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BACKGROUND: The ultrasound guided brachial plexus block is a precise technique of providing anaesthesia & post op analgesia in surgical procedures involving upper limb. This study was conducted to compare two doses of dexmedetomidine given as adjuvant to 0.5% ropivacaine in ultrasound guided brachial plexus block in upper limb surgeries. METHODS : This was a randomised control trial carried out in 60 patients, 18-60 years of age of both sexes posted for upper limb surgeries . Patients were randomly divided into two groups of 30 patients each. Group A received 0.5% Ropivacaine 25 mL plus 30 micrograms dexmedetomedine (0.3 mL) plus 4.7 mL distilled water and Group B received 0.5% Ropivacaine 25 mL plus 50 micrograms (0.5 mL) dexmedetomedine plus 4.5 mL distilled water. Patients were assesed for onset and duration of sensory and motor block, time of rescue analgesia, hemodynamic responses and complications or any side effects. RESULT : Onset of sensory and motor block in Group A was 10.07 ± 0.69 mins and 14.23 ± 0.77 mins respectively while in Group B was 7.47 ± 0.63 mins and 10.0 ± 0.83 mins respectively. Mean duration of sensory block in Group A was 654.40 ± 28.42 mins and in Group B was 942.0 ± 54.32 mins while mean duration of motor block in Group A was 537.03 ± 27.07 mins and Group B was 798.67 ± 67.84 mins. CONCLUSION : We concluded that, 50 micrograms of dexmedetomedine when compared with 30 micrograms of dexmedetomedine with 0.5% ropivacaine produced early onset of both sensory and motor block, longer duration of sensory and motor block and longer postoperative pain relief. [ABSTRACT FROM AUTHOR]

Purpose: Angiotensin-(1–12) [Ang-(1–12)] serves as a primary substrate to generate angiotensin II (Ang II) by angiotensin-converting enzyme and/or chymase suggests it may be an unrecognized source of Ang II-mediated microvascular complication in hypertension-mediated retinopathy. We investigated Ang-(1–12) expression and internalization in adult retinal pigment epithelial-19 (ARPE-19) cultured cells. We performed the internalization of Ang-(1–12) in ARPE-19 cells in the presence of a highly specific monoclonal antibody (mAb) developed against the C-terminal end of the Ang-(1–12) sequence. Methods: All experiments were performed in confluent ARPE-19 cells (passage 28–35). We employed high-performance liquid chromatography to purify radiolabeled, 125I-Ang-(1–12) and immuno-neutralization with Ang-(1–12) mAb to demonstrate Ang-(1–12)'s internalization in ARPE-19 cells. Internalization was also demonstrated by immunofluorescence (IF) method. Results: These procedures revealed internalization of an intact 125I-Ang-(1–12) in ARPE-19 cells. A significant reduction (∼53%, P < 0.0001) in 125I-Ang-(1–12) internalization was detected in APRE-19 cells in the presence of the mAb. IF staining experiments further confirms internalization of Ang-(1–12) into the cells from the extracellular culture medium. No endogenous expression was detected in the ARPE-19 cells. An increased intensity of IF staining was detected in cells exposed to 1.0 μM Ang-(1–12) compared with 0.1 μM. Furthermore, we found hydrolysis of Ang-(1–12) into Ang II by ARPE-19 cells' plasma membranes. Conclusions: Intact Ang-(1–12) peptide is internalized from the extracellular spaces in ARPE-19 cells and metabolized into Ang II. The finding that a selective mAb blocks cellular internalization of Ang-(1–12) suggests alternate therapeutic approaches to prevent/reduce the RPE cells Ang II burden. [ABSTRACT FROM AUTHOR]

The sedimentological/mineralogical characteristics of the aquifer material have been determined and their impact on groundwater chemistry is evaluated in the Aligarh district. It is found that 35 % of the aquifer is characterized by sand fraction containing (17–8) % of plagioclase and rock fragment (4–5%). Dominant aquifer material (silt and clay) fraction is dominated by plagioclase, K-feldspar, calcite, chlorite, kaolinite/mica, and halite. Spatial variation in relative positions and thickness of aquifer of silt, clay, and sandy layers resulting to particular hydro-chemical types. Major ions in groundwater shows a high degree of spatial variation along with multisource for the ions. Water quality index suggests that 22% of the water samples fall under the unsuitable category in the area characterized by aquifer material dominant with clay layers. Groundwater types in the area are dominated by Na+-Cl− and Ca2+ - HCO3−, Ca+2 Mg+ - HCO3− Ca+2 Mg+2 - Cl− (mixed type). Silicate weathering, Carbonates, salt dissolution, and base ion exchange are the major mechanisms that control the major ionic composition of the groundwater. It is saturated with calcite, dolomite, chalcedony, and Mg-silicate (Sepiolite). The unstable Speiolite under climate conditions prevails in the region rapidly change to smectite clay, which constitutes a major clay mineral of Indo-Gangetic alluvium. ANN (Artificial Neural Networking) analysis indicated that irrigation quality parameters Permeability Index (PI) and Na% are showing strong relation with selected parameters EC, and Na+ concentration. SAR values mostly depend on Na+, Mg+2 conc. and EC, while residual sodium carbonate (RSC) of groundwater can be predicted using Mg2+, HCO3−, and Ca2+ concentration in groundwater. [ABSTRACT FROM AUTHOR]

This study's goal is to use a Box–Behnken design [BBD] methodology to create a new reverse-phase high-performance liquid chromatography diode-array detection [RP-HPLC-DAD] method for the simultaneous quantification of Amitriptyline and Propranolol in tablet dosages. The amitriptyline and propranolol standard drug peaks were obtained using a C-18 column with a dimension of 4.6 × 100 mm and a particle size packing of 2.5 µm at the retention time of 5.328 and 7.48 min, respectively. The mobile phase composition was a 75:25 mixture of methanol and 0.1 percent orthophosphoric acid, flowing at 1.0 mL/min at 26 °C. The peaks were identified at 257 nm after injecting 20 µL of the sample. An assay of the marketed tablets was performed, and the result was 101.33 and 99.4% for amitriptyline and propranolol, respectively, when compared to the standard calibration curve. Forced degradation investigations, such as acid, base, H2O2, and neutral condition, were performed. The results for both medications in term of % degradation were as follows: amitriptyline (16.07, 91.92, 26.98, and 0.64) and propranolol (15.84, 11.52, 9.09, and 3.62). According to the ICH criteria, the findings of the validation parameters were within an acceptable range. The new RP-HPLC-DAD method with BBD application is easy, accurate, and time-saving. [ABSTRACT FROM AUTHOR]

Background Scalp defect repair can be done in a number of ways depending on the depth, site and size of the defects. Objective To study the various characteristics of patients presenting with scalp defects at Allama Iqbal Memorial Teaching Hospital, Sialkot and the reconstruction methods used in these patients. Methods 14 Patients with scalp defects underwent reconstruction with local flaps, skin grafting and primary closure. Results 10 men and 4 women participated in the study. Wound size varied from large (20-50cms), very large (50-100cm) and extremely large (>100cm). Defects were treated with primary closure, rotation flap, advancement flap and bipedicle flap. Most of the defects in men were traumatic in nature. Conclusion Strong knowledge of the anatomy of the scalp is required for obtaining successful results. [ABSTRACT FROM AUTHOR]

Mucormycosis is a progressive, opportunistic fungal infection with high risk of mortality. Rampant use of steroids in the treatment coronavirus disease 2019 creates a fertile environment for mucor growth. Perioperative challenges for the anesthesiologist in a patient having post-coronavirus disease mucormycosis include increased risks of arterial and venous thromboembolism, poor glycemic control and myocardial dysfunction, adrenal insufficiency from corticosteroid use, pulmonary dysfunction, and residual neuromuscular weakness. So, a complete biochemical workup of renal functions, hypothalamic-pituitary-adrenal axis, electrolyte, coagulation profile, optimization of blood glucose, and pulmonary function should be done. [ABSTRACT FROM AUTHOR]

The virulence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the aggressive nature of the disease has transformed the universal pace of research in the desperate attempt to seek effective therapies to halt the morbidity and mortality of this pandemic. The rapid sequencing of the SARS-CoV-2 virus facilitated identification of the receptor for angiotensin converting enzyme 2 (ACE2) as the high affinity binding site that allows virus endocytosis. Parallel evidence that coronavirus disease 2019 (COVID-19) disease evolution shows greater lethality in patients with antecedent cardiovascular disease, diabetes, or even obesity questioned the potential unfavorable contribution of angiotensin converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers as facilitators of adverse outcomes due to the ability of these therapies to augment the transcription of Ace2 with consequent increase in protein formation and enzymatic activity. We review, here, the specific studies that support a role of these agents in altering the expression and activity of ACE2 and underscore that the robustness of the experimental data is associated with weak clinical long-term studies of the existence of a similar regulation of tissue or plasma ACE2 in human subjects. [ABSTRACT FROM AUTHOR]

The quality of groundwater is determined in parts of Ramganga basin, Bareilly, UP, India. Spatial variation of all the major ions shows south-eastern increasing trend except chloride and sulphate. Groundwater in the area belongs to the Mg2+-Ca2+-HCO3− cation facies. The monsoonal rainfall changes the ionic abundance order from HCO3−>Cl−>NO3−>SO4−2> F− and Mg2+> Ca2+> K+>Na+ of pre-monsoon to HCO3−>Cl−> SO4−2>NO3−>F− and Na+> Mg2+> Ca2+> K+ of post-monsoon. Solute acquisition processes indicated that the rock weathering is the major mechanism of ions sources in groundwater. A coupled carbonate and silicate weathering type along with ion exchange processes are responsible for particular groundwater chemistry. Groundwater quality parameters were tested for drinking, irrigation and corrosion purposes. It is found that 8.5%, 26%, 49%, 14% and 3% of the samples fall under the excellent, good, poor, very poor and unsuitable category respectively. SAR, Na%, RSC and Kelly index suggests that groundwater is safe for irrigation purposes. But high TDS of few samples suggested the salinity hazard while using it for irrigation purposes. Low CR values indicated a lower degree of corrosion hazard to the underground metal pipelines in the area. [ABSTRACT FROM AUTHOR]

Proglacial streams play an important role in water–rock interaction due to different climatic conditions at different altitudes. The main objective of the present study is to analyze the variation of glacier hydrochemistry and sedimentation processes at different altitudes. The results show that the bed sediments in higher altitude streams are fine sand, poorly sorted, leptokurtic in nature and dominated with high proportion of feldspar and biotite. At lower altitude, the bed sediment is coarse sand, moderately sorted and platykurtic in nature with relatively high proportion of quartz. The high concentration of biotite and feldspar in silt/lay size fraction are responsible for high proportion of magnesium in Gangotri proglacier meltwater than others. Meltwater is slightly acidic and hydrochemical facies shows Ca+2–Mg+2–HCO3− type. The concentration of Ca+2, Mg+2, Na+, and K+ decreases with altitude due to dilution produced by augmentation of freshly monsoonal recharged groundwater from meadow and forest in downstream. The cation exchange, carbonate/silicate weathering and groundwater, subglacial water sources control the hydrochemistry of proglacial streams at lower altitude. [ABSTRACT FROM AUTHOR]

In the fields of chemical graph theory, topological index is a type of a molecular descriptor that is calculated based on the graph of a chemical compound. In this paper, M-polynomial OKn and OPn networks are computed. The M-polynomial is rich in information about degree-based topological indices. By applying the basic rules of calculus on M-polynomials, the first and second Zagreb indices, modified second Zagreb index, general Randić index, inverse Randić index, symmetric division index, harmonic index, inverse sum index, and augmented Zagreb index are recovered. [ABSTRACT FROM AUTHOR]

The Bhagirathi streams are a major source of fresh water in the form of glaciers meltwater streams and monsoonal phenomena. The watersheds of the Bhagirathi basin is trending towards water chemistry as well as changing morphological and land cover features due to the climatic and anthropogenic activity. To understand seasonal hydrochemistry and the impact of watershed morphology a total of 32 stream water samples collected during post and pre-monsoon seasons. The bicarbonate is the most dominant ion in the streams water followed by Na+, Ca+2, SO4−2, Cl−, SiO2, K+, and Mg+2. The results were found that HCO3− is in very good correlation with the base cations Ca+2, Mg+2 and Na+ in both pre and post-monsoon seasons. The higher concentration of HCO3− in Bhagirathi stream water and its positive correlation with Ca+2 and Mg+2 indicates that their main source comes from the dissolution of carbonates. Most of the hydro-chemical parameters (EC, pH) and ions (Ca+2, Mg+2, Na+, K+, HCOf−, SO4−2, Cl−, and F−) indicated a relationship with morphometric and land cover and these parameters vary with the season. It is observed that elevation, relief, basin length, area, and perimeter impact on stream water chemistry. Due to the processes of chemical weathering, mixing of the groundwater, snow/glacier meltwater, and surface water components responsible for the seasonal variation in the hydro-chemistry of streams. Impact of agriculture land is more dominant than any land cover followed by barren land and glacier cover that influence the hydrochemistry of streams. [ABSTRACT FROM AUTHOR]

Angiotensin processing peptidases (carboxypeptidase A (CPA) and chymase) are stored in cardiac mast cell (MC) secretory granules in large quantity and are co-released into the extracellular environment after activation/degranulation. In the human heart, chymase is primarily responsible for angiotensin II (Ang II) generation from the alternate substrate angiotensin-(1–12) (Ang-(1–12)). We investigated the individual and combined hydrolytic specificity of CPA and chymase enzymes (1:1 and 1:⅓ ratio) in the processing of the human Ang-(1–12) (hAng-(1–12)) substrate. To determine the K m and V max , the CPA and recombinant human chymase (rhChymase) enzymes were incubated with increasing concentrations of hAng-(1–12) substrate (0–300 μM). We found that CPA alone sequentially metabolized hAng-(1–12) substrate into angiotensin-(1–9) (Ang-(1–9), 53%), Ang II (22%) and angiotensin-(1–7) (Ang-(1–7), 11%) during a 15 min incubation. In the presence of rhChymase alone, 125I-hAng-(1–12) was directly metabolized into Ang II (89%) and no further hydrolysis of Ang II was detected. In the presence of both CPA + rhChymase enzymes (1:1 or 1:⅓ ratio), the amount of Ang II formation from 125I-hAng-(1–12) within a 5 min incubation period were 68% or 65%, respectively. In the presence of both (CPA + rhChymase), small amounts of Ang-(1–9) and Ang-(1–7) were generated from 125I-hAng-(1–12). The K m and V max values were 150 ± 5 μM and 384 ± 23 nM/min/mg of CPA and 40 ± 9 μM and 116 ± 20 nM/min/mg of rhChymase. The catalytic efficiency (V max /K m ratio) was higher for rhChymase/hAng-(1–12) compared to CPA/hAng-(1–12). Compared to CPA, chymase has a much higher affinity to hydrolyze the hAng-(1–12) substrate directly into Ang II. In addition, Ang II and Ang-(1–7) are the end products of chymase and CPA, respectively. Overall, our findings suggest that the Ang II generation from hAng-(1–12) is primarily mediated by chymase rather than CPA. • Mast cell peptidases (CPA and chymase) hydrolyze the human Ang-(1–12) substrate differently. • CPA alone hydrolyzed the human Ang-(1–12) substrate into Ang-(1–9), Ang II and Ang-(1–7). Chymase alone hydrolyzed the human Ang-(1–12) substrate directly into Ang II. • In the presence of both enzymes (CPA and chymase), Ang-(1–12) rapidly metabolized into Ang II. • Compared to CPA, chymase has higher affinity to hydrolyze the Ang-(1–12) substrate directly into Ang II. • Selective inhibition of chymase may provide greater benefit in the management of adverse cardiac remodeling. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency of hyperuricemia in acute ischemic stroke. Study Design: Cross sectional study. Place and Duration of Study: Medical Unit, Pakistan Air Forces Hospital, Mushaf Sargodha, from Aug 2015 to Jan 2016. Methodology: A total of 125 patients were included in this study that fulfils the inclusion criteria, ischemic stroke on CT scan brain plain (hypo dense area) presented to hospital within 24 hours. Patients with transient ischemic attack (TIA), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), space occupying lesion (SOL) on neuroimaging (CT scan) and with diagnosed Autoimmune or connective tissue disorders were excluded. Acute ischemic stroke was confirmed by neuroimaging (CT scan brain non contrast) reported by consultant Radiologist (FCPS Radiology) and uric acid level was measured within hospital lab with photometry using the diagnostic kit for quantification of uric acid prepared by (Pars Azmoon Company) and was verified by consultant pathologist. All information and reports were collected on proforma. Results: Age range in this study was from 30-90 years with mean age 60.832 ± 12.01 years and mean uric acid level was 5.773 ± 1.95 mg/dl. Majority of the patients were male (86.4%). Hyperuricemia was seen in 40 (32%) patients. Conclusion: Prevalence of hyperuricemia in patients with acute stroke is significantly higher than normal population. [ABSTRACT FROM AUTHOR]

The aim of this study was to formulate and evaluate acrylic acid‐based topical hydrogel patches of mupirocin for new pharmaceutical controlled release application. These cross‐linked hydrogel patches were synthesized by modified aqueous‐based polymerization technique. Acrylic acid was cross‐linked with 2‐acrylamido‐2‐methylpropanesulfonic acid (AMPS) with the help of cross‐linker N,N‐methylenebisacrylamide (MBA). Hydrogel patches were characterized by FTIR, TGA, DSC, SEM, swelling behavior, in vitro percent drug release at different pH, permeation across skin, ex vivo drug retention study, and irritation evaluation of mupirocin‐loaded hydrogels. Developed patches were spherical, thick, adhesive and with good elastic strength. FTIR confirmed the cross‐linking and formation of new structure having appropriate characteristics needed for controlled release delivery system. Dug (mupirocin) release through rabbit's skin was evaluated by Franz diffusion cell and up to 3,991.95 μg/L.5 cm2 was permeated, and drug retention in skin revealed substantial retention up to 1,261 μg/L.5 cm2. Formulated hydrogel patches were nonirritant to the skin up to 48 hr as validated by Draize patch test. Enhanced retention of drug in skin demonstrated good potential of topical delivery for skin bacterial infections. [ABSTRACT FROM AUTHOR]

The relatively low efficacy of ACE-inhibitors in the treatment of heart failure in women after estrogen loss may be due to their inability to reach the intracellular sites at which angiotensin (Ang) II is generated and/or the existence of cell-specific mechanisms in which ACE is not the essential processing pathway for Ang II formation. We compared the metabolic pathway for Ang II formation in freshly isolated myocytes (CMs) and non-myocytes (NCMs) in cardiac membranes extracted from hearts of gonadal-intact and ovariectomized (OVX) adult WKY and SHR rats. Plasma Ang II levels were higher in WKY vs. SHR (strain effect: WKY: 62 ± 6 pg/ml vs. SHR: 42 ± 9 pg/ml; p < 0.01), independent of OVX. The enzymatic activities of chymase, ACE, and ACE2 were higher in NCMs versus CMs, irrespective of whether assays were performed in cardiac membranes from WKY or SHR or in the presence or absence of OVX. E2 depletion increased chymase activity, but not ACE activity, in both CMs and NCMs. Moreover, cardiac myocyte chymase activity associated with diastolic function in WKYs and cardiac structure in SHRs while no relevant functional and structural relationships between the classic enzymatic pathway of Ang II formation by ACE or the counter-regulatory Ang-(1-7) forming path from Ang II via ACE2 were apparent. The significance of these novel findings is that targeted cell-specific chymase rather than ACE inhibition may have a greater benefit in the management of HF in women after menopause. [ABSTRACT FROM AUTHOR]

Carbon sequestration study was conducted in grazed and in un-grazed sites at Pabbi hills Kharian, District Gujarat, Pakistan. The study area was surveyed and homogeneous sites for conducting experiment were selected for grazed and un-grazed range land at Pabbi hills Kharian, District Gujarat, Pakistan. Carbon is played a vital role in the green house gases. Carbon sequestration during the photosynthesis process via plant biomass is the extent of this atmospheric gas. An experiment the data for above and below phytomass for grazed and un-grazed range land was collected and carbon pool was estimated by Wet Combustion and Dry Combustion method. Four transect lines were drawn in each experimental plot. Twenty four samples of each experimental plot were collected with the help of ADC one m 2 quadrate methods, weighed and then oven dried at 60 oC to find out the dry weight for above pytomass carbon Mg C ha-1 (Brown and Lugo, 1982). Similarly, the same 1 m2 quadrate area was dug up to the depth of root zone for each grass and the root portion was separated, weighed, oven dried at 60 Co for estimating below ground pytomass carbon Mg C ha-1. Carbon pool in above ground phtyomass was 0.08 MgCha-1 while below ground phytomass carbon was estimated as 0.05 MgCha-. In grazed and un-grazed sites, the SOC (%) MgCha-1 decreased depth wise as well as in total carbon MgCha-1. In grazed site, the carbon decreased due to their shallow roots habit and also least portion of phytomass was left behind on the soil surface. Therefore, maximum carbon was leached down into soil. Similarly in un-grazed site, as their above portion of grass was not so grazed, but the carbon was leached into soil due to their shallow roots all the carbon leached down into soil. The carbon sequestration in underground and the aerial phytomass depends upon the management practices, climate and response of different species. [ABSTRACT FROM AUTHOR]

We showed previously that rat angiotensin-(1-12) [Ang-(1-12)] is metabolized by chymase and angiotensin converting enzyme (ACE) to generate Angiotensin II (Ang II). Here, we investigated the affinity of cardiac chymase and ACE enzymes for Ang-(1-12) and Angiotensin I (Ang I) substrates. Native plasma membranes (PMs) isolated from heart and lung tissues of adult spontaneously hypertensive rats (SHR) were incubated with radiolabeled 125 I-Ang-(1-12) or 125 I-Ang I, in the absence or presence of a chymase or ACE inhibitor (chymostatin and lisinopril, respectively). Products were quantitated by HPLC connected to an in-line flow-through gamma detector. The rate of 125 I-Ang II formation from 125 I-Ang-(1-12) by chymase was significantly higher (heart: 7.0 ± 0.6 fmol/min/mg; lung: 33 ± 1.2 fmol/min/mg, P < 0.001) when compared to 125 I-Ang I substrate (heart: 0.8 ± 0.1 fmol/min/mg; lung: 2.1 ± 0.1 fmol/min/mg). Substrate affinity of 125 I-Ang-(1-12) for rat cardiac chymase was also confirmed using excess unlabeled Ang-(1-12) or Ang I (0–250 μM). The rate of 125 I-Ang II formation was significantly lower using unlabeled Ang-(1-12) compared to unlabeled Ang I substrate. Kinetic data showed that rat chymase has a lower K m (64 ± 6.3 μM vs 142 ± 17 μM), higher V max (13.2 ± 1.3 μM/min/mg vs 1.9 ± 0.2 μM/min/mg) and more than 15-fold higher catalytic efficiency (ratio of V max /K m ) for Ang-(1-12) compared to Ang I substrate, respectively. We also investigated ACE mediated hydrolysis of 125 I-Ang-(1-12) and 125 I-Ang I in solubilized membrane fractions of the SHR heart and lung. Interestingly, no significant difference in 125 I-Ang II formation by ACE was detected using either substrate, 125 I-Ang-(1-12) or 125 I-Ang I, both in the heart (1.8 ± 0.2 fmol/min/mg and 1.8 ± 0.3 fmol/min/mg, respectively) and in the lungs (239 ± 25 fmol/min/mg and 248 ± 34 fmol/min/mg, respectively). Compared to chymase, ACE-mediated Ang-(1-12) metabolism in the heart was several fold lower. Overall our findings suggest that Ang-(1-12), not Ang I, is the better substrate for Ang II formation by chymase in adult rats. In addition, this confirms our previous observation that chymase (rather than ACE) is the main hydrolyzing enzyme responsible for Ang II generation from Ang-(1-12) in the adult rat heart. [ABSTRACT FROM AUTHOR]

Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions. [ABSTRACT FROM AUTHOR]

L7802 --> 954.1 --> Introduction: The characterization, by this laboratory, of angiotensin‐(1‐12) [Ang‐(1‐12)] as a primary angiotensin II (Ang II)‐forming substrate may be an unrecognized source of Ang II‐mediated microvascular complication in hypertension‐mediated retinopathy. We found that the plasma Ang‐(1‐12) level was 12‐66‐fold higher when compared to the angiotensin I in normal human subjects. For the first time, we investigated the endogenous expression and incorporation of Ang‐(1‐12) in cultured adult retinal pigment epithelial‐19 (ARPE‐19) cells. We also investigated the internalization of Ang‐(1‐12) in the presence of a highly specific monoclonal antibody (mAb) that was developed by us against the C‐terminus of the human Ang‐(1‐12) sequence. Method: ARPE‐19 cells (passage 28‐30) were grown to post‐confluence in 10% serum supplemented DMEM/F12 medium for 2‐3 days. An immunofluorescence (IF) staining was performed to detect the internalized Ang‐(1‐12) using the human Ang‐(1‐12) mAb (1:5000 dilution) and the Alexa Flour 488 secondary antibody (1:1000 dilution). Internalization was also confirmed in ARPE‐19 using radiolabeled Ang‐(1‐12) [125I‐Ang‐(1‐12), purity >99%] in the presence and absence of the mAb by HPLC. For this, the APRE‐19 cells were incubated (4 h) with Ang‐(1‐12) alone or Ang‐(1‐12) + mAb. Afterward, cells were washed and harvested in isotonic buffer. The lysed cells were centrifuged at 28,000 g and the membrane pellet and supernatants (cytosolic fractions) were counted on a gamma counter. The cytosolic fractions were further analyzed by HPLC using a C18 column to confirm the internalization of intact Ang‐(1‐12) sequence. Results: Our IF staining shows that Ang‐(1‐12) is endogenously expressed in ARPE‐19 cells. Further, an increased intensity of staining was detected in ARPE‐19 cells exposed to Ang‐(1‐12) (100 nM). High Ang‐(1‐12) radiolabeled counts were detected in the cytosolic fractions (3.1% of the total loaded radiolabeled) and very low counts in the membrane pellet (0.2%). We found that the internalization of 125I‐Ang‐(1‐12) was significantly decreased (~40%, P<0.0001) in the presence of the human Ang‐(1‐12) mAb (Fig. 1). The detection of a large peak (88%) of 125I‐Ang‐(1‐12) in the cytosolic fraction in the HPLC chromatogram further confirms that the intact Ang‐(1‐12) sequence is internalized by the cells (Fig. 2). Conclusions: Ang‐(1‐12) is internalized by ARPE‐19 cells from extracellular spaces of the retina and the internalization of Ang‐(1‐12) decreased following exposure to the human Ang‐(1‐12) mAb. Overall our data suggests the human Ang‐(1‐12) mAb may be used as a novel therapeutic agent to prevent circulating Ang‐(1‐12) internalization into the retinal cells and subsequently reduce the intracellular generation of the Ang II from the Ang‐(1‐12) substrate. [ABSTRACT FROM AUTHOR]

Simultaneous estimation of rilpivirine (RLVN) and dolutegravir (DTGR) in bulk and tablet dosage forms via RP-HPLC-PDA with a Box–Behnken design (BBD) has been performed in this study to develop a fast, precise, timely and cost-saving method for estimating RLVN and DTGR in bulk and tablet dosage forms. The chromatographic conditions were optimized via the BBD, and the developed method was validated according to the ICH guidelines. Additionally, forced degradation studies were also conducted. RLVN and DTGR peaks were observed at retention times of 2.167 and 2.716 min, respectively, in a 6-min runtime. Kromasil 150 mm× 4.6 mm, 5 µm C 18 column was used. The flow rate of the mobile phase was 1.0 mL/min at a temperature of 30 °C. The mobile phase composition was a 0.1% OPA buffer and acetonitrile (ACN) in a 60:40 ratio. Elutes were measured at 260 nm (max) after being injected in a sample volume of 10 µL. The assay result of the marketed tablet was 99.19% and 99.09% for RLVN and DTGR, respectively. The results of forced degradation studies in different chemical environments conditions such as acid, base, dry heat, photo-stability, neutral, and oxidation conditions were observed for RLVN (5.96, 4.79, 3.27, 2.36, 0.99, and 4.35 in percentage degradation) and DTGR (5.67, 4.44, 4.09, 1.81, 0.43, and 4.28 in percentage degradation). The results of the validation parameters were within an acceptable range. The newly formed RP-HPLC-PDA method is novel, fast, precise, time-saving, and cost-effective. [ABSTRACT FROM AUTHOR]

Lessons learned from the characterization of the biological roles of Ang-(1-7) [angiotensin-(1-7)] in opposing the vasoconstrictor, proliferative and prothrombotic actions of AngII (angiotensin II) created an underpinning for a more comprehensive exploration of the multiple pathways by which the RAS (renin-angiotensin system) of blood and tissues regulates homoeostasis and its altered state in disease processes. The present review summarizes the progress that has been made in the novel exploration of intermediate shorter forms of angiotensinogen through the characterization of the expression and functions of the dodecapeptide Ang-(1-12) [angiotensin-(1-12)] in the cardiac production of AngII. The studies reveal significant differences in humans compared with rodents regarding the enzymatic pathway by which Ang-(1-12) undergoes metabolism. Highlights of the research include the demonstration of chymase-directed formation of AngII from Ang-(1-12) in human left atrial myocytes and left ventricular tissue, the presence of robust expression of Ang-(1-12) and chymase in the atrial appendage of subjects with resistant atrial fibrillation, and the preliminary observation of significantly higher Ang-(1-12) expression in human left atrial appendages. [ABSTRACT FROM AUTHOR]

Since angiotensin-(1-12) [Ang-(1-12)] is a non-renin dependent alternate precursor for the generation of cardiac Ang peptides in rat tissue, we investigated the metabolism of Ang-(1-12) by plasma membranes (PM) isolated from human atrial appendage tissue from nine patients undergoing cardiac surgery for primary control of atrial fibrillation (MAZE surgical procedure). PM was incubated with highly purified 125I-Ang-(1-12) at 37°C for 1 h with or without renin-angiotensin system (RAS) inhibitors [lisinopril for angiotensin converting enzyme (ACE), SCH39370 for neprilysin (NEP), MLN-4760 for ACE2 and chymostatin for chymase; 50 μM each]. 125I-Ang peptide fractions were identified by HPLC coupled to an inline γ-detector. In the absence of all RAS inhibitor, 125I-Ang-(1-12) was converted into Ang I (2±2%), Ang II (69±21%), Ang-(1-7) (5±2%), and Ang-(1-4) (2±1%). In the absence of all RAS inhibitor, only 22±10% of 125I-Ang-(1-12) was unmetabolized, whereas, in the presence of the all RAS inhibitors, 98±7% of 125I-Ang-(1-12) remained intact. The relative contribution of selective inhibition of ACE and chymase enzyme showed that 125I-Ang-(1-12) was primarily converted into Ang II (65±18%) by chymase while its hydrolysis into Ang II by ACE was significantly lower or undetectable. The activity of individual enzyme was calculated based on the amount of Ang II formation. These results showed very high chymase-mediated Ang II formation (28±3.1 fmol×min-1×mg-1, n = 9) from 125I-Ang-(1-12) and very low or undetectable Ang II formation by ACE (1.1±0.2 fmol×min-1×mg-1). Paralleling these findings, these tissues showed significant content of chymase protein that by immunocytochemistry were primarily localized in atrial cardiac myocytes. In conclusion, we demonstrate for the first time in human cardiac tissue a dominant role of cardiac chymase in the formation of Ang II from Ang-(1-12). [ABSTRACT FROM AUTHOR]

Background: Angiotensin-(1-12) [Ang-(1-12)] functions as an endogenous substrate for the productions of Ang II and Ang- (1-7) by a non-renin dependent mechanism. This study evaluated whether Ang-(1-12) is incorporated by neonatal cardiac myocytes and the enzymatic pathways of 125I-Ang-(1-12) metabolism in the cardiac myocyte medium from WKY and SHR rats. Methodology/Principal Findings: The degradation of 125I-Ang-(1-12) (1 nmol/L) in the cultured medium of these cardiac myocytes was evaluated in the presence and absence of inhibitors for angiotensin converting enzymes 1 and 2, neprilysin and chymase. In both strains uptake of 125I-Ang-(1-12) by myocytes occurred in a time-dependent fashion. Uptake of intact Ang-(1-12) was significantly greater in cardiac myocytes of SHR as compared to WKY. In the absence of renin angiotensin system (RAS) enzymes inhibitors the hydrolysis of labeled Ang-(1-12) and the subsequent generation of smaller Ang peptides from Ang-(1-12) was significantly greater in SHR compared to WKY controls. 125I-Ang-(1-12) degradation into smaller Ang peptides fragments was significantly inhibited (90% in WKY and 71% in SHR) in the presence of all RAS enzymes inhibitors. Further analysis of peptide fractions generated through the incubation of Ang-(1-12) in the myocyte medium demonstrated a predominant hydrolytic effect of angiotensin converting enzyme and neprilysin in WKY and an additional role for chymase in SHR. Conclusions/Significance: These studies demonstrate that neonatal myocytes sequester angiotensin-(1-12) and revealed the enzymes involved in the conversion of the dodecapeptide substrate to biologically active angiotensin peptides. [ABSTRACT FROM AUTHOR]

Evidence of differences in bioavailability from different oral formulations of the same therapeutic agents had become obvious by the early 1960s. The consequent 40 years have produced the body of scientific belief, debate, and policy on the subject of bioequivalence. The motivating force behind many of these events has been the continued interest of the food and drug administration (FDA) to improve the manner in which these studies are conducted, the quality of the data generated from such studies, and the methods by which they are evaluated. Bioanalytical data used to support regulatory submission needs to be accurate and reproducible. In order to have confidence in the reliability of the data, it is important that the analytical method used to generate it is well characterized and fully validated. However, bioavailability assessment (BA) and bioequivalence (BE) studies are necessary in filing of the data towards the drug approval. This review article describes the methods for assessing bioavailability and bioequivalence; and bioanalytical approaches of pharmaceuticals in vivo and in vitro and also a waiver of BA/BE studies based on the biopharmaceutical classification (BCS) system. [ABSTRACT FROM AUTHOR]

Abstract: The environmental carcinogen 5-methylchrysene (5MC) can be activated to mutagenic metabolites by several isozymes of cytochrome P-450 (CYP). The resulting reactive diol-epoxides can be detoxified via conjugation by glutathione S-transferases (GST). We investigated whether expression of human glutathione S-transferase P1 (hGSTP1) would differentially protect cells against the cytotoxicity or mutagenicity of 5MC or its 1,2-dihydrodiol intermediate (5MC-1,2-diol) in V79MZ cells with activation via stably transfected human CYP1B1 (hCYP1B1) as compared to activation by human CYP1A1 (hCYP1A1). The parent compound 5MC was only 2-fold more cytotoxic in the CYP-expressing cell lines than in the V79MZ parental cell line, while 5MC-1,2-dihydrodiol was more than 30-fold more cytotoxic in CYP-transfected cells compared to V79MZ cells. Cells co-expressing either hCYP1B1 or hCYP1A1 together with hGSTP1 were 2-fold less sensitive to 5MC or 5MC-1,2-diol cytotoxicity than their CYP-only parent lines. The 5MC was highly mutagenic with similar potency in both hCYP-transfected cell lines, while 5MC-1,2-diol was 2-fold more mutagenic in hCYP1B1-transfected cells as compared to hCYP1A1 cells. Coexpression of hGSTP1 with either hCYP reduced 5MC or 5MC-1,2-diol mutagenicity by 1.4–4.5-fold compared to the corresponding hCYP-only expressing cell lines. The greater protection against mutagenicity of 5MC is in contrast to our previous studies in which we found greater protection by hGSTP1 against cytotoxicity than mutagenicity of benzo[a]pyrene in cells co-expressing hCYP1A1. Protection against mutagenicity by hGSTP1 was greater with activation of either compound by hCYP1B1 than with hCYP1A1 activation. These studies show that the relative efficacy of protection by hGSTP1 against mutagenicity of 5MC or 5MC-1,2-diol is in part determined by the specific CYP pathway that catalyzes activation to the toxic or mutagenic metabolites. [Copyright &y& Elsevier]

Background. The activity of the organic anion transporter 1 (OAT1) has been implicated recently in the basolateral uptake of thiol conjugates of inorganic mercury in renal proximal tubular cells. However, very little is known about the role of OAT1 in the renal epithelial transport of organic forms of mercury, such as methylmercury (CH3Hg+), especially when it is in the form of the cysteine (Cys) S-conjugate of methylmercury (CH3Hg-Cys), which is believed to be a biologically relevant form of mercury. Methods. Accordingly, the present study, was designed to characterize the transport of CH3Hg-Cys in Madin-Darby canine kidney (MDCK) cells transfected stably with the human isoform of OAT1 (hOAT1) and in proximal tubular–derived NRK-52E cells. Results. Data on saturation kinetics, time dependency, substrate specificity, and temperature dependency demonstrate that CH3Hg-Cys is transported by hOAT1. Substrate-specificity data from the control cells also show that CH3Hg-Cys is a substrate of one or more transporter(s) that is/are not hOAT1. Additional findings indicate that at least one amino acid transport system is involved in the uptake of CH3Hg-Cys in MDCK cells. Furthermore, in the presence of cytotoxic concentrations of CH3Hg-Cys, rates of survival were lower in hOAT1-transfected cells than in wild-type control cells. Conclusion. The present data demonstrate clearly that CH3Hg-Cys is indeed a transportable substrate of OAT1. Moreover, the collective findings from the MDCK cells and NRK-52E cells infer that CH3Hg-Cys is a likely transportable mercuric species in proximal tubular epithelial cells that is taken up in vivo by both OAT1 and amino acid transporters. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is an industrial and environmental pollutant that affects adversely a number of organs in humans and other mammals, including the kidneys, liver, lungs, pancreas, testis, and placenta. The liver and kidneys, which are the primary organs involved in the elimination of systemic Cd, are especially sensitive to the toxic effects of Cd. Because Cd ions possess a high affinity for sulfhydryl groups and thiolate anions, the cellular and molecular mechanisms involved in the handling and toxicity of Cd in target organs can be defined largely by the molecular interactions that occur between Cd ions and various sulfhydryl-containing molecules that are present in both the intracellular and extracellular compartments. A great deal of scientific data have been collected over the years to better define the toxic effects of Cd in the primary target organs. Notwithstanding all of the new developments made and information gathered, it is surprising that very little is known about the cellular and molecular mechanisms involved in the uptake, retention, and elimination of Cd in target epithelial cells. Therefore, the primary purpose of this review is to summarize and put into perspective some of the more salient current findings, assertions, and hypotheses pertaining to the transport and handling of Cd in the epithelial cells of target organs. Particular attention has been placed on the molecular mechanisms involved in the absorption, retention, and secretion of Cd in small intestinal enterocytes, hepatocytes, and tubular epithelial cells lining both proximal and distal portions of the nephron. The purpose of this review is not only to provide a summary of published findings but also to provide speculations and testable hypotheses based on contemporary findings made in other areas of research, with the hope that they may promote and serve as the impetus for future investigations designed to define more precisely the cellular mechanisms involved in the transport and handling of Cd within the body. [Copyright &y& Elsevier]

Many modes of action for arsenic carcinogenesis have been proposed, but few theories have a substantial mass of supporting data. Three stronger theories of arsenic carcinogenesis are production of chromosomal abnormalities, promotion of carcinogenesis and oxidative stress. This article presents the oxidative stress theory along with some supporting experimental data. In the area of which arsenic species is causually active, recent data have suggested that trivalent methylated arsenic metabolites, particularly monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), have a great deal of biological activity. Some evidence now indicates that these trivalent, methylated, and relatively less ionizable arsenic metabolites may be unusually capable of interacting with cellular targets such as proteins and even DNA. Thus for inorganic arsenic, oxidative methylation followed by reduction to trivalency may be a activation, rather than a detoxification pathway. This would be particularly true for arsenate. In forming toxic and carcinogenic arsenic species, reduction from the pentavalent state to the trivalent state may be as or more important than methylation of arsenic. [Copyright &y& Elsevier]

Both dimethylarsinic acid (DMA(V)) and dimethylarsinous acid (DMA(III)) release iron from human liver ferritin (HLF) with or without the presence of ascorbic acid. With ascorbic acid the rate of iron release from HLF by DMA(V) was intermediate (3.37 nM/min, P<0.05) and by DMA(III) was much higher (16.3 nM/min, P<0.001). No pBR322 plasmid DNA damage was observed from in vitro exposure to arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)) or DMA(V) alone. DNA damage was observed following DMA(III) exposure; coexposure to DMA(III) and HLF caused more DNA damage; considerably higher amounts of DNA damage was caused by coexposure of DMA(III), HLF and ascorbic acid. Diethylenetriaminepentaacetic acid (an iron chelator), significantly inhibited DNA damage. Addition of catalase (which can increase Fe2+ concentrations) further increased the plasmid DNA damage. Iron-dependent DNA damage could be a mechanism of action of human arsenic carcinogenesis. [Copyright &y& Elsevier]

The dodecapeptide angiotensin-(1–12) [Ang-(1–12)] functions as an intracrine/paracrine substrate for local production of angiotensin II. We developed a reliable and specific radioimmunoassay (RIA) method for the measurement of Ang-(1–12) in human plasma and urine using an affinity purified antibody fraction directed towards the C-terminus of the human Ang-(1–12) sequence. The RIA method was applied to quantify the Ang-(1–12) in plasma and urine collected from thirty-four human subjects (29 treated with antihypertensive medicines and 5 untreated patients). Plasma Ang-(1–12) level was significantly higher (P < 0.05) in patients with systolic blood pressure ≥140 mm Hg (n = 10) compared to the group with systolic blood pressure <140 mm Hg (n = 24). No significant difference (P = 0.22) was found in spot urine between the groups. Our study also shows that the polyclonal antibody neutralizes the cleavage sites of the human Ang-(1–12) from recombinant human chymase (rhChymase) and serum angiotensin converting enzyme (ACE) mediated Ang II generating hydrolysis. Overall, this newly developed RIA method is reliable and applicable to accurately quantify the Ang-(1–12) level in clinical samples (plasma and urine). Further, our in vitro neutralization study suggests that the anti-Ang-(1–12)-antibody might be used as an in vivo therapeutic agent for preventing Ang-(1–12)/Ang II-mediated hypertension and organ damage. [ABSTRACT FROM AUTHOR]

The nonlinear Schrödinger–Poisson equation with gravitational potential field is examined, along with its many soliton interactions and travelling wave solutions. By applying Hirota Bilinear scheme, we will give a brief study on transformation of solitons, also by Sine–Gordon expansion scheme solitary travelling wave solutions will be obtained in terms of trigonometric and hyperbolic functions. The innovative Hirota bilinear method is a powerful and standard technique, play a crucial role in producing soliton solutions as well as lump solutions. With the assistance of this method one can transformed integrable equation into Hirota bilinear form under dependent variable transformation. Soliton solutions obtained by Hirota bilinear method are significant in mathematical physics, may be superimposed in fibers. These solitons are applicable in optical communications, which enable to produce faster, richer, more secure and more flexible communication systems. Also we will investigate the gravitational potential's behaviour on soliton solutions, such as parabolic, bright, dark, anti-dark, combination and S-shaped solitons. Contour plots and three-dimensional soliton solutions are provided. These solitons are important in nonlinear processes, magnetic devices, and lasers beams because of variations in gravitational field. [ABSTRACT FROM AUTHOR]

Background: In India, the cosmetics industry has expanded significantly because of changing lifestyles and increased awareness. In terms of earning the most money from the personal care and cosmetics industry in 2021, India is ranked fourth globally. Many cosmetics sold in India include ingredients that cannot be used on humans. Objective: To assess knowledge, attitudes, and practice toward the uses of cosmetics and cosmetovigilance in India. Methods: A cross‑sectional study was conducted, from April to May 2022, among the general population living in the Delhi NCR region, India. Study questionnaires (printed and survey link) were distributed in public as well as at workplaces for the survey. Results: Around 268 (54.78%) females and 223 (45.21%) males participated in the survey. Amongst the total respondents ‑ 407 (83%) agreed that they are using cosmetic products on a daily basis, females 229 (85.44%), being the majority users compared to males 178 (80%), with a significant P value = 0.011. Most of the people reported side effects of shampoos ‑ 7.13% (hair fall, hair thinning, dryness of the scalp, itching), followed by allergic reactions to moisturizers ‑ 5.70%. Conclusion: Because of the right safety and effectiveness mentorship of cosmetics, regulatory agencies and stakeholders should adopt this broadly. Cosmetovigilance needs to be put into practice. [ABSTRACT FROM AUTHOR]

There is one report where an NG tube passed through i-gel was found to form a knot.[[2]] It is not expected that the NG tube would coil when passed through the i-gel because its gastric channel prevents the tube from bending and facilitates its entry into the oesophagus. Sir, Second-generation supraglottic airway devices (SADs) are routinely used nowadays to perform laparoscopic cholecystectomy as they have a gastric channel to clear the gastric content and prevent obscurement of the surgical view close to the gall bladder bed. The airway was managed with a second-generation SAD, LMA Supreme™ (Laryngeal Mask Company, San Diego, CA) no. 4, and a 10 FG nasogastric (NG) tube was introduced through its gastric channel to decompress the stomach. [Extracted from the article]

State estimation (SE) is a primary data processing algorithm which is utilised by the control centres of advanced power systems. The most generally utilised state estimator is based on the weighted least squares (WLS) approach which is ineffective in addressing gross errors of input data of state estimator. This paper presents an innovative robust estimator for SE environments to overcome the non-robustness of the WLS estimator. The suggested approach not only includes the similar functioning of the customary loss function of WLS but also reflects loss function built on the modified WLS (MWLS) estimator. The performance of the proposed estimator was assessed based on its ability to decrease the impacts of gross errors on the estimation results. The properties of the suggested state estimator were investigated and robustness of the estimator was studied considering the influence function. The effectiveness of the proposed estimator was demonstrated with the help of examples which also indicated non-robustness of MWLS estimator in SE algorithm. [ABSTRACT FROM AUTHOR]

The current study evaluated the inhibitory effect of Moringa oleifera leaves methanolic extract (MOL) against the in vitro growth of Babesia bovis (B. bovis), B. caballi, B. bigemina, and Theileria equi (T. equi), as well as in vivo growth of B. microti in mice. Active principles of MOL extract were determined using liquid chromatography mass spectrometry (LC-MS). MOL's anti-piroplasm efficacy was assessed both in vitro and in vivo using the SYBR Green I fluorescence assay. Every 96 hours, the hematological parameters, including red blood cell count (RBCs; 104/UL), hemoglobin content (HGB; g/dl), and hematocrit percent (HCT; %), in the treated mice were monitored using a Celltac MEK6450 automated hematological analyzer. LC-MS of MOL revealed that the most abundant polyphenolic catechism found in the MOL extract was isoquercetin and rutin. MOL inhibited B. bovis, B. caballi, B. bigemina, and T. equi in vitro growth in a dose-dependent way, with IC50 values of 45.29 ± 6.14, 19.16 ± 0.45, 137.49 ± 16.07, and 9.29 ± 0.014 μg/ml, respectively. MOL's in vitro antibabesial activity was enhanced when administrated simultaneously with either diminazene aceturate (DA) or MMV665875 compound from malaria box. In mice infected by B. microti, a combination of MOL and a low dose of DA (12.5 mg·kg−1) resulted in a significant (P < 0.05) reduction in B. microti growth. These findings suggest that MOL is an effective herbal anti-piroplasm therapy, especially when combined with a low dosage of either DA or MMV665875. [ABSTRACT FROM AUTHOR]

Solid lipid nanoparticles second generation, nanostructure lipid carrier (NLC), is one of the most important biodegradable nanoparticles. Nanostructure Lipid carrier (NLC) was used to encapsulate methylene blue (MB) dye, carvacrol and citronellal and their efficacy as insecticidal against Culex pipiens (Cx. pipiens) were distinguished. The prepared nanoformulation revealed very good physicochemical properties, especially the homogeneity of the particle size. Transmission electron microscope showed spherical shaped nanoparticles within range less than 200 nm. The prepared NLC-MB-MT system showed a very competitive insecticidal activity and high virulence against the mosquito larvae with higher mortality rate of LC50 of 0.141 µl/mL, in addition to high level of Oxidative stress parameters obtained through all the tested enzymes including hydrogen peroxide (4.8 ppm), protein carbonyl amount (0.12 OD/mg protein), ascorbic acid (0.15 mg) and Superoxide dismutase (SOD) showed strong increasing (0.09 OD/mg protein/min) at 6 µg/mL, respectively. Whereas paradoxical results of the oxidative stress enzymes were obtained from different concentration of nanoformulation that introduce a convenient reason for their potential insecticidal effect. The cytotoxic effect of NLC-MB-MT was evaluated using WI38 human lung cell lines, the LC50 was 6.4 mg/mL. The low cytotoxic reactivity towards the tested cell line makes the NLC-MB-MT nanoformulation has its promising insecticidal efficacy. Molecular docking study for each component were done against acetylcholine esterase protein and accepted binding modes achieved by the three compounds. [ABSTRACT FROM AUTHOR]

The safe and effective option for the therapeutic management of psoriasis was attempted by preparing transferosomes of Betamethasone valerate (BV) and incorporating into formulation of gel to get more skin permeation, more effectiveness in drug entrapment and sustained release. Batches of experimental design of transferosome containing 100 mg of BV were produced by using Lipova E 80 and Span 20 as surfactant in varying quantities and incorporated in 1.5% HPMC gel base. Formulation was optimized to attain maximum drug entrapment, % drug release, ex-vivo permeation, pH, viscosity, spreadability and extrudability. The size and stability was ascertained by using Zeta sizer and and TEM was utilized to assess the surface morphology. The optimized formulation entrapped 59.87 % of the drug, pH 6.57, the average size of the particle was found to be 108.93 nm and viscosity were 436.19 centipoise.The residual analyses by gas chomatography confirms the elimination of formulation's organic solvent and stability studies were conducted in accordance of the ICH guidelines. The developed formulation showed diffusion of BV through the rat's skin at sustained rate for 10 hrs while marketed preparation sustained for 7 hrs only. It promises of localized action at the affected psoriatic sites for prolonged period with better release characteristics as compared to marketed formulation. The optimized formulation was found to be stable during the period of study. [ABSTRACT FROM AUTHOR]

Epidural catheter occlusion, kinking are common complications encountered while placing epidural causing failure of administering the drug through it.[[1]] However, leakage due to the kinking of the catheter is uncommon. Hence, we should consider the possibility of catheter site leak even in case of negative aspiration to CSF/blood and causing the loss of administered drug.{Figure 1} Informed consent Informed consent was taken from the patient. [Extracted from the article]

The potential reproductive toxic effects of oral TiO2 NPs in adult male rats as well as the possible alleviation of chitosan administration was investigated. Animals were allocated to four groups; the first group received deionized water and was assigned as a control group. In the second group, rats received chitosan at a dose of 5 mg/kg BW/day. The third group was designed for administration of TiO2 NPs at a dose of 150 mg/kg BW/day (1/80 LD50). Rats in the fourth group received both TiO2 NPs and chitosan. After 14 days, TiO2 NPs induced testicular lipid peroxidation as well as oxidative stress. Nano-titanium significantly upregulated genes that encode apoptosis and inflammation in testicular tissue. Moreover, it induced histological alteration in the testicular structure with impairment in spermatogenesis via reduction of PCNA immune-staining. Chitosan administration significantly improved the activities of testicular GPx, SOD, and CAT enzymes. In addition, it significantly down-regulated the relative expressions of pro-apoptotic and pro-inflammatory testicular genes. Chitosan was able to improve the testicular architecture as well as spermatogenesis. The current study revealed the capability of chitosan to ameliorate nano-titanium induced testicular toxicity. Thus, attention should be given to the extensive consumption of nano-titanium particles. [ABSTRACT FROM AUTHOR]

The ethanolic extracts of Spondias mangifera fruit (SMFE) were evaluated for aphrodisiac activity. The in-vitro phosphodiesterase-5 (PDE-5) inhibition was assessed based on in-silico molecular docking and simulation studies. In addition, the in-vivo sexual behavior was analyzed in the form of mount (MF, ML), intromission (IF, IL), and ejaculation (EF, EL) frequencies and latencies to validate the in-vitro results. Some biochemical parameters, including PDE-5, nitric oxide, and testosterone, were also observed. The above extract constituted β-amyrin, β-sitosterol, and oleanolic acid and showed tremendous binding with phosphodiesterase-5 and sildenafil. Both the sildenafil and ethanolic extracts (200 and 400 mg/kg/d bodyweight) significantly (p < 0.1, p < 0.05) increased MF, IF, and EF, respectively. In contrast, ML and IL significantly (p < 0.1) decreased, and EL significantly (p < 0.1) increased compared with a normal group of animals. The ethanolic extracts (200 and 400 mg/kg/d bodyweight) and sildenafil further significantly (p < 0.05, p < 0.1) diminished PDE-5 activity significantly (p < 0.05, p < 0.1) and enhanced nitric oxide and testosterone levels, as compared with normal rodents. Therefore, the S. mangifera ethanolic extract might be a valuable alternate aphrodisiac for erectile dysfunction. [ABSTRACT FROM AUTHOR]

Dietary supplements such as vitamins are widely used worldwide including Saudi Arabia. The present study was designed to assess community pharmacists' knowledge, attitude, and practice regarding vitamin D and other dietary supplements. This cross-sectional study was conducted on representative samples of the community pharmacists (N = 246) in different areas in Jazan. The study utilized a validated anonymous questionnaire consisting of 25 questions to gather information. Approximately, 69.5% of the pharmacists were in the age group of 25-35 years (P = 0.000). Descriptive and inferential statistical analyses were performed by using SPSS. The knowledge found in the participants was high, but there is no significant association with the demographic variables (P > 0.05). The attitude of the pharmacists toward vitamin D and dietary supplements was highly positive. A significant difference was found in the community pharmacists' practice toward vitamin D and other dietary supplements with age (P = 0.043), position in the pharmacy (P = 0.009), and type of pharmacy (P = 0.038). This study showed that the pharmacists' level of knowledge regarding vitamin D and other dietary supplements significantly correlated with their attitude (R2 = 0.202, P = 0.000) and practice (R2 = 0.122, P = 0.000). However, their knowledge, attitude, and practice are not in tandem with their educational qualification. Hence, more attention should be paid to continuing education and training of the pharmacists. [ABSTRACT FROM AUTHOR]

Abstract: Under optimized reaction conditions, an efficient synthetic method has been developed to afford the functionalized flavone-triazole-tetrahydropyran conjugates via click reactions. The Cu-catalyzed 1,3-dipolar cycloaddition reaction gave the pure products, 5-iodo- and 5-H-1-(tetrahydropyran)-1,2,3-triazol-4-(3-methoxylflavone) derivatives in excellent yield (90–98%) within 1–3 h. Further, Pd-catalyzed Suzuki coupling of 5-iodo-1,2,3-triazoles with phenylboronic acids afforded 5-phenyl-1-(tetrahydropyran)-1,2,3-triazol-4-(3-methoxylflavone) derivatives in excellent yield (93–95%) in 4–5 h. Products (3a–l, 4a–j) were screened in vitro for their anti-proliferative activity against three human cancer cell lines (MDA-MB 231, KCL22 and Hela). Compounds 3c, 3g, 3i, 3j, 4c and 4h have shown better cytotoxicity (IC50 0.61–1.68 μM) than the reference drugs. Compounds 4e (IC50 0.70 μM), 3j (IC50 0.61 μM) and 4d (IC50 0.65 μM) exhibited anti-proliferative activity better than the reference drugs against the MDA-MB 231 cells, KCL22 cells and HeLa cells respectively. [Copyright &y& Elsevier]

Following our previously reported Prins cyclization strategy, a series of novel and highly functionalized flavonoid based THPs (Prins products) were designed, synthesized and evaluated for their antiproliferative activity. Novel products were afforded in excellent yields (72–96%) within 20–90 min at 62 °C using flavonoid aldehydes, homoallylic alcohols, p-TSA·H2O (catalyst and reagent) and MS 4 Å in CHCl3. Deprotection of tosyl group was achieved with TFA (catalyst and solvent) at 140 °C to obtain 4-hydroxytetrahydropyrans and further reaction of 4-hydroxytetrahydropyrans with cinnamoyl chloride afforded 4-cinnamate tetrahydropyrans under neat condition. Synthesized compounds evaluated against human cancer cell lines (Hep3β, MCF-7 and Hela), have shown moderate to good antiproliferative activity in vivo. Compounds 3q and 3zb exhibited similar cytotoxicity (IC50 6.6 ± 1.4, 6.9 ± 1.0 μM, respectively) to the reference drug doxorubicin (IC50 7.6 ± 0.9 μM) against the MCF-7 cancer cell line. Compound 3zb was found equally active as the standard drug (IC50 4.48 ± 2.1 μM) against the Hep3β cell line and compounds 3c and 3q showed moderate cytotoxicity (IC50 10.40 ± 1.1, 12.9 ± 1.7 μM, respectively) against the HeLa cell line. [ABSTRACT FROM AUTHOR]

[Display omitted] • Microwave-assisted sensitive spectrofluorimetric estimation of mirabegron. • Comprehensive strategy of white analytical chemistry and DoE approach. • Assay of formulations and in-vivo pharmacokinetic study of mirabegron. • Assessment of methods using RGB model, AGREE and GAPI metrics. The USFDA recently approved mirabegron, a novel once-daily β-3 adrenoceptor agonist for oral administration, as a transformative treatment for overactive bladder. Despite the existence of numerous analytical methods for the assay and bioanalysis of mirabegron, it's perplexing that none have explored the domain of microwave-assisted sensitive spectrofluorimetric method for mirabegron estimation, even after extensive literature review. Adding to the enigma is the insistence of current analytical methods on using expensive and harmful organic solvents, posing a threat to marine life and the broader environment. Recently, the white analytical chemistry approach has been introduced to develop analytical methods that are cost-effective, environmentally friendly, and user-friendly. Consequently, a white analytical chemistry-based, sensitive, and eco-friendly spectrofluorimetric estimation of mirabegron has been initiated, using 4-Chloro-7-nitrobenzofurazan as a fluorescent biosensing probe. The development of this robust method involved a series of experiments designed to minimize solvent and time wastage. Through a combination of fractional factorial and Box-Behnken designs, researchers identified the critical variables and optimized the method to perfection. This method was validated according to the stringent ICH Q2 (R2) and USFDA guidelines, ensuring its reliability and accuracy. Once approved, this sensitive spectrofluorimetric method was tested, accurately estimating mirabegron levels in commercial formulations and rat plasma samples. To further enrich the study, a comprehensive evaluation of existing analytical methods was conducted alongside the proposed spectrofluorimetric method, using advanced tools like the AGREE calculator, GAPI software, and RGB model to assess their eco-friendliness and effectiveness in mirabegron estimation. [ABSTRACT FROM AUTHOR]

Abstract: We have used V79MZ hamster lung fibroblasts stably transfected with human cytochrome P450-1A1 (hCYP1A1; cell line designated V79MZh1A1) or P450-1B1 (hCYP1B1; cell line designated V79MZh1B1) alone, or in combination with human glutathione-S-transferase (GST) alpha-1 (hGSTA1), in order to examine GST protection against cytotoxicity and mutagenicity of dibenzo[a,l]pyrene (DBP) and the intermediate dihydrodiol metabolite (±)-DBP-11,12-dihydrodiol (DBPD). At comparable expression levels of hCYP1A1 and hCYP1B1, both DBP and DBPD were more cytotoxic in V79MZ1A1 (IC50 =2.7 and 0.7nM, respectively) than in V79MZh1B1 (IC50 =6.0 and 4.8nM, respectively). In contrast, both DBP and DBPD were two- to four-fold more mutagenic in V79MZh1B1 than in V79MZ1A1. Co-expression of hGSTA1 with hCYP1A1 decreased DBP cytotoxicity two-fold compared to V79MZh1A1 with hCYP1A1 alone, and provided a small, yet still statistically significant, 1.3-fold protection against DBPD. Protection against mutagenicity of these compounds was comparable to that for cytotoxicity in cells expressing hCYP1A1. In V79MZh1B1 cells, co-expression of hGSTA1 conferred up to five-fold protection against DBP cytotoxicity, and up to nine-fold protection against the (±)-DBP-dihydrodiol cytotoxicity relative to the cells expressing hCYP1B1 alone. Co-expression of hGSTA1 also reduced mutagenicity of DBP or its dihydrodiol to a lesser extent (1.3–1.8-fold) than the protection against cytotoxicity in cells expressing hCYP1B1. These findings demonstrate that the protective efficacy of hGSTA1 against DBP and DBPD toxicity is variable, depending on the compound or metabolite present, the specific cytochrome P450 isozyme expressed, and the specific cellular damage endpoint examined. [Copyright &y& Elsevier]

Human organic anion transporter 1 mediates cellular uptake of cysteine- S conjugates of inorganic mercury. Background. The epithelial cells lining the renal proximal tubule have been shown to be the primary cellular targets where mercuric ions gain entry, accumulate, and induce pathologic effects in vivo. Recent data have implicated at least one of the organic anion transport systems in the basolateral uptake of inorganic mercury (Hg2+). Methods. Using a line of Madin-Darby canine kidney (MDCK) II cells transfected stably with the human organic anion transporter 1 (hOAT1), and oocytes from Xenopus laevis microinjected with cRNA for hOAT1, we tested the hypothesis that hOAT1 can transport biologically relevant mercuric conjugates of cysteine (Cys). Results. Indeed, MDCK II cells expressing a functional form of hOAT1 gained the ability to transport the mercuric conjugate 2-Amino-3-(2-amino-2-carboxy-ethylsulfanyl-mercuricsulfanyl)-propionic acid (Cys- S-Hg- S-Cys), but not the corresponding di-glutathione S-conjugate of Hg2+ (G- S-Hg- S-G). Moreover, p-aminohippurate (PAH), adipate, and glutarate (but not succinate or malonate) inhibited individually the uptake of Cys- S-Hg- S-Cys in a dose-dependent manner. Uptake of Cys- S-Hg- S-Cys, but not G- S-Hg- S-G, was also documented in Xenopus oocytes expressing hOAT1. Conclusion. These data represent ostensibly the most direct line of evidence implicating a specific membrane protein (i.e., hOAT1) in the transport of a biologically relevant molecular species of Hg2+ in a mammalian cell. Moreover, these data indicate that the organic anion transporter(s) likely play a prominent role in the basolateral transport of mercuric ions by proximal tubular cells and in the nephropathy induced by Hg2+. [ABSTRACT FROM AUTHOR]