Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival.

It is well known that solid hypoxic tumour cells oxidise glucose through glycolysis, and the end product of this pathway is fermented into lactate which accumulates in the tumour microenvironment (TME). Initially, it was proclaimed that cancer cells cannot use lactate; therefore, they dump it into the TME and subsequently augment the acidity of the tumour milieu. Furthermore, the TME acts as a lactate sink with stope variable amount of lactate in different pathophysiological condition. Regardless of the amount of lactate pumped out within TME, it disappears immediately which still remains an unresolved puzzle. Recent findings have paved pathway in exploring the main role of lactate acidosis in TME. Cancer cells utilise lactate in the de novo fatty acid synthesis pathway to initiate angiogenesis and invasiveness, and lactate also plays a crucial role in the suppression of immunity. Furthermore, lactate re-programme the lipid biosynthetic pathway to develop a metabolic symbiosis in normoxic, moderately hypoxic and severely hypoxic cancer cells. For instance: severely hypoxic cancer cells enable to synthesizing poly unsaturated fatty acids (PUFA) in oxygen scarcity secretes excess of lactate in TME. Lactate from TME is taken up by the normoxic cancer cells whereas it is converted back to PUFAs after a sequence of reactions and then liberated in the TME to be utilized in the severely hypoxic cancer cells. Although much is known about the role of lactate in these biological processes, the exact molecular pathways that are involved remain unclear. This review attempts to understand the molecular pathways exploited by lactate to initiate angiogenesis, invasiveness, suppression of immunity and cause re-programming of lipid synthesis. This review will help the researchers to develop proper understanding of lactate associated bimodal regulations of TME.

Clinical application of a previously validated pregnancy-specific screening tool for sleep apnea in a cohort with a high prevalence of obesity.

Objective: The purpose of this project was to determine the positive predictive value of existing obstructive sleep apnea (OSA) screening tools in clinical use, in a real-world clinical population of gravidae, and to explore the development of a new questionnaire for screening for OSA during pregnancy. Methods: Pregnant people were administered sleep screening questionnaires as part of routine clinical care. These included Facco's four variable OSA screening tool, the STOP-BANG, and the Epworth Sleepiness Scale. Those who screened positive were referred for diagnostic sleep testing, typically with a type III home monitoring device. Here we analyzed the screening responses used by those who completed diagnostic testing to determine the positive predictive value of the existing tools. Results: 159 pregnant people completed diagnostic OSA testing and were included in this analysis. The positive predictive value of Facco's four variable sleep screening tool was 74.3%, STOP-BANG was 75.3%, and the Epworth Sleepiness Scale was 69.8%. Our sample size was insufficient to create a new screening tool. Conclusions: Here we calculated the positive predictive value of Facco's 4 variable screening tool for screening for OSA in pregnancy in a real-world pregnant population. While we were not able to generate a new screening tool for screening for OSA during pregnancy, both STOP-BANG and Facco's four variable tool had positive predictive values over 70% in our population which was characterized by high BMI and advanced maternal age. Increased clinical use of the pregnancy-specific tool may be warranted.

Continuous positive airway pressure treatment of obstructive sleep apnea and hypertensive complications in high-risk pregnancy.

PURPOSE: To evaluate whether or not continuous positive airway pressure (CPAP) treatment in pregnancies complicated by obstructive sleep apnea (OSA) is associated with a decrease in hypertensive disorders of pregnancy. METHODS: This was a retrospective cohort study of perinatal outcomes in women who underwent objective OSA testing and treatment as part of routine clinical care during pregnancy. Where diagnostic criteria for OSA were reached (respiratory event index (REI) ≥ 5 events per hour), patients were offered CPAP therapy. Obstetrical outcomes were compared between the control group (no OSA), the group with untreated OSA (OSA diagnosed, not CPAP compliant), and the group with treated OSA (OSA diagnosed and CPAP compliant), with CPAP compliance defined as CPAP use ≥ 4 h, 70% of the time or greater. A composite hypertension outcome combined diagnoses of gestational hypertension (gHTN) and preeclampsia (PreE) of any severity. RESULTS: The study comprised outcomes from 177 completed pregnancies. Our cohort was characterized by obesity, with average body mass indices > 35 kg/m2, and average maternal age > 30 years old. CPAP was initiated at an average gestational age of 23 weeks (12.1-35.3 weeks), and average CPAP use was 5.9 h (4-8.5 h). The composite hypertension outcome occurred in 43% of those without OSA (N = 77), 64% of those with untreated OSA (N = 77), and 57% of those with treated OSA, compliant with CPAP (N = 23) (p = 0.034). CONCLUSION: Real-world data in this small study suggest that CPAP therapy may modulate the increased risk of hypertensive complications in pregnancies complicated by OSA.

Nutraceuticals: A Promising Approach Towards Diabetic Neuropathy.

BACKGROUND: Various nutraceuticals from different sources have various beneficial actions and have been reported for many years. The important findings from the research conducted using various nutraceuticals exhibiting significant physiological and pharmacological activities have been summarized. METHODS: An extensive investigation of literature was done using several worldwide electronic scientific databases like PUBMED, SCOPUS, Science Direct, Google Scholar, etc. The entire manuscript is available in the English language that is used for our various compounds of interest. These databases were thoroughly reviewed and summarized. RESULTS: Nutraceuticals obtained from various sources play a vital role in the management of peripheral neuropathy associated with diabetes. Treatment with nutraceuticals has been beneficial as an alternative in preventing the progression. In particular, in vitro and in vivo studies have revealed that a variety of nutraceuticals have significant antioxidant and anti-inflammatory properties that may inhibit the early diabetes-driven molecular mechanisms that induce DPN. CONCLUSION: Nutraceuticals obtained from different sources like a plant, an animal, and marine have been properly utilized for the safety of health. In our opinion, this review could be of great interest to clinicians, as it offers a complementary perspective on the management of DPN. Trials with a well-defined patient and symptom selection have shown robust pharmacological design as pivotal points to let these promising compounds become better accepted by the medical community.

Biosynthesis and Response of Zinc Oxide Nanoparticles against Periimplantitis Triggering Pathogens.

Periimplantitis due to pathogenic bacteria is considered as a major cause for dental implants failures. Biogenic zinc oxide nanoparticles (ZnPs) are known to inhibit periimplantitis triggering pathogens. The current investigation intended to perform ZnPs biosynthesis and evaluation against periimplantitis triggering bacteria. The current study involved ZnPs biosynthesis using Andrographis paniculata leaves aqueous extract (APLAE), followed by optimization, stability, characterization, and in vitro evaluation against periimplantitis triggering bacteria. The experimental results indicated the success of ZnPs biosynthesis based on the optimization of zinc acetate (1.5 g), plant extract (5 mL), pH 12, and temperature (25 °C), and using the stability study (absorbance between 365-370 nm) and characterization data exhibiting broad and shifted bands (in FTIR spectrum), the size was found to be below 98.61 nm (determined by FESEM and XRD spectra) and 71.54% zinc was observed in the EDX spectrum. Biogenic ZnPs exhibited a high inhibitory activity against periimplantitis-triggering pathogens (E. coli and S. aureus). Based on the experimental results, the present study concludes that biogenic ZnPs possess a high inhibitory potential against periimplantitis-triggering bacteria, and it is established that the biosynthesis of ZnPs using APLAE is a useful method.

Modulation of Host Immune Response Is an Alternative Strategy to Combat SARS-CoV-2 Pathogenesis.

The novel SARS-CoV-2virus that caused the disease COVID-19 is currently a pandemic worldwide. The virus requires an alveolar type-2 pneumocyte in the host to initiate its life cycle. The viral S1 spike protein helps in the attachment of the virus on toACE-2 receptors present on type-2 pneumocytes, and the S2 spike protein helps in the fusion of the viral membrane with the host membrane. Fusion of the SARS-CoV-2virus and host membrane is followed by entry of viral RNA into the host cells which is directly translated into the replicase-transcriptase complex (RTC) following viral RNA and structural protein syntheses. As the virus replicates within type-2 pneumocytes, the host immune system is activated and alveolar macrophages start secreting cytokines and chemokines, acting as an inflammatory mediator, and chemotactic neutrophils, monocytes, natural NK cells, and CD8+ T cells initiate the local phagocytosis of infected cells. It is not the virus that kills COVID-19 patients; instead, the aberrant host immune response kills them. Modifying the response from the host immune system could reduce the high mortality due to SARS-CoV-2 infection. The present study examines the viral life cycle intype-2 pneumocytes and resultant host immune response along with possible therapeutic targets.

Chemical Characterization and Anti-Inflammatory Activity of Phytoconstituents from Swertia alata.

Swertia alata C.B Clarke (Gentianaceae) is a well-reported plant in the traditional system of medicine. The present study was intended to isolate the phytoconstituents from the ethanolic extract of the aerial parts of S. alata; and evaluate for in vitro COX-1/COX-2 inhibition activity, in vivo anti-inflammatory and ulcerogenic activity. Phytoisolation involved partitioning of S. alata ethanolic extract into petroleum ether and chloroform soluble fractions using silica gel-based column chromatography. The isolation afforded two phytoisolates, namely oleanolic acid (SA-1) and 3-hydroxylup-12-(13)-ene-17-carboxylic acid (SA-4). Phytoisolates structures were established by melting point, ultraviolet (UV), attenuated total reflection-Fourier-transform infrared (ATR-FTIR), nuclear magnetic resonance (1H-NMR, 13C-NMR and HMBC) and mass spectrometry. Phytoisolates were further evaluated for in vitro cyclooxygenase (COX-1/COX-2) inhibitory activity, in vivo anti-inflammatory and ulcerogenic activity. The study revealed SA-4 (COX-1/COX-2 inhibition activity of 104/61.68 µM with % inhibition of 61.36) to be more effective than SA-1 (COX-1/COX-2 inhibition activity of 128.4/87.25 µM, with % inhibition of 47.72). SA-1 and SA-4, when subjected to ulcerogenic study, exhibited significant gastric tolerance. The current study reports chromatographic isolation and spectrometric characterization of SA-1 and SA-4. The present study concludes that compound SA-4 possess significant anti-inflammatory activity and less irritant property over gastric mucosa with no significant ulcerogenicity in comparison to indomethacin.

Evaluation of antidiabetic and hypolipidemic activity of Barleria cristata Linn. leaves in alloxan-induced diabetic rats.

The present study was undertaken to evaluate the antidiabetic and hypolipidemic action of leaf extract of Barleria cristata Linn in rats. Diabetes was induced in the rats by a single intraperitoneal (IP) injection of alloxan (150 mg/kg) and randomly divided into 7 groups. Animals were treated with low (250 mg/kg) and high (500 mg/kg) doses of ethyl acetate leaf extract (EALE) and hydro-alcoholic leaf extract (HALE) up to 21 days. The body weight and blood glucose level (BGL) were measured on weekly basis. The rats were killed under mild ether anesthesia on 21st day, blood and the vital organ were collected to estimate biochemical parameters and to study histopathological changes. A single-dose administration of alloxan induced hyperglycemia in all the groups. A regular increase in BGL was observed in toxic control groups when compared with the normal control. Daily oral administration of rats with extracts (HALE and EALE) and standard drug (Glimepiride, 5 mg/kg), reduced elevated BGL significantly (p < 0.001), and body weight was regained in diabetic rats. The extract treatment also improved the normal functioning of the liver and kidneys as evidenced by the restoration of the biochemical profile. The study revealed that B. cristata possesses promising antidiabetic and hypolipidemic activity.

Comprehensive Review of Methodology to Detect Reactive Oxygen Species (ROS) in Mammalian Species and Establish Its Relationship with Antioxidants and Cancer.

Evidence suggests that reactive oxygen species (ROS) mediate tissue homeostasis, cellular signaling, differentiation, and survival. ROS and antioxidants exert both beneficial and harmful effects on cancer. ROS at different concentrations exhibit different functions. This creates necessity to understand the relation between ROS, antioxidants, and cancer, and methods for detection of ROS. This review highlights various sources and types of ROS, their tumorigenic and tumor prevention effects; types of antioxidants, their tumorigenic and tumor prevention effects; and abnormal ROS detoxification in cancer; and methods to measure ROS. We conclude that improving genetic screening methods and bringing higher clarity in determination of enzymatic pathways and scale-up in cancer models profiling, using omics technology, would support in-depth understanding of antioxidant pathways and ROS complexities. Although numerous methods for ROS detection are developing very rapidly, yet further modifications are required to minimize the limitations associated with currently available methods.

Anti-inflammatory and ulcerogenic activity of newer phytoisolates of Swertia alata C.B. Clarke.

The present study was intended to evaluate the in vitro (COX-1/COX-2) and in vivo anti-inflammatory and ulcerogenic activity of newer phytoconstituents isolated from the aerial parts of Swertia alata C.B. Clarke (Gentianaceae). For isolation of newer phytoconstituents, the ethanolic extract of aerial parts of S. alata was subjected to column chromatography using mixture of petroleum ether and chloroform in various concentrations, which yielded two phytoisolates characterised as nonacosyl triacontanoate (SA-3) and 8-O-glucpyranosyl-(2-acetyl)-1,3-dihydroxy-5-methoxy-xanthone (SA-9). Identification of compounds was based on melting point, UV, FTIR, 1H-NMR, 13C-NMR and mass spectrometric data. The isolates were screened for in vitro COX-1/COX-2 inhibitory activity, in vivo anti-inflammatory and ulcerogenic activity. Among the two compounds, SA-3 was found to be more effective than SA-9. The ulcerogenic study revealed significant gastric tolerance of SA-3 and SA-9 in comparison to indomethacin.

Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer.

Liver cancer is the fifth (6.3% of all cancers i.e., 548,000 cases/year) and ninth (2.8% of all cancers i.e., 244,000 cases/year) most prevalent cancer worldwide in men and women, respectively. Although multiple choices of therapies are offered for Hepatocellular Carcinoma (HCC) like liver resection or transplant, radiofrequency ablation, transarterial chemoembolization, radioembolization, and systemic targeted agent, by the time of diagnosis, most of the cases of HCC are in an advanced stage, which renders therapies like liver transplant or resection and local ablation impractical; and targeted therapy has its shortcomings like general toxicity, imprecise selectivity, several adversative reactions, and resistance development. Therefore, novel drugs with specificity and selectivity are needed to provide the potential therapeutic response. Various researches have shown the potential of phytomedicines in liver cancer by modulating cell growth, invasion, metastasis, and apoptosis. However, their therapeutic potential is held up by their unfavorable properties like stability, poor water solubility, low absorption, and quick metabolism. Nonetheless, the advancement of nanotechnology-based innovative nanocarrier formulations has improved the phytomedicines' profile to be used in the treatment of liver cancer. Nanocarriers not only improve the solubility and stability of phytomedicines but also extend their residence in plasma and accomplish specificity. In this review, we summarize the advancements introduced by nanotechnology in the treatment of liver cancer. In particular, we discuss quite a few applications of nanophytomedicines like curcumin, quercetin, epigallocatechin-3-gallate, berberine, apigenin, triptolide, and resveratrol in liver cancer treatment.

RSM-CCD optimized sodium alginate/gelatin based ZnS-nanocomposite hydrogel for the effective removal of biebrich scarlet and crystal violet dyes.

The present work represents RSM-CCD (Response Surface Methodology integrated Central composite Design) optimized synthesis scheme of semi-IPN (semi interpenetrating network) NaAla-Gel-cl-polyAAm and ZnS nanocomposite adsorbent NaAla-Gel-cl-polyAAm/ZnS. Under optimized reaction parameters semi-IPN NaAla-Gel-cl-polyAAm showed maximum swelling percentage of 3191.73%. Maximum dye removal percentage (97.37%) was observed with ZnS nanocomposite for the removal of biebrich scarlet. The adsorption isotherm data indicated that Langmuir and Freundlich adsorption isotherm fitted well for biebrich scarlet (R2 = 0.964) and crystal violet (R2 = 0.960), respectively. ΔG°, ΔH° and ΔS° values indicated the thermodynamic feasibility of the reaction. Excellent recyclability and reusability of the adsorbent materials suggested their applicability towards textile industry and water purification purpose.

Selective removal of cationic dyes using response surface methodology optimized gum acacia-sodium alginate blended superadsorbent.

Gum acacia and sodium alginate were blended to synthesize highly efficient superadsorbent formed by grafting of poly(acrylic acid) (AA) used as monomer onto the hybrid of gum acacia and sodium alginate and the polymeric chains were crosslinked through N,N'-methylene bisacrylamide (MBA). The overall reaction followed free radical polymerization with ammonium persulphate (APS) used as initiator. Response surface methodology integrated with central composite design (RSM-CCD) could synthesize semi-Interpenetrating network (semi-IPN) having maximum swelling capacity of 1749.2% at MBA, APS and AA concentrations of 0.89 × 10-2 mol L-1, 3.29 × 10-2 mol L-1 and 1.46 mol L-1, respectively using 15 mL water at 70 °C for 2.5 h. The synthesized sample was found to be selective for removal of cationic dyes upto 97.49%, 95.39% and 94.56% for auramine-O (AO), malachite green (MG) and crystal violet (CV), respectively. Adsorption capacities at equilibrium were calculated experimentally as 2.01 mg g-1, 3.06 mg g-1 and 7.55 mg g-1 for AO, MG and CV, respectively. These dyes could be desorbed with 0.1 N HCl for the recyclization of semi-IPN. Adsorption mechanism involved monolayer formation with three step process of adsorption and followed first order kinetics. Exothermic nature of adsorption was revealed by thermodynamic studies.

Efficient capture of eosin yellow and crystal violet with high performance xanthan-acacia hybrid super-adsorbent optimized using response surface methodology.

Blending of xanthan and acacia gives a unique hybrid that was used for the synthesis of semi-interpenetrating network (semi-IPN) in which poly(acrylamide) chains were grafted onto hybrid of xanthan-acacia followed by their cross-linking (Xan-Aca-cl-poly(AAm)). Optimization was carried out under response surface methodology-central composite design (RSM-CCD). Maximum percentage swelling of semi-IPN obtained was 496.57%. The concentrations of acrylamide, citric acid and ammonium persulphate used as monomer, cross-linker and initiator, respectively were found to be significant parameters. The blend was highly effective in removal of both cationic (crystal violet) and anionic dyes (eosin yellow) showing maximum dye removal capacity of 97.58% and 95.42%, respectively under optimized parameters - 0.4 g semi-IPN dose in 15 ml dye solution of 10 mg L-1 concentration within 16 h. Adsorption mechanism of both the dyes followed three steps in accordance with intraparticle diffusion model along with mono layer langmuir adsorption criteria. Second order kinetics was followed in case of both dyes. Thermodynamic studies gave idea about the exothermic nature of adsorption. Semi-IPN could be recycled up to eight consecutive cycles and hence, can be utilized for industrial purpose for removal of dyes.

Response surface methodology directed synthesis of luminescent nanocomposite hydrogel for trapping anionic dyes.

The present research work reveals semi-interpenetrating network (semi-IPN) synthesis using response surface methodology-central composite design (RSM-CCD) based optimization. The maximum swelling of 362.11% was obtained with monomer, crosslinker and initiator concentrations 4.39 mol L-1, 1.52 mol L-1 and 4.58 mol L-1, respectively, temperature 70 °C, time 3 h and pH 4.0. The synthesized hydrogel showed 94.16% and 95.62% removal for eosin yellow (EY) and eriochrome black-T (EBT) dyes, respectively. The incorporation of cadmium sulphide nanodots into the hydrogel network enhanced the % dye removal (96.82% EY and 98.73% EBT) along with fluorescent behavior. Various conditions optimized for EY and EBT dye removal with respect to semi-IPN were: 0.4 g adsorbent dose each, dye concentrations 10 mg L-1 and 120 mg L-1, contact time 24 h each, respectively. Adsorption studies followed langmuir theory for both dyes. Second order and first order kinetics along with intraparticle diffusion of dye molecules were favorable to EY and EBT, respectively. Thermodynamic study reveals exothermic nature of adsorption. Recyclability of the adsorbent is superior as tested by desorption-adsorption tests.

Simultaneous HPTLC analysis and in vitro antileishmanic activity of various secondary metabolites in extract of the traditional medicinal herb Artabotrys hexapetalus (L.f.).

BACKGROUND: Artabotrys hexapetalus [(L.F) Bhandari] a medicinal plant is commonly known as 'Hari Champa' and its roots and fruits are used for treating malaria and scrofula, respectively. OBJECTIVE: The aim of this work was to develop a sensitive, fast and reproducible high-performance thin-layer chromatographic (HPTLC) method for simultaneous analysis of quercetin and apigenin in various extracts of Artabotrys hexapetalus (L. f.) Bhandari (Family Annonaceae) and further to assess antileishmanic effects of different extracts of A. hexapetalus against Leishmania donovani. MATERIALS AND METHODS: Metabolic fingerprinting was developed using HPTLC with quantification of markers (quercetin and apigenin). The method was validated for linearity, specificity, precision, accuracy and robustness. Among the different combinations of mobile phases used, best separation was achieved in toluene:ethyl acetate:formic acid (6.5:3:0.5, v/v/v). Densitometric scanning of the plates directly at 254 nm was used for analysis of quercetin as well as apigenin. The concentration-response curve was plotted and IC50 values were determined using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. RESULTS: Compact bands for quercetin and apigenin were obtained at Rf 0.52 ± 0.001 and 0.73 ± 0.002, linearity were found satisfactory for quercetin and apigenin. Linearity range for quercetin and apigenin were 100-1000 ng/spot and 100-2000 ng/spot, respectively, with r 2 = 0.996 ± 0.002 and 0.993 ± 0.003, limit of detection (15.56 and 13.78 ng/spot), limit of quantification (51.8 and 45.94 ng/spot), recovery (98.7%-99.7% and 96.8%-98.8%) and precision with %RSD <2%. Various dried extracts were found to contain quercetin in the range of 0.35%-4.26% (w/w) and apigenin in the range of 0.64%-8.46% (w/w). Cytotoxicity assay of extracts over promastigotes showed that petroleum ether extract was found to be most cytotoxic (IC50 30.28 ± 1.06 µg/mL) after 96 h in comparison to other extracts. The finding of this study indicates that this plant is effective against L. donovani in vitro. CONCLUSION: The present HPTLC method is being reported for the first time and can be used for routine quality control. The petroleum ether extract of A. hexapetalus displayed potent antileishmanial activity and can be further explored for the development of antileishmanial treatment regimen.

Preclinical screening methods in cancer.

Cancer, a group of diseases of unregulated cell proliferation, is a leading cause of death worldwide. More than 80% of compounds which have shown promising effects in preclinical studies could not get through Phase II of clinical trials. Such high attrition rate is due to improper or selective use of preclinical modalities in anticancer drug screening. The various preclinical screening methods available such as in vitro human cancer cell lines, in vivo tumor xenograft model, or genetically engineered mouse model have their respective pros and cons. Scrupulous use of these preclinical screening methods vis-à-vis efficacy of potential anticancer compound with diverse mechanism of action can help in bringing down the rate of failure of anticancer compound at clinical phase. This article provides an insight into the various preclinical methods used in anticancer studies along with their advantages and disadvantages.