) were enrolled in this cross-sectional study., Results: The mean ages of patients and control participants were comparable (21.99 ± 4.78 vs 21.92 ± 5.83 years; P = .947) as was body mass index (24.47 ± 3.92 vs 23.66 ± 3.43; P = .271). Clinical and androgen excess symptoms were significantly better in the OCP group compared with the drug-naive group (P = .01, P = .04). Total cholesterol and low-density lipoprotein cholesterol levels were significantly higher in the OCP group (P = .01). Plasma ICAM-1 levels, TNF-α levels, and MCP-1 levels showed a higher trend in patients but reached statistical significance only in cases of ICAM-1 and TNF-α (P = .01)., Conclusion: OCP treatment of 6 months increases plasma ICAM-1, MCP-1, and TNF-α levels among women with PCOS, although OCPs significantly help in ameliorating features of hyperandrogenism and regularizing menstrual cycles. These cytokines correlate positively with many metabolic parameters including plasma glucose, lipids, and homeostatic model assessment-insulin resistance. Further investigation with well designed, randomized, longitudinal studies might help to ascertain the effect of OCPs on proinflammatory profiles among women with PCOS., (Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is responsible for initiation, chemo-resistance, and poor prognosis of colorectal cancer (CRC). Therefore, PI3K pathway inhibition can provide a plausible way of attaining CRC treatment. We report PI3K target specific synthesis and selection of a potent molecule, that is, 2,3-dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) from quinazolinone series based on the structural activity relationship after evaluation in diverse cancers. This molecule inhibited the PI3K enzyme activity and transcriptional as well as translational expression levels in colorectal cancer (CRC) models. This was associated with subsequent decrease in phosphorylation of its downstream effector proteins, that is, p-Akt (Ser-473) and p-mTORC1 (Ser-2448) and decreased ERK signaling. Furthermore, DHNQ decreased expression of cyclins that caused G 1 arrest and decreased Bcl-2/Bax ratio after mitochondrial membrane potential loss, reactive oxygen species generation, and an increase in cytosolic Ca 2+ loads that is responsible for the decreased CRC cell proliferation and survival. These biochemical changes triggered apoptotic cell death with altered autophagic Beclin-1 and LC3β expression. It seemed that the PI3K-Akt signaling regulated apoptosis and autophagy through different mechanisms but mTORC1 mediated autophagy appeared not to be involved in the cell death induction by DHNQ. The molecule also showed significant anticancer efficacy in in vivo tumor models without any mortality indicating its non-toxic nature with possible clinical significance. Overall, the selective elucidation of DHNQ molecular mechanism will provide the possible strategies for the clinical development in CRC that may respond to this specific, potent and novel P13K inhibitor. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: The ambiguity in relating expression dynamics of stress response proteins with human esophageal squamous cell carcinoma (ESCC) has sidelined the potential of stress proteins as therapeutic targets. This study was an attempt to unequivocally relate the stress protein dynamics with stage and propensity of ESCC., Methods: Surgically resected tumor and adjacent histologically normal tissue from 46 patients with esophageal squamous cell carcinoma were investigated in the present study. Expression of HSPs was analyzed by Western blotting and immunohistochemistry., Results: HSP expression was observed in all 46 cases both in adjacent normal and tumor tissues. The expression and the localization of individual HSP showed no significant correlation with depth of invasion, tumor grade, and pathological stage of the tumor. HSP 27 was the most abundant protein followed by HSP 90 and HSP 70. The HSP 27 localized exclusively in the cytoplasm of adjacent normal and tumor cells. HSP 70 showed dispersed expression with predominating nuclear localization in both normal and tumor tissue cells and HSP 90 was localized in cytoplasm of adjacent normal and in nucleus of tumor cells in majority of the cases., Conclusion: Our data advocate lack of relationship between stress protein expression and the progression of ESCC. The data renew the prospect of anti-HSP drugs as therapeutic resources in light of the possibility that their use would continue to sensitize cancer cells towards drug induced apoptosis for tumor regression.

Context: Crataegus songarica K. Koch (Rosaceae) has been used in folk medicine to treat various diseases., Objective: This study evaluates the effect of C. songarica methanol extract on the kidney and heart tissue damage of albino rats, and to determine cytotoxic activity of various extracts of songarica on various human cancer cell lines., Materials and Methods: Rats were divided into six groups, Group I received water only; Group II received CCl4 (1 mL/kg b wt) intraperitoneal; C. songarica extract (at doses of 100, 200 and 300 mg/kg b wt) orally for 15 days. Cytotoxic activity was determined by SRB method using MCF-7, HeLa, HepG2, SF-295, SW480 and IMR-32 cell lines., Results: Compared with CCl4 group, administration of C. songarica extract at the dose of 300 mg/kg b wt, significantly decreases serum creatinine (59.74%), urea (40.23%) and cholesterol (54 mg/dL), MDA (0.007 nmol/mg protein) in kidney and (0.025 nmol/mg protein) in heart tissue, along with evaluation of GSH (209.79 ± 54.6), GR (111.45 ± 2.84), GPx (94.01 ± 14.80), GST (201.71) in kidney tissue and GSH (51.47 ± 1.47), GR (45.42 ± 6.69), GPx (77.19 ± 10.94), GST (49.89) in heart tissue. In addition, methanol, ethanol and ethyl acetate extracts exhibited potent anticancer activity on six cancer cell lines with IC50 values ranging from 28.57 to 85.106 µg/mL., Discussion and Conclusion: Crataegus songarica methanol extract has a potential antioxidant effect as it protects the kidney and heart tissue against CCl4-induced toxicity, prevents DNA damage and showed strong anticancer activity.

Phosphatidylinositol 3-kinase (PI3K) pathway drives cancer progression through direct regulation of most oncogenic properties. Here, we report that PI3K pathway signaling up-regulates cancer cell proliferation, metastasis and angiogenesis through modulation of cancer metabolism. These oncogenic metabolic processes were disrupted, by a novel PI3K inhibitor, 3-Dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) in colon cancer cells. DHNQ inhibited the Warburg effect and lipid synthesis by reducing gene expression of glycolytic and lipogenesis regulatory enzymes. This downregulation at gene level by DHNQ inhibited metabolic flux to repress proliferation, migration and invasion characteristics of colon cancer. Furthermore, the metabolic attenuation caused repression of in vitro/in vivo angiogenesis providing new insights in PI3K regulated angiogenesis via metabolic alterations. Our results suggest that multifaceted targeting of oncogenic metabolism by their upstream PI3K regulatory signaling may be an effective cancer treatment approach., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Phytochemicals modulate key cellular signaling pathways and have proven anticancer effects. Alcea rosea(AR; Hollyhock) is an ornamental plant with known anti-inflammatory properties. This study explored its role as an anticancer agent. The AR seed extract (AR extract) inhibited proliferation and colony formation in a dose- and time-dependent manner and promoted apoptosis as was evidenced by cleavage of PARP and increased expression of Bax accompanying reduced levels of BCL-xl protein in HCT116 and SW480 cells, respectively. In addition, AR extract-arrested cells at Go/G1 phase of cell cycle and exhibited decreases in Cyclin D1. AR extract-treated cells exhibited reduced number and size of colonospheres in a dose-dependent manner concomitant with decreases in cancer stem cell (CSC) markers ALDH1A1 and Dclk1. Relative levels of β-catenin, Notch-ICD, Hes1 and EZH2 were also attenuated by AR extract. TOP-flash reporter activity, a measure of Wnt signaling, decreased significantly in response to treatment while overexpression of wild type but not mutant EZH2, reversed the inhibitory effects. Moreover, WIF1 (a Wnt antagonist) promoter activity increased dramatically following treatment with AR extract which phenocopied increases in WIF1 reporter activity following EZH2 knockdown.In vivo, AR extract attenuated tumor growth due probably to reduced levels of EZH2, β-catenin, CyclinD1 and Ki-67 along with reduced levels of CSC markers. Since partial purification via HPLC yielded a prominent peak, efforts are underway to identify the active ingredient(s). Taken together, the results clearly suggest that AR extract/active component(s) can be an effective preventative/therapeutic agent to target colon cancer., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Mitochondria play a central role in cellular physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions, including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis, and control of apoptosis. Simultaneously, mitochondria are the main producer and target of ROS with the result that multiple mitochondrial diseases are related to ROS-induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide synthase (iNOS) activity, enhanced nitric oxide (NO) production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pores have all been suggested as factors responsible for impaired mitochondrial function. Because of these, neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and aging, are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an anti-oxidant and as a regulator of mitochondrial bioenergetic function. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other anti-oxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. With these functions in mind, this article reviews the protective role of melatonin with mechanistic insights against mitochondrial diseases and suggests new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights are also discussed.

Derailed inflammation causes severe damage to the normal tissues resulting in various pathological conditions such as auto-inflammatory disorders, neurodegenerative diseases and cancer. Cure of inflammatory diseases is a big challenge. Medicinal herbs used traditionally represent the best option for obtaining effective anti-inflammatory therapeutics. Present review provides a thorough insight about various pathways, consequences and therapeutic strategies of inflammation with prime focus to expose indigenous anti-inflammatory herbal compounds along with their structures and diverse range of mechanisms of action. Over hundred medicinal plants with scientifically reported anti-inflammatory properties were reviewed. Different parts of the plants like roots, stem, bark, leaves, flowers and seeds contain active compounds with potential anti-inflammatory properties. Such compounds act at multiple targets in the inflammatory response pathways and regulate multitude of chemical mediators, enzymes, genes or cellular functions to alleviate inflammation. Although a large number of antiinflammatory herbal compounds have been isolated but the mechanism of action of bulk of compounds has not been elucidated comprehensively. Besides there is need for conducting well designed clinical trials so that the promising compounds could be used as effective antiinflammatory therapeutic agents in future.

Background: Polycystic ovary syndrome (PCOS) is considered to be a multifactorial disorder resulting from the interaction of several predisposing and protective genetic variants. PCOS is associated with low-grade chronic inflammation. Elevated levels of inflammatory markers including intercellular adhesion molecule-1 (ICAM-1) are demonstrated in women with PCOS. Recent evidence indicates a significant linkage between a locus on chromosome 19p13 and multifactorial diseases that have an inflammatory component. The aim of the study was to assess the possible association of Gly241Arg polymorphism of ICAM-1 gene located on chromosome 19p13 in determining risk of PCOS in Kashmiri women., Materials and Methods: Gly241Arg SNP in DNA from peripheral blood leukocytes of 220 PCOS cases and 220 age matched non-PCOS healthy controls was analysed using allel specific PCR., Results: The genotype and allele frequency distributions of Gly241Arg SNP showed insignificant difference between the PCOS cases and control women, indicating no role of this SNP in PCOS susceptibility. The odds ratio for Arg/Arg genotype was 0.87 (95% CI=0.32-2.3) [P=0.79], for Gly/Arg genotype was 0.98 (95% CI= 0.66-1.47) [P=1] and for Arg/Arg+Gly/Arg genotype was 0.97 (95% CI=0.65-1.45) [P=0.92]. The genotypic frequencies of ICAM-1codon 241 showed statistically insignificant difference between cases and controls (χ2=0.07; p=0.96) Nor the studied polymorphism was found to affect clinical and laboratory parameters significantly., Conclusions: Although Gly241Arg polymorphism have not shown significant association with PCOS. Further, specifically designed studies on large cohorts are required to conclusively establish any role of ICAM-1 gene polymorphisms in PCOS in our study.

Epigenetic mechanisms such as DNA methylation are being increasingly recognized to play an important role in cancer and may serve as a cancer biomarker. The aim of this study was to evaluate the promoter methylation status of MGMT (O6-methylguanine-DNA methyltransferase) and a possible correlation with the expression of MGMT and standard clinicopathological parameters in invasive ductal breast carcinoma patients (IDC) of Kashmir. Methylation-specific PCR was carried out to investigate the promoter methylation status of MGMT in breast tumors paired with the corresponding normal tissue samples from 128 breast cancer patients. The effect of promoter methylation on protein expression in the primary breast cancer and adjacent normal tissues was evaluated by immunohistochemistry (n = 128) and western blotting (n = 30). The frequency of tumor hypermethylation was 39.8 % and a significant difference in methylation frequency among breast tumors were found (p < 0.001) when compared with the corresponding normal tissue. Immunohistochemical analysis showed no detectable expression of MGMT in 68/128 (53.1 %) tumors. MGMT promoter methylation mediated gene silencing was associated with loss of its protein expression (rs = -0.285, p = 0.001, OR = 3.38, 95 % CI = 1.59-7.17). A significant correlation was seen between loss of MGMT and lymph node involvement (p = 0.030), tumor grade (p < 0.0001), loss of estrogen receptors (ER; p = 0.021) and progesterone receptors (PR) (p = 0.016). Also, MGMT methylation was found to be associated with tumor grade (p = 0.011), tumor stage (p = 0.009), and loss of ER (p = 0.003) and PR receptors (p = 0.009). To our knowledge, our findings, for the first time, in Kashmiri population, indicate that MGMT is aberrantly methylated in breast cancer and promoter hypermethylation could be attributed to silencing of MGMT gene expression in breast cancer. Our data suggests that MGMT promoter hypermethylation could have a potential function as molecular biomarker of breast oncogenesis. Also, based on their predictive value of response to therapy, the immunohistochemical evaluation and interpretation of MGMT may also help in future to establish therapeutic strategies for patients with breast cancer.

Mitochondria is one of the main source of oxidative stress (ROS), as it utilizes the oxygen for the energy production. ROS and RNS are normally generated by tightly regulated enzymes. Excessive stimulation of NAD(P)H and electron transport chain leads to the overproduction of ROS, results in oxidative stress, which is a good mediator to injure the cell structures, lipids, proteins, and DNA. Various oxidative events implicated in many diseases due to oxidative stress include alteration in mitochondrial proteins, mitochondrial lipids and mitochondrial DNA, Which in turn leads to the damage to nerve cell as they are metabolically very active. ROS/RNS at moderate concentrations also play roles in normal physiology of many processes like signaling pathways, induction of mitogenic response and in defense against infectious pathogens. Oxidative stress has been considered to be the main cause in the etiology of many diseases, which includes Parkinson's and Alzheimer diseases. Several PD associated genes have been found to be involved in mitochondrial function, dynamics and morphology as well. This review includes source of free radical generation, chemistry and biochemistry of ROS/RNS and mitochondrial dysfunction and the mechanism involved in neurodegenerative diseases., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

General anesthesia is a routine anesthetic technique for kidney transplantation. This study evaluated and compared the peri-operative hemodynamic, cardiopulmonary and general condition status in patients in whom spinal anesthesia (SA) or general anesthesia (GA) was used for kidney transplantation. A prospective study was carried out on 49 consecutive patients who underwent kidney transplantation with either GA (19 patients, mean age 37.53 ± 11.78 years) or SA (30 patients, mean age 42.17 ± 14.89 years), without any selection bias. One obese patient with a body mass index of 32.52 kg/m 2 died 22 days after transplantation in the GA group. One other patient, who developed severe nausea and vomiting, was changed from SA to GA. There were no statistical differences in gender, mean age, body mass index and hemodynamic and cardiopulmonary status between the two groups. Time to post-operative diet tolerance, defecation, ambulation and adequate urination were significantly better in the SA group. The mean operation time was 264.32 ± 18.91 and 233 ± 15.12 min in the GA and SA groups, respectively. Brisk diuresis was seen in all patients except one in the SA group. Our study suggests that kidney transplantation under SA is feasible and safe, particularly for patients who cannot receive GA.

Ethnopharmacological Relevance: Atropa acuminata has been widely used in traditional medicine against arthritis and several associated inflammatory disorders., Aim of the Study: The present study was undertaken to investigate the anti-arthritic activities of ethanolic extract of Atropa accuminata (AAEE) and to explore the probable mechanism of action., Materials and Methods: The anti-arthritic activity of AAEE was evaluated within a dose range of 125-500 mg/kg b.w. in adjuvant induced-arthritis in male wistar rats. An array of pro-inflammatory mediators (PGE2 NO, IL-1β and LTB4) and T-cell-mediated cytokines (IL-2, TNF-a, IFN-c, IL-4, IL-10, IL-12, IL-17, IL-6) were assayed in arthritic paw tissue homogenate of the treated animals. In addition the effects on arthritic lesions, changes in body weight; haematological (Hb, ESR, WBC and RBC) and biochemical parameters (SOD, GSH, GR) and the serum markers (CRP, RF) were also observed., Results: Significant anti-arthritic activity was observed for AAEE in the polyarthiritis test both in the developing and developed phase of the disease. This was associated with dose dependant suppression of pro-inflammatory mediators (PGE2, NO, IL-1β and LTB4)., Th1-Th17 cytokines (IL-2, TNF-α, IFN-γ, IL-12, IL-17, IL-6) and upregulation of Th2 cytokines (IL-4 and IL-10). AAEE was also observed to protect rats against the primary and secondary arthritic lesions, body weight changes and haematological perturbations. In addition, inhibitory effects of AAEE on biochemical parameters and the serum markers further confirmed that it reduced signs on chronic inflammatory responses., Conclusion: The present investigation therefore suggested that AAEE is a potent anti-arthritic agent. The multipronged attack on the inflammatory mediators and T-helper cytokines and strong potency of AAEE may have relevance for inhibition of the chronic inflammatory responses in arthritis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The synthesis and bio-evaluation of naturally occurring boswellic acids (BAs) as an alternate CAP for the design of new HDAC inhibitors is described. All the compounds were screened against a panel of human cancer cell lines to identify leads, which were subsequently examined for their potential to inhibit HDACs. The identified lead compound showed IC50 value of 6μm for HDACs, found to induce G1 cell cycle arrest at significantly low concentration (1μM) and caused significant loss in mitochondrial membrane potential at 5 and 10μM. Furthermore, specific interactions of the lead molecule inside the catalytic domain were also studied through in silico molecular modeling., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Human papillomavirus (HPV) infection is a central and necessary, although not sufficient, cause of cervical cancer. Besides HPV, the additional multiple risk factors related with the onset of cervical cancer are early-age sexual activities; high number of sexual partners, which is the most salient risk factor; suppression and alteration of the immune status; long-term use of oral contraceptives; and other hormonal influences. The tumor-suppressor proteins p53 and pRb are degraded and destabilized through ubiquitination by viral oncoproteins E6 and E7. Over 95% of cervical cancer cases worldwide test positive for oncogenic HPV DNA. Although cervical screening procedures have been successful in reducing the disease burden associated with HPV infection because of lack of resources or inadequate infrastructure many countries have failed to reduce cervical cancer mortality. Therefore, prevention may be a valuable strategy for reducing the economic and disease burden of HPV infection. At present, two successful prophylactic HPV vaccines are available, quadrivalent (HPV16/18/6/11) 'Gardasil' and bivalent (HPV16/18) 'Cervarix' for vaccinating young adolescent girls at or before the onset of puberty. Recent data indicate that vaccination prevents the development of cervical lesions in women who have not already acquired the vaccine-specific HPV types. Moreover, several therapeutic vaccines that are protein/peptide-based, DNA-based, or cell-based are in clinical trials but are yet to establish their efficacy; these vaccines are likely to provide important future health benefits. The therapeutic vaccination mode of prevention is a promising area of research, as revealed in preclinical trials; however, clinical trials based on large populations are warranted before reaching a valid conclusion. This review summarizes the studies on the epidemiology of HPV infection, the pathogenesis of viral oncoproteins in the oncogenesis of cervical cancer, the economic and health burden of HPV-related diseases, and, finally, focuses on the results of recent clinical vaccination trials.

Background: Polycystic ovary syndrome (PCOS) is the most complex and common endocrine disorder of women in reproductive years. In addition to irregular menstrual cycles, chronic anovulation and hyperandrogenism, it has many metabolic manifestations such as obesity, hyperlipidemia, hyperinsulinemia, insulin resistance, dysglycemia, increased risk of cardiovascular disease or possibly endometrial cancer. Familial clustering of PCOS in consistence with the genetic susceptibility has been described., Materials and Methods: The present study assessed the clinical, biochemical and hormonal parameters including prevalence of metabolic syndrome by two different criteria in the first- degree relatives of patients with PCOS., Results: The average age of 37 index patients was 23 ± 3.6 years, with the mean age of menarche as 13.3 ± 1.2 years. The mean age and age of menarche in mothers (n = 22) was 48.8 ± 5.1 and 13 ± 1.3 years, respectively, whereas as it was 23.5 ± 4.7 and 13.3 ± 1.2 years in sisters (n = 22), respectively. Metabolic syndrome (MS) defined by International Diabetes Federation (IDF) criteria was present in 10 index patients, 1 brother, 4 sisters, 17 mothers and 15 fathers while as by Adult Treatment Panel III (ATP III) it was in 8 index patients, 5 sisters, 16 mothers and 11 fathers., Conclusion: The presence of MS or related metabolic derangements is high in the family members of women with PCOS.