Protective Effects of Dexmedetomidine Infusion on Genotoxic Potential of Isoflurane in Patients Undergoing Emergency Surgery.

Background: Isoflurane (ISO) has been extensively uses in general anesthesia and reported to cause deoxyribonucleic acid (DNA) damage in prolonged surgical procedures. Dexmedetomidine (DEX) is an adrenergic agonist and having antioxidant activity that may reduce the genotoxic potential (DNA damage) and oxidative stress induced by ISO in patients undergoing major neurosurgical procedures. Methods and Findings. Twenty-four patients of ASA (American Society of Anesthesiologists) classes I and II were randomly divided into two groups (n = 12). Group A patients received ISO, while group B patients received DEX infusion for maintenance of anesthesia. Venous blood samples were collected at different time intervals and used to evaluate the oxidative stress marker malondialdehyde (MDA) and endogenous antioxidants superoxide dismutases (SOD) and catalases (CAT). A single-cell gel electrophoresis (SCGE)-comet assay was used to investigate the genotoxic potential of ISO. Conclusion: Increased level of antioxidants and decreased value of MDA and genetic damage index were seen in group B (P < 0.001) in a time-dependent manner. Genetic damage was highest at point T 2 (0.77 vs. 1.37), and continued to decrease till T 3 (0.42 vs. 1.19), with respect to negative controls or baseline values following DEX infusion. Significantly, higher level of MDA was recorded in serum of group A (P < 0.001) as compared to group B (1.60 ± 0.33 vs. 0.03 ± 0.001). Enzymatic activities of CAT and SOD were significantly higher in group B than group A (10.11 ± 2.18 vs. 5.71 ± 0.33), (1.04 ± 0.05 vs. 0.95 ± 0.01), respectively. It may play a contributing role in daily anesthesia practice and improve the toxic effects on patients as well as anesthesia personnel. Trial Registration. Ethical Committee of Post Graduate Medical Institute (PGMI), Lahore General Hospital approved the use of humans in this study vide human subject application number ANS-6466 dated February 04, 2019. Furthermore, as the clinical trials required registration from an appropriate registry approved by World Health Organization (WHO), this trail also retrospectively registered at Thai Clinical Trials Registry (an approved WHO registry for clinical trials registration) under reference ID TCTR20211230001 on December 30, 2021.

Effect of methanolic extract of Citrus limetta peel on cellular and humoral immune response in mice.

Citrus limetta is well known for its anti-inflammatory, antimicrobial, antifungal, antidiabetic and antioxidant properties. Methanolic extract of Citrus limetta (MECL) was used to assess cellular and humoral immune responses in mice by carrying out cyclophosphamide-induced neutropenia, delayed-type hypersensitivity (DTH), carbon clearance assay, haemagglutination assay (HA) and mice lethality assay. Methanolic extract of Citrus limetta peel was administered orally to mice in two doses 200mg/kg and 400mg/kg.The extract treated groups showed improvement in neutropenia induced by cyclophosphamide and improvement in the WBC profile. Skin thickness was significantly (P<0.05) higher in 200mg/kg and 400mg/kg groups in comparison to control in DTH. The phagocytic index was significantly (P<0.05) more in 400mg/kg group in carbon clearance assay. Mice were vaccinated with hemorrhagic septicemia vaccine before challenge with Pasteurella multocida for mice lethality test. Percentage mortality was decreased in 400mg/kg treated group in comparison to negative control Antibody titre response to sheep red blood cells was significantly (P<0.05) higher with dose 400mg/kg in HA. Results suggested the effectiveness of the methanolic extract of Citrus limetta as an immunostimulating agent.

Pharmacokinetics of thymoquinone in layer chickens following oral and intravenous administration.

Thymoquinone (TQ) is the major constituent of Nigella sativa and known to possess a variety of pharmacological effects. This study was designed to evaluate the pharmacokinetic profile of TQ following oral (PO) and intravenous (IV) administration in layer chickens. The layer chickens were equally divided into two groups (six chickens in each group, total 12 chickens), and TQ was administered via PO and IV routes. For PO route, the dose was 20 mg/kg b.w. and for IV route, 5 mg/kg b.w. was administered, respectively. A sensitive and accurate High-Performance Liquid Chromatography (HPLC) technique was validated for the quantification of TQ from plasma. The limit of detection (LOD) and limit of quantification (LOQ) were 0.02 µg/ml and 0.05 µg/ml, respectively with >80% recovery. Maximum plasma concentration (Cmax ) following PO and IV administration was 8.805 and 4.497 µg/ml, respectively, while time to reach at maximum concentration (Tmax ) was 1 and 0.1 hr, respectively. The elimination half-lives were recorded as 1.02 and 0.978 hr, whereas the mean residence times were 1.79 and 1.036 hr following both PO and IV administration, respectively. The 85% PO bioavailability was indicative that TQ could be used for various therapeutic purposes in layer chickens.

Association of textile industry effluent with mutagenicity and its toxic health implications upon acute and sub-chronic exposure.

Complex industrial discharges pose certain risks to the ecosystem. This study was aimed at identifying acute and sub-chronic toxicological effects of the textile industry wastewater. The textile wastewater was evaluated for the metals and organic pollutants by atomic absorption spectrophotometer and GC-MS respectively. In vitro genotoxicity and mutagenicity were assessed by Comet assay in peripheral lymphocytes isolated from Ovis aries and Ames test in Salmonella typhimurium strains TA-100 and 102 respectively. Physiological and behavioral changes along with systemic toxicity were determined in Rattus norvegicus albinus following acute and sub-chronic exposure. High amount of heavy metals such as Cr, Pb, Hg, As, and Cd were detected in textile wastewater. Organic pollutants such as 25-deacetoxy cucurbitacin-b, E-14-Hexadecenal, 11-Tricosene, and phthalates were also found. In vitro genotoxicity assessment in lymphocytes showed statistically significant DNA damaging potential of textile wastewater. Textile wastewater also showed significantly higher (p˂ 0.05) mutagenic potential in Salmonella TA-100 and TA-102 strains than sodium azide and 2-amino anthracycline. Acute exposure of textile wastewater to Rattus norvegicus was associated with several physiological changes and behavioral symptoms. Sub-chronic exposure of textile wastewater in Rattus norvegicus instigated the degeneration and necrosis of epithelial cells in renal tubules, hydropic degeneration and necrosis of hepatocytes, peri-bronchiolar infiltration and emphysema of the alveoli, and the degradation of myocardial cells. This study concludes that the textile wastewater may cause genotoxicity and mutagenicity, result in physiological and behavioral changes upon acute exposure, and inflict various pathological lesions upon sub-chronic exposure.

Endophyte bioprospecting in South Asian medicinal plants: an attractive resource for biopharmaceuticals.

From the last several years, there has been an increasing interest in plant-associated bacteria commonly referred to as endophytes that reside asymptomatically in the internal plant tissues. This interest peaked since the last two decades due to the recognition that endophytes within medicinal plants have the capability to mimic and produce the bioactive metabolites of the host plant. A number of medicinal plants have been used for centuries by the people of South Asia to cure various diseases and this has led to abundant usage experience. Relating to prior ethanopharmacological experiences, scientists have searched for medicinal plants that could be valued sources for endophytes yielding novel metabolites of pharmaceutical importance. This review is therefore an effort to encompass the most recent efforts in the exploration of medicinal plants of South Asia and their endophytes.

Evaluation of cytotoxic and antiviral activities of aqueous leaves extracts of different plants against foot and mouth disease virus infection in farming animals.

Cytotoxic and antiviral activity of aqueous leaves extracts of three plants: Azadirachta indica, Moringa oleifera and Morus alba against Foot and Mouth disease virus (FMDV) were determined using MTT assay (3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide). Eight different concentrations of each plant were evaluated. Cytotoxic and antiviral activity of each extract was evaluated as cell survival percentage and results were expressed as Means ± S.D. From the tested plant extracts, Azadirachta indica & Moringa oleifera exhibited cytotoxicity at 200 & 100 µ/ml respectively. In case of antiviral assay, Moringa oleifera showed potent antiviral activity (p<0.05) while Azadirachta indica showed significant antiviral activity in the range of 12.5-50 µ/ml & 50-100 µ/ml respectively. In contrast no anti-FMDV activity in the present study was observed with Morus alba, although all the tested concentrations were found to be safe.

Nanotoxicity of Inert Materials: The Case of Gold, Silver and Iron.

Nanotechnology has opened a new horizon of research in various fields including applied physics, chemistry, electronics, optics, robotics, biotechnology and medicine. In the biomedical field, nanomaterials have shown remarkable potential as theranostic agents. Materials which are considered inert are often used in nanomedicine owning to their nontoxic profile. At nanoscale, these inert materials have shown unique properties that differ from bulk and dissolved counterparts. In the case of metals, this unique behavior not only imparts paramount advantages but also confers toxicity due to their unwanted interaction with different cellular processes. In the literature, the toxicity of nanoparticles made from inert materials has been investigated and many of these have revealed toxic potential under specific conditions. The surge to understand underlying mechanism of toxicity has increased and different means have been employed to overcome toxicity problems associated with these agents. In this review, we have focused nanoparticles of three inert metallic materials i.e. gold, silver and iron as these are regarded as biologically inert in the bulk and dissolved form. These materials have gained wider research interest and studies indicating the toxicity of these materials are also emerging. Oxidative stress, physical binding and interference with intracellular signaling are the major role player in nanotoxicity and their predominance is highly dependent upon size, surface coating and administered dose of nanoparticles. Current strategies to overcome toxicity have also been reviewed in the light of recent literature. The authors also suggested that uniform testing standards and well-designed studies are needed to evaluate nanotoxicity of these materials that are otherwise considered as inert. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Toxicity Appraisal of Untreated Dyeing Industry Wastewater Based on Chemical Characterization and Short Term Bioassays.

Characterizing wastewaters only on a chemical basis may be insufficient owing to their complex nature. The purpose of this study was to assess toxicity of textile dyeing wastewater based on analytical techniques and short term toxicity based bioassays. In this study, screening of the fractionated wastewater through GC-MS showed the presence of phenols, phthalic acid derivatives and chlorpyrifos. Metal analysis revealed that chromium, arsenic and mercury were present in amounts higher than the wastewater discharge limits. Textile dyeing wastewater was found to be highly mutagenic in the Ames test. DNA damage in sheep lymphocytes decreased linearly with an increase in the dilution of wastewater. MTT assay showed that 8.3 percent v/v wastewater decreased cell survival percentage to 50 %. It can be concluded from this study that short term toxicity tests such as Ames test, in vitro comet assay, and cytotoxicity assays may serve as useful indicators of wastewater pollution along with their organic and inorganic chemical characterizations.

ANALGESIC, ANTIPYRETIC AND ANTI-INFLAMMATORY ACTIVITIES OF GREWIA ASIATICA FRUIT EXTRACTS IN ALBINO MICE.

The present study was aimed to assess biological (analgesic, antipyretic and anti-inflammatory) activities of methanolic and aqueous fruit extracts of Grewia asiatica. The study was performed on albino mice. Analgesic effect of the extracts was determined by acetic acid induced writhing. Antipyretic potential of the tested fruit extracts was assessed by brewer's yeast induced pyrexia. Carrageenan induced paw edema method was used to evaluate the anti-inflammatory activity. Both the extracts showed biological effects in a dose dependent fashion at doses 125 mg/kg, 250 mg/kg and 500 mg/kg orally. Analysis of variance (ANOVA) was used for data analysis and the values having p-value smaller than 0.05 were considered significant. Both the extracts had significant analgesic, antipyretic and anti-inflammatory activities.

Transforming growth factor-ß-induced differentiation of airway smooth muscle cells is inhibited by fibroblast growth factor-2.

In asthma, basic fibroblast growth factor (FGF-2) plays an important (patho)physiological role. This study examines the effects of FGF-2 on the transforming growth factor-ß (TGF-ß)-stimulated differentiation of airway smooth muscle (ASM) cells in vitro. The differentiation of human ASM cells after incubation with TGF-ß (100 pM) and/or FGF-2 (300 pM) for 48 hours was assessed by increases in contractile protein expression, actin-cytoskeleton reorganization, enhancements in cell stiffness, and collagen remodeling. FGF-2 inhibited TGF-ß-stimulated increases in transgelin (SM22) and calponin gene expression (n = 15, P < 0.01) in an extracellular signal-regulated kinase 1/2 (ERK1/2) signal transduction-dependent manner. The abundance of ordered α-smooth muscle actin (α-SMA) filaments formed in the presence of TGF-ß were also reduced by FGF-2, as was the ratio of F-actin to G-actin (n = 8, P < 0.01). Furthermore, FGF-2 attenuated TGF-ß-stimulated increases in ASM cell stiffness and the ASM-mediated contraction of lattices, composed of collagen fibrils (n = 5, P < 0.01). However, the TGF-ß-stimulated production of IL-6 was not influenced by FGF-2 (n = 4, P > 0.05), suggesting that FGF-2 antagonism is selective for the regulation of ASM cell contractile protein expression, organization, and function. Another mitogen, thrombin (0.3 U ml(-1)), exerted no effect on TGF-ß-regulated contractile protein expression (n = 8, P > 0.05), α-SMA organization, or the ratio of F-actin to G-actin (n = 4, P > 0.05), suggesting that the inhibitory effect of FGF-2 is dissociated from its mitogenic actions. The addition of FGF-2, 24 hours after TGF-ß treatment, still reduced contractile protein expression, even when the TGF-ß-receptor kinase inhibitor, SB431542 (10 µM), was added 1 hour before FGF-2. We conclude that the ASM cell differentiation promoted by TGF-ß is antagonized by FGF-2. A better understanding of the mechanism of action for FGF-2 is necessary to develop a strategy for therapeutic exploitation in the treatment of asthma.

Multilevel pharmacological manipulation of adenosine-prostaglandin E2/cAMP nexus in the tumor microenvironment: a 'two hit' therapeutic opportunity.

Novel trends in cancer treatment research are focused on targeting the tumor microenvironment, thereby developing chemo-immunotherapeutic strategies which not only directly kill tumor cells, but also trigger the anti-tumor immune effector responses. Ectonucleotidases (CD39 and CD73)-generated extracellular adenosine and cyclooxygenase-2 (COX2)-derived prostaglandin E2 (PGE2) are amongst the tumor microenvironmental factors that have emerged as attractive targets in this regard. Both comprise a pivotal axis in tumor progression and immune escape via autocrine and paracrine activation of a common intracellular signaling pathway, the cAMP-protein kinase A (PKA) pathway, in cancer and immune cells. In this review, we venture a potential and realistic strategy that this adenosine-PGE2/cAMP nexus is targetable at different levels, thereby pointing out a 'two hit' chemo-immunotherapeutic proposition: direct killing of tumor cells on one hand, and the rescuing of endogenous anti-tumor immune response on the other. The reviewed experimental, preclinical and clinical data provide the proof of concept that 'two hit' multilevel pharmacological manipulation of adenosine-E2/cAMP nexus is achievable within the tumor microenvironment.

Soluble laticifer proteins from Calotropis procera as an effective candidates for antimicrobial therapeutics.

Calotropis procera is a latex-producing plant with plenty of pharmacologically active compounds. The principal motivation behind this study was to separate and characterize laticifer proteins to check their antimicrobial potential. Laticifer proteins were separated by gel filtration chromatography (GFC) and investigated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The SDS-PAGE assay detected proteins of molecular weights of 10 to 30 kDa but most of them were in the range of 25 to 30 kDa. The soluble laticifer proteins (SLPs) were tested against Gram-positive bacteria i.e., Streptococcus pyogenes and Staphylococcus aureus whereas Escherichia coli and Pseudomonas aeruginosa were tested as Gram-negative bacteria, we determined a profound anti-bacterial activity of these proteins. In addition, SLPs were also investigated against Candida albicans via the agar disc diffusion method which also showed significant anti-fungal activity. SLP exhibited antibacterial activity against P. aeruginosa, E. coli, and S. aureus with a minimum inhibitory concentration (MIC) of 2.5 mg/mL for each, while MIC was found at 0.625 mg/mL for S. pyogenes and 1.25 mg/mL for C. albicans. Moreover, enzymatic activity evaluation of SLP showed the proteolytic nature of these proteins, and this proteolytic activity was greatly enhanced after reduction which might be due to the presence of cysteine residues in the protein structure. The activity of the SLPs obtained from the latex of C. procera can be associated with the involvement of enzymes either proteases or, protease inhibitors and/or peptides.

Isolation of alkaloidal and glycosidal fractions from leaves of Trigonella foenum-graecum L. cv. Desi indigenous to Pakistan for antiprostaglandin evaluation as substitute of nonsteroidal anti-inflammatory drugs.

ETHNOPHARMACOLOGICAL RELEVANCE: Trigonella foenum graecum (fenugreek) has been in use for a long time as a traditional medicine and natural food additive. The reported gastro-protective property makes it unique among other herbs. Seeds and leaves have been shown to exert significant antiatherogenic, antidiabetic, antianorexic, antioxidant, anticarcinogenic, antihyperlipidemic, galactogogue and anti-inflammatory effects in several animal and human models. But its use as a substitute for ulcerative nonsteroidal anti-inflammatory drugs needs to be confirmed. AIM OF THE STUDY: Nonsteroidal anti-inflammatory drugs (NSAIDs) are in common use in treating inflammation associated with a variety of ailments, fever and pain such as menstrual cramps, back pain, arthritic pain and headaches. Their toxicity profile includes the risk of severe gastro-intestinal adverse events like increased bleeding tendency, ulceration, perforation, etc. Conventional NSAIDs have also been reported to reduce the glomerular filtration rate (GFR) by affecting afferent arterioles in nephrons. Exacerbated potassium levels were noted in patients using NSAIDs concomitantly with antihypertensive drugs belonging to the angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) classes. In this context, the need of the hour is to discover and isolate new compounds from the reported medicinal plants for evaluation of antiprostaglandin potential and safety profile in terms of the hepato-renal system. These compounds may be used as substitutes for NSAIDs in the future management of inflammation and pain with therapeutic equivalency and organ safety. In this scenario, the present study aimed to assess the antiprostaglandin potential of alkaloidal and glycosidal fractions from the leaves of Trigonella foenum-graecum L. cv. Desi variety, indigenous to Pakistan, in albino mice along with safety profile. The herb has been used as folk medicine since ancient times for treating inflammation and pain. MATERIAL AND METHODS: Alkaloidal and glycosidal fractions were separated from a methanol extract of leaves of the fenugreek Desi variety. After separation of fractions, their subsiding effects on carrageenan-induced inflammation, air pouch exudate prostaglandin-E2 levels, Brewer's yeast induced pyrexia and acetic acid induced abdominal constrictions were assessed in adult male albino mice. The safety profile of fractions was assessed by measuring their effects on mice sera hepato-renal biomarkers. RESULT: Alkaloidal fraction of T. foenum Desi variety was found to be significantly effective in reducing inflammation, air pouch exudate PGE2 levels, fever (≤37 °C) and pain by inhibiting writhes (up to 96.58%) Gradual inhibition of paw edema was observed 1-6 h post-dose, with maximum reduction percentages of 62.82% and 62.57% for 100 mg and 200 mg, respectively. Both fractions did not disturb the normal physiology of the hepato-renal system by showing normal biomarker values. CONCLUSION: In summary, the results demonstrate the potent antiprostaglandin potential of the alkaloidal fraction of gastroprotective fenugreek "Desi" leaves with hepato-renal system safety and hence justify its use as a substitute for ulcerative nonsteroidal anti-inflammatory drugs.

Functional Studies of Cytogenotoxic Potential of Laticifer Proteins of Calotropis procera against Viral Disease.

Plant products are widely used for health and disease management. However, besides their therapeutic effects, some plants also have potential toxic activity. Calotropis procera is a well-known laticifer plant having pharmacologically active proteins playing a therapeutically significant role in curing diseases like inflammatory disorders, respiratory diseases, infectious diseases, and cancers. The present study was aimed to investigate the antiviral activity and toxicity profile of the soluble laticifer proteins (SLPs) obtained from C. procera. Different doses of rubber free latex (RFL) and soluble laticifer protein (ranging from 0.019 to 10 mg/mL) were tested. RFL and SLPs were found to be active in a dose-dependent manner against NDV (Newcastle disease virus) in chicken embryos. Embryotoxicity, cytotoxicity, genotoxicity, and mutagenicity of RFL and SLP were examined on chicken embryos, BHK-21 cell lines, human lymphocytes, and Salmonella typhimurium, respectively. It was revealed that RFL and SLP possess embryotoxic, cytotoxic, genotoxic, and mutagenic activity at higher doses (i.e., 1.25-10 mg/mL), while low doses were found to be safe. It was also observed that SLP showed a rather safer profile as compared to RFL. This might be due to the filtration of some small molecular weight compounds at the time of purification of SLPs through a dialyzing membrane. We suggest that SLPs could be used therapeutically against viral disorders but the dose should be critically monitored.

Pharmacological effect of Argyrolobium roseum (Camb.) Jaub & Spach extracts against lead-induced toxicity in rats.

Argyrolobium roseum (Camb.) Jaub & Spach (Papilionaceae) is a medicinal plant, cultivated in northern areas of Pakistan. The consumption of trace minerals (lead) is very toxic to the vital organs of the body, therefore the overcome of these minerals is very necessary. In this regard, this study aimed to assess the potential pharmacological effect of aqueous and ethanolic extract of Argyrolobium roseum (Camb.) Jaub & Spach against pb-induced oxidative stress, histological changes in Pb-induced rats' liver and kidney, and anti-inflammatory effect. The metal concentrations in liver and kidney homogenates were measured through atomic absorption spectrophotometer. The antioxidant activity was measured through DPPH and FRAP assay. Pb concentrations were significantly higher in liver and kidney homogenates after injection of Pb acetate was given intraperitoneally (45.2 ± 6.8 and 58.8 ± 7.9, respectively; p < .0001). The level of Pb in liver and kidney homogenates was significantly reduced by aqueous and ethanolic extracts of Argyrolobium roseum (Camb.) Jaub & Spach. The Pb + Aq-600 mg/kg-treated rats exhibited a protective effect on hepatocytes cells against Pb-induced liver injury and restored the cells of the kidney. Pb + Aq-600 mg/kg showed higher antioxidant activity as compared to other treated groups. The highest decreased MDA level was found in liver and kidney homogenate of Pb + Aq-600 mg/kg rats (11.2 ± 1.51 nmol/mg; p < .001) and GSH and CAT levels tended to normal after treatment of Pb + Aq-600 mg/kg in rats. The ALAD, ALT, AST, and ALP level were enhanced and tended to be normal after the Aq-400 and Aq-600 mg/kg treatment in Pb-exposed rats. The result showed that 600 mg/kg Aq + Pb exhibited significant (p < .001) anti-inflammatory activity. The findings of this study concluded that treatment of the aqueous extract of Argyrolobium roseum (Camb.) Jaub & Spach reduces the renal and hepatic damage in Pb-induced rats and it also decreases oxidative stress via improving antioxidant components.

Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy.

Non-steroidal anti-inflammatory drugs (NSAIDs) have received considerable importance in cancer chemoprevention over the last few years. They are now being considered as prospective candidates in cancer immunotherapy because of their striking immune-enhancing impact on various effector elements of anti-tumour immunity on one hand, and to augment the efficacy of different anti-cancer immunotherapeutic strategies on the other. This review specifically discusses the role of NSAIDs in anti-tumour immunity by describing their immunomodulatory effects on different immune cells including tumour-associated macrophages (TAM), dendritic cells (DC), natural killer (NK) cells, T effector cells, and T regulatory cells (Treg). Secondly, the therapeutic perspective of NSAIDs in combination with different anti-cancer immunotherapeutic approaches, in particular the cancer vaccines, tumour-specific monoclonal antibodies, and cytokine-based therapy, has been outlined. At the end, the impact of anti-inflammatories other than NSAIDs on tumour immunity and immunotherapy, and the immunopharmacological potential of selective E-prostanoid (EP) receptor antagonists with respect to cancer immunity have also been discussed briefly.

Exploration of potential ligands against cancer-causing transcription factor E2F3.

The transcription factor-based therapeutic approaches are the mainstay of current anticancer drug design options to develop highly selective agents with novel modes of action. In this paper, a homology model of DNA-binding domain of transcription factor E2F3 was generated according to X-ray structure of E2F4. As a first step of our proposed project aspired towards exploration of highly selective potential E2F3 ligands, we performed structure-based virtual screening of ZINC 3D chemical database by using Dock Blaster server. Then 31 compounds, selected by filtration step, were docked against the prominent DNA binding site residues of E2F3 model. Two of them have shown a promising interaction with respect to binding poses. The aim is to propose new active ligands against neoplasias characterized by overexpression of E2F3 transcription factor.

Niclosamide Modulates the Cellular and Humoral Immune Response in Balb/c Mice.

BACKGROUND: Niclosamide, a STAT3 inhibitor, is widely under investigation due to its anti-cancer properties. STAT3 also exhibits an exciting role in the immune responses. OBJECTIVE: This study aimed to evaluate the impact of niclosamide on immune response of mice. METHODS: Niclosamide was administered to balb/c mice. To evaluate cell-mediated immune response, a contact-hypersensitivity (CHS) test, cyclophosphamide-induced neutropenic assay, and carbon clearance test were performed, whereas a humoral immune response was evaluated by hemagglutination assay (HA) and mice lethality test. The concentration of TGF-ß1 was determined by enzyme-linked immunosorbent assay (ELISA) on murine peritoneal macrophages. RESULTS: In the CHS test, niclosamide caused a decrease in skin thickness, significantly exhibiting a decrease in inflammation. A highly significant decrease in overall leukocyte count (lymphocytes and neutrophils) was observed before and after cyclophosphamide injection as compared with the control group. However, only a highly significant decrease in the neutrophil percentage was observed. Niclosamide has decreased the phagocytic process immensely compared with the control. In the HA titer, niclosamide was found to reduce the antibodies' titer compared with the negative control group. In the mice lethality test, the treatment groups have shown an increase in the percentage of mortality. TGF-ß1 elevated in peritoneal macrophages when treated with niclosamide, in a dose-dependent manner. CONCLUSION: Niclosamide exerts potent immunomodulatory effects by significantly suppressing cell-mediated and humoral immune responses and increasing the levels of TGF-ß1 in mice. Niclosamide might be added as an adjuvant to immunosuppressive drugs for the treatment of autoimmune diseases.

Aspirin significantly decreases the nonopsonic phagocytosis and immunogenicity of macrophages in mice.

OBJECTIVE AND DESIGN: The effect of acetylsalicyclic acid (ASA) on the phagocytosis and immunogenicity of macrophages remains to be determined. MATERIAL OR SUBJECTS: BALB/c mice and peritoneal macrophages were used. TREATMENT: BALB/c mice were treated with ASA (0, 6, or 60 mg/kg/day) intraperitoneally for 1 week. METHODS: Flow cytometry and phagocytosis assay were employed. RESULTS: ASA significantly decreased cell numbers, nonopsonic phagocytosis, and immunogenicity as well as changing the phenotypes of peritoneal macrophages in vivo. After in vitro treatment with ASA, macrophages expressed low levels of MHC-II, CD80, and CD47 molecules, and showed significantly decreased phagocytosis. Importantly, ASA blocked the differentiation of macrophages from bone marrow cells in vitro as indicated by decreased macrophage cell numbers and phenotype alteration. CONCLUSIONS: The present study provides basic information on the direct effect of ASA on macrophages, supporting the potential application of ASA in patients with allo-grafts or autoimmune diseases.

Diphenhydramine and levofloxacin combination therapy against antimicrobial resistance in respiratory tract infections.

Background: Antibiotics are in use since decades to treat various infections caused by Gram-positive and Gram-negative bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. Diphenhydramine, an H1 receptor blocker possesses a weak antibiotic action but when combined with other antibiotics may potentiate their antibacterial activity. Materials & methods: This study investigated in vitro antibacterial activity of diphenhydramine when used alone and in combination with levofloxacin against methicillin-resistant S. aureus and P. aeruginosa. Results: The combined antibacterial effect of the drugs against bacteria showed a fractional inhibitory concentration index of ≤0.5, in other words, synergism. No cytotoxicity was observed as percentage cell viability was >50%. Conclusion: The combination of diphenhydramine and levofloxacin exerted antibacterial activity, and was not found to be cytotoxic when given in combination against P. aeruginosa and S. aureus.