Transbilayer lipid interactions mediate nanoclustering of lipid-anchored proteins.

Understanding how functional lipid domains in live cell membranes are generated has posed a challenge. Here, we show that transbilayer interactions are necessary for the generation of cholesterol-dependent nanoclusters of GPI-anchored proteins mediated by membrane-adjacent dynamic actin filaments. We find that long saturated acyl-chains are required for forming GPI-anchor nanoclusters. Simultaneously, at the inner leaflet, long acyl-chain-containing phosphatidylserine (PS) is necessary for transbilayer coupling. All-atom molecular dynamics simulations of asymmetric multicomponent-membrane bilayers in a mixed phase provide evidence that immobilization of long saturated acyl-chain lipids at either leaflet stabilizes cholesterol-dependent transbilayer interactions forming local domains with characteristics similar to a liquid-ordered (lo) phase. This is verified by experiments wherein immobilization of long acyl-chain lipids at one leaflet effects transbilayer interactions of corresponding lipids at the opposite leaflet. This suggests a general mechanism for the generation and stabilization of nanoscale cholesterol-dependent and actin-mediated lipid clusters in live cell membranes.

Enhancing productivity and sustainability of ravine lands through horti-silviculture and soil moisture conservation: A pathway to land degradation neutrality.

Ravine lands are the worst type of land degradation affecting soil quality and biodiversity. Crop production in such lands is impossible without adopting proper conservation measures. In-situ moisture conservation techniques could play an instrumental role in restoring ravine lands by improving soil moisture. We hypothesized that restoring ravine land through a combination of tree planting, fruit crop cultivation, and in-situ moisture conservation practice would result in significant improvements in productivity, profitability, and soil fertility. An experiment was conducted involving the combination of Malabar Neem (Melia dubia) and Dragon fruit (Hylocereus undatus) in conjunction with in-situ soil moisture conservation measures specifically involving half-moon structures (HM). The experiment was conducted under randomized block design (RBD) comprising eight treatments. These treatments include sole Melia cultivation (MD 3m × 3m), sole cultivation of dragon fruit (DF 3m × 3m), silviculture system (MDF-3m × 3m), horti-silviculture system with larger spacing (MDF-4m × 4m), sole Melia cultivation with in-situ moisture conservation (MDH-3m × 3m), sole Dragon fruit cultivation with in-situ moisture conservation (DFH-3m × 3m), horti-silviculture system of Melia and Dragon fruit with in-situ moisture conservation (MDFH-3m × 3m), and horti-silviculture system with larger spacing and in-situ moisture conservation (MDFH-4m × 4m). Each treatment was replicated thrice to evaluate their impact on productivity, profitability, soil fertility, and carbon sequestration for 8 years (2016-2023). The results revealed that the horti-silviculture system (MDFH-3 × 3 m) exhibited the highest total tree biomass and total carbon sequestration with an increase of 183.2% and 82.8% respectively, compared to sole Melia cultivation without HM and sole Melia with HM. Furthermore, sole Melia with HM augmented soil nutrients (N, P, K, and SOC) by 74.4%, 66.4%, 35.2%, and 78.3%, respectively, compared to control (no planting), with performance at par with MDFH-3 × 3 m. Similarly, sole Melia with HM enhanced SOC stock and SOC sequestration rate by 79.2% and 248% over control. However, it was found at par with MDFH-3 × 3 m. The horti-silviculture system (MDFH-3 × 3 m) consistently produced the highest fruit yield throughout the years surpassing other treatments. This treatment increased the average dragon fruit yield by 115.3% compared to sole dragon fruit without HM. Hence, the adoption of the horti-silviculture system (MDFH-3 × 3 m) could be a promising strategy for achieving enhanced environmental and economic benefits in ravine lands. Therefore, dragon fruit based horti-silviculture system (MDFH-3 × 3 m) could be recommended for restoration of ravine lands, improving land productivity, and mitigating impact of soil erosion particularly in Western India or similar agro-climatic regions of the world.

Transcutaneous oximetry values in chronic ulcer patients during Hyperbaric treatment at 1.4 ATA compared to 2 ATA.

Chronic wounds have a significant impact on a patient's quality of life. Different pathologies, such as poor blood supply and tissue breakdown, may lead to inadequate oxygenation of the wound. Hyperbaric oxygen (HBO2) is a widely used treatment for an increasing number of medical practices. A new so-called "hyperbaric treatment" trend has emerged. The use of low-pressure, soft-sided, or inflatable chambers represents a growing trend in hyperbaric medicine. Used in professional settings as well as directly marketed to individuals for home use, they are promoted as equivalent to clinical hyperbaric treatments provided in medical centers. However, these chambers are pressurized to 1.3 atmospheres absolute (ATA) on either air or with an oxygen concentrator, both generate oxygen partial pressures well below those used in approved hyperbaric centers for UHMS-approved indications. A total of 130 consecutive patients with chronic ulcers where tested. TcPO2 was measured near the ulcer area while the patient was breathing 100% O2 at 1.4 ATA for five and 10 minutes. The average TcPO2 at 1.4 ATA after 10 minutes of O2 breathing was 161 mmHg (1-601 mmHg, standard deviation 137.91), compared to 333 mmHg in 2 ATA (1-914±232.56), p < 0.001. Each electrode tested was also statistically significant, both after five minutes of O2 breathing and after 10 minutes. We have not found evidence supporting the claim that 1.4 ATA treatment can benefit a chronic ulcer patient. The field of HBO2 is constantly evolving. We have discovered new ways to treat previously incurable ailments. Nevertheless, it is important to note that new horizons must be examined scientifically, supported by evidence-based data. The actual effect of 1.4 ATA on many ailments is yet to be determined.

Scoparone chemical modification into semi-synthetic analogues featuring 3-substitution for their anti-inflammatory activity.

Natural products (NPs) continue to serve as a structural model for the development of new bioactive molecules and improve the process of identifying novel medicines. The biological effects of coumarins, one of the most researched compounds among NPs, are currently being thoroughly investigated. In the present investigation, we reported the synthesis of nineteen semi-synthetic 3-substituted scoparone analogues, followed by their characterization using analytical methods such as NMR, HPLC, and HRMS. All compounds screened for in vitro and in vivo study for their ability to reduce inflammation. The SAR study worked effectively for this particular scoparone 3-substitution, as compounds 3, 4, 9, 16, 18, and 20 displayed improved in vitro results for TNF-α than the parent molecule. Similarly, compounds 3, and 17 showed a higher percentage of IL-6 inhibition. Compounds 3, 4, and 12 have also been identified by in vivo studies as promising candidates with higher percent inhibition than the parent scoparone molecule. As evident from all in vitro and in vivo studies, compound 3 showed the most potent anti-inflammatory activity among all.

Oncological outcomes of visibly complete transurethral resection prior to neoadjuvant chemotherapy for bladder cancer.

PURPOSE: To evaluate the potential oncologic benefit of a visibly complete transurethral resection of a bladder tumor (TURBT) prior to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). MATERIALS AND METHODS: We identified patients who received NAC and RC between 2011-2021. Records were reviewed to assess TURBT completeness. The primary outcome was pathologic downstaging (

Stereoselective Synthesis of Nonpsychotic Natural Cannabidiol and Its Unnatural/Terpenyl/Tail-Modified Analogues.

Here, we report a three-step concise and stereoselective synthesis route to one of the most important phytocannabinoids, namely, (-)-cannabidiol (-CBD), from inexpensive and readily available starting material R-(+)-limonene. The synthesis involved the diastereoselective bifunctionalization of limonene, followed by effective elimination leading to the generation of key chiral p-mentha-2,8-dien-1-ol. The chiral p-mentha-2,8-dien-1-ol on coupling with olivetol under silver catalysis provided regiospecific (-)-CBD, contrary to reported ones which gave a mixture. The newly developed approach was further extended to its structural analogues cannabidiorcin and other tail/terpenyl-modified analogues. Moreover, its opposite isomer (+)-cannabidiol was also successfully synthesized from S-(-)-limonene.

Stability of the Gross Motor Function Classification System over time in children with cerebral palsy.

AIM: To assess the stability of the Gross Motor Functional Classification System (GMFCS) in children with cerebral palsy (CP) from time of preliminary diagnosis (~2 years of age) to time of diagnosis (~5 years of age), and to examine factors associated with reclassification. METHOD: We conducted a longitudinal study using a sample from the Canadian CP Registry. Stability was analysed by using the percentage of agreement between timepoints and a weighted prevalence and bias adjusted kappa statistic. Univariate and multivariate logistic regressions were performed to identify variables associated with reclassification. RESULTS: The study included 1670 children (857 males, 713 females) with a mean age of 11 years 4 months (SD 4 years, range 3 years 5 months-20 years 1 month) at time of data extraction (3rd September 2019), of which 1435 (85.9%) maintained a stable GMFCS, with a weighted kappa of 0.91 (95% confidence interval 0.89-0.92). Univariate logistic regression showed that initial GMFCS level, CP subtype, and the presence of cognitive impairment were associated with the likelihood of change in the GMFCS level (p < 0.1). In the multivariate analysis, however, the likelihood was associated with initial GMFCS level only (odds ratio 7.10-8.88, p < 0.00). INTERPRETATION: The GMFCS has good stability in early childhood. For the majority of children, it is predictive of their long-term motor function. WHAT THIS PAPER ADDS: The Gross Motor Function Classification System (GMFCS) rating in early childhood is stable over time. There is no directionality in the reclassification of the GMFCS. The initial GMFCS level was related to the likelihood of change in follow-up GMFCS level.

An analysis of diversity within academic urology leadership.

INTRODUCTION: Women, underrepresented minorities, and international medical graduates are underrepresented in urology. We sought to compare demographics of leaders in academic urology to urology faculty and academic medical faculty. MATERIALS AND METHODS: The Association of American Medical Colleges provided academic medical faculty demographics. Women, underrepresented minorities, and international medical graduates in leadership roles (department/division chair or full professor) were identified. Fisher's exact tests were performed to compare proportions of those groups in urology leadership to academic urology, academic medicine leadership, and academic medicine. RESULTS: In 2019, there were 179,105 faculty in academic medicine with 41,766 in leadership and 1,614 faculty in urology with 567 in leadership. Significantly fewer women were in urology leadership compared to academic urology (7.4% vs. 22.0%, p < 0.0001), academic medical leadership (7.4% vs. 25.0%, p < 0.0001), and academic medicine (7.4% vs. 42.0%, p < 0.0001). Significantly fewer underrepresented minorities were in urology leadership compared to academic medicine (6.9% vs. 9.4%, p = 0.04) with no significant difference when compared to urology faculty (6.9% vs. 8.1%, p = 0.4) or medical faculty leadership (6.9% vs. 6.4%, p = 0.6). Significantly more international medical graduates were in urology leadership compared to across academic urology, (32% vs. 24%, p = 0.0006), but significantly fewer than those in leadership across all medical specialties (32% vs. 40%, p = 0.0001). CONCLUSIONS: Women and underrepresented minorities are significantly underrepresented in academic urologic leadership while international medical graduates are statistically overrepresented. Considering calls for diversity, equity, and inclusion, these data highlight a need for increased representation in leadership positions in academic urology.

Oxytocin for the treatment of autism spectrum disorder in children.

QUESTION: Several parents have recently asked me if oxytocin would be helpful for treating their children with autism spectrum disorder (ASD). What do we currently know about the use of oxytocin for the treatment of children with ASD? ANSWER: Autism spectrum disorder is prevalent among children in Canada, with most affected children experiencing difficulties with social function. Behavioural and educational interventions are the first-line treatments for children with ASD. Multiple studies of oxytocin in children with ASD from the past 2 decades provide equivocal results related to social functioning, and a recent large study did not show benefit from treatment with oxytocin. Small sample sizes and differences in participant age, oxytocin formulation and dose, treatment duration, outcome measures, and analytic methods may help explain some of these disparities. The fact that ASD has a range of clinical presentations may also contribute to mixed results. The use of oxytocin has limited benefit in changing social function in children with ASD and there is no support for its current use in the treatment of this population.

Appraising the need for audiological assessment before autism spectrum disorder referral.

Objectives: Mandatory audiological testing before autism spectrum disorder (ASD) assessment is common practice. Hearing impairment (HI) in the general paediatric population is estimated at 3%; however, hearing impairment prevalence among children with ASD is poorly established. Our objective was to determine which children referred for ASD assessment require preliminary audiological assessment. Methods: Retrospective chart review of children (n=4,173; 0 to 19 years) referred to British Columbia's Autism Assessment Network (2010 to 2014). We analyzed HI rate, risk factors, and timing of HI diagnosis relative to ASD referral. Results: ASD was diagnosed in 53.4%. HI rates among ASD referrals was 3.3% and not significantly higher in children with ASD (ASD+; 3.5%) versus No-ASD (3.0%). No significant differences in HI severity or type were found, but more ASD+ females (5.5%) than ASD+ males (3.1%) had HI (P<0.05). Six HI risk factors were significant (problems with intellect, language, vision/eye, ear, genetic abnormalities, and prematurity) and HI was associated with more risk factors (P<0.01). Only 12 children (8.9%) were diagnosed with HI after ASD referral; all males 6 years or younger and only one had no risk factors. ASD+ children with HI were older at ASD referral than No-ASD (P<0.05). Conclusions: Children with ASD have similar hearing impairment rates to those without ASD. HI may delay referral for ASD assessment. As most children were diagnosed with HI before ASD referral or had at least one risk factor, we suggest that routine testing for HI among ASD referrals should only be required for children with risk factors.

Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization.

NLRP3 inflammasome is involved in several chronic inflammatory diseases. The inflammatory effect of the NLRP3 inflammasome is executed through IL-1ß and IL-18. Therefore, IL-1ß is one of the primary targets in chronic inflammatory conditions. However, current treatment regimens are dependent on anti- IL-1ß biologicals. The therapies targeting IL-1ß through inhibition of NLRP3 inflammasome are thus being actively explored. We identified safranal, a small molecule responsible for the essence of saffron as a potential inhibitor of the NLRP3 inflammasome. Safranal significantly suppressed the release of IL-1ß from ATP stimulated J774A.1 and bone marrow-derived macrophages (BMDMs) by regulating CASP1 and CASP8 dependent cleavage of pro-IL-1ß. Safranal markedly suppressed the expression of NLRP3 and its ATPase activity. Safranal treatment enhanced the expression of NRF2, whereas, si-RNA mediated silencing of Nrf2 abrogated the anti-NLRP3 effect of safranal. Furthermore, safranal inhibited ASC oligomerization and formation of ASC specks. Safranal also displayed anti-NLRP3 activity in multiple mice models. Treatment of animals with safranal reduced the production of IL-1ß in ATP elicited peritoneal inflammation, MSU induced air pouch inflammation, and MSU injected foot paw edema in mice. Thus, our data projects safranal as a potential preclinical drug candidate against NLRP3 inflammasome triggered chronic inflammation.

Optimization and validation of RT-LAMP assay for diagnosis of SARS-CoV2 including the globally dominant Delta variant.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 pandemic, has infected more than 179 million people worldwide. Testing of infected individuals is crucial for identification and isolation, thereby preventing further spread of the disease. Presently, Taqman™ Reverse Transcription Real Time PCR is considered gold standard, and is the most common technique used for molecular testing of COVID-19, though it requires sophisticated equipments, expertise and is also relatively expensive. OBJECTIVE: Development and optimization of an alternate molecular testing method for the diagnosis of COVID-19, through a two step Reverse Transcription Loop-mediated isothermal AMPlification (RT-LAMP). RESULTS: Primers for LAMP were carefully designed for discrimination from other closely related human pathogenic coronaviruses. Care was also taken that primer binding sites are present in conserved regions of SARS-CoV2. Our analysis shows that the primer binding sites are well conserved in all the variants of concern (VOC) and variants of interest (VOI), notified by World Health Organization (WHO). These lineages include B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.427/B.1.429, P.2, B.1.525, P.3, B.1.526 and B.1.617.1. Various DNA polymerases with strand displacement activity were evaluated and conditions were optimized for LAMP amplification and visualization. Different LAMP primer sets were also evaluated using synthetic templates as well as patient samples. CONCLUSION: In a double blind study, the RT-LAMP assay was validated on more than 150 patient samples at two different sites. The RT-LAMP assay appeared to be 89.2% accurate when compared to the Taqman™ rt-RT-PCR assay.

Screening of compound library identifies novel inhibitors against the MurA enzyme of Escherichia coli.

Bacterial cell has always been an attractive target for anti-infective drug discovery. MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) enzyme of Escherichia coli (E.coli) is crucial for peptidoglycan biosynthetic pathway, as it is involved in the early stages of bacterial cell wall biosynthesis. In the present study we aim to identify novel chemical structures targeting the MurA enzyme. For screening purpose, we used in silico approach (pharmacophore based strategy) for 52,026 library compounds (Chembridge, Chemdiv and in house synthetics) which resulted in identification of 50 compounds. These compounds were screened in vitro against MurA enzyme and release of inorganic phosphate (Pi) was estimated. Two compounds (IN00152 and IN00156) were found to inhibit MurA enzyme > 70% in primary screening and IC50 of 14.03 to 32.30 µM respectively. These two hits were further evaluated for their mode of inhibition studies and whole-cell activity where we observed 2-4 folds increase in activity in presence of Permeabilizer EDTA (Ethylenediaminetetraacetic acid). Combination studies were also performed with known antibiotics in presence of EDTA. Hits are reported for the first time against this target and our report also support the use of OM permeabilizer in combination with antibacterial compounds to address the permeability and efficacy issue. These lead hits can be further optimized for drug discovery. KEY POINTS: • Emerging Gram negative resistant strains is a matter of concern. • Need for new screening strategies to cope with drying up antibiotics pipeline. • Outer membrane permeabilizers could be useful to improve potency of molecules to reach its target.

Membrane transporters: the key drivers of transport of secondary metabolites in plants.

KEY MESSAGE: This review summarizes the recent updates in the area of transporters of plant secondary metabolites, including their applied aspects in metabolic engineering of economically important secondary metabolites. Plants have evolved biosynthetic pathways to produce structurally diverse secondary metabolites, which serve distinct functions, including defense against pathogens and herbivory, thereby playing a pivotal role in plant ecological interactions. These compounds often display interesting bioactivities and, therefore, have been used as repositories of natural drugs and phytoceuticals for humans. At an elevated level, plant secondary metabolites could be cytotoxic to the plant cell itself; therefore, plants have developed sophisticated mechanisms to sequester these compounds to prevent cytotoxicity. Many of these valuable natural compounds and their precursors are biosynthesized and accumulated at diverse subcellular locations, and few are even transported to sink organs via long-distance transport, implying the involvement of compartmentalization via intra- and intercellular transport mechanisms. The transporter proteins belonging to different families of transporters, especially ATP binding cassette (ABC) and multidrug and toxic compound extrusion (MATE) have been implicated in membrane-mediated transport of certain plant secondary metabolites. Despite increasing reports on the characterization of transporter proteins and their genes, our knowledge about the transporters of several medicinally and economically important plant secondary metabolites is still enigmatic. A comprehensive understanding of the molecular mechanisms underlying the whole route of secondary metabolite transportome, in addition to the biosynthetic pathways, will aid in systematic and targeted metabolic engineering of high-value secondary metabolites. The present review embodies a comprehensive update on the progress made in the elucidation of transporters of secondary metabolites in view of basic and applied aspects of their transport mechanism.

Determinants of Congregational Attendees' Psychological Outcomes.

Congregational membership is known to enhance physical and mental health, as well as providing psychological outcomes (subjective well-being and loneliness). However, it is not clear whether these outcomes can be attributed to social resources or personal resources. The study was conducted in Israel among 260 active synagogue members between 18 and 88 years of age (mean = 32.91). Structural equation modeling suggested that personal resources were the strongest predictors of subjective well-being and loneliness, whereas social resources had lower predictive power. The article offers unique insights into the role of social and personal factors in congregation members' subjective well-being and loneliness.

Management of low-risk prostate cancer in patients with enlarged glands and lower urinary tract symptoms: robotic total prostatectomy, a novel technique.

PURPOSE: Low-risk prostate cancer (PCa) is primarily managed with Active Surveillance (AS). A subset of these patients have significantly enlarged glands and lower urinary tract symptoms (LUTS) recalcitrant to medical therapy. Radical treatment in this patient population risks compromise to both erectile function and continence. Therefore, our primary aim is to introduce a novel surgical technique, robotic total prostatectomy (RTP), for the management of severely enlarged prostate hyperplasia with concomitant suspicion of low-risk prostate cancer. METHODS: After IRB approval and patient consultation/education, we performed RTP on 12 consecutive patients who presented with low-risk PCa and significantly enlarged prostate glands with LUTS. Inclusion criteria included patients with suspicion of low-risk malignancy, subjective/objective complaint of LUTS, and pre-operative prostate size > 60 g. Preoperative, perioperative and postoperative variables were studied in the following domains: surgical, oncologic, continence and erectile function. RESULTS: A total of 12 patients underwent RTP. Mean preoperative prostate volume and PSA was estimated at 96.96 g and 8.79, respectively. Surgical time, EBL and LOS was estimated at 180.8 min, 189.6 ml, and 2 days, respectively. Post-operative variables confirmed resolution of LUTS (mean PVR 41.78/IPSS 8.3) and efficient oncologic control (mean PSA 0.04), with minimal compromise of sexual function. 100% continence was achieved at 3 months. CONCLUSION: RTP is a novel, efficient surgical procedure for the treatment of patients with at-risk for low-grade malignancy and symptomatic LUTS in an enlarged gland. Expanding the indication to patients with low-risk malignancy, irrespective of prostate size may alleviate the adverse effects of radical treatment in this select subset of patients.

Total Synthesis of Phospholipomannan of Candida albicans.

First, total synthesis of the cell surface phospholipomannan anchor [ß-Manp-(1 → 2)-ß-Manp]n-(1 → 2)-ß-Manp-(1 → 2)-α-Manp-1 → P-(O → 6)-α-Manp-(1 → 2)-Inositol-1-P-(O → 1)-phytoceramide of Candida albicans is reported. The target phospholipomannan (PLM) anchor poses synthetic challenges such as the unusual kinetically controlled (1 → 2)-ß-oligomannan domain, anomeric phosphodiester, and unique phytoceramide lipid tail linked to the glycan through a phosphate group. The synthesis of PLM anchor was accomplished using a convergent block synthetic approach using three main appropriately protected building blocks: (1 → 2)-ß-tetramannan repeats, pseudodisaccharide, and phytoceramide-1-H-phosphonate. The most challenging (1 → 2)-ß-tetramannan domain was synthesized in one pot using the preactivation method. The phytoceramide-1-H-phosphonate was synthesized through an enantioselective A3 three-component coupling reaction. Finally, the phytoceramide-1-H-phosphonate moiety was coupled with pseudodisaccharide followed by deacetylation to produce the acceptor, which on subsequent coupling with tetramannosyl-H-phosphonate provided the fully protected PLM anchor. Final deprotection was successfully achieved by Pearlman's hydrogenation.

Indian Morinda species: A review.

Morinda is a largest genus of Rubiaceae family, and its 11 species are found in India. In India, plant species are known by several common names as great morinda, Indian mulberry, noni, beach mulberry and cheese fruit. Various Morinda products (capsules, tablets, skin products and fruit juices) are available in the market, used by people for treatment of several health complaints. A diversity of phytochemicals including iridoids, flavonoids, flavonoid glycosides, anthraquinones, coumarins, lignanas, noniosides, phenolics and triterpenoids have been reported from Morinda species. Morinda species are used in the treatment of inflammation, cancer, diabetes, psyquiatric disorders, and bacterial and viral infections. The noni fruit juice (Morinda citrifolia) and its products are used clinically in the treatment of cancer, hypertension and cervical spondylosis affecting patients. M. citrifolia fuit juice, with different doses, is used in the maintaining blood pressure and reducing of superoxides, HDL and LDL levels. Similarly, oligosaccharide capsules and tablets of root extract of M. officinalis are recommended as medicine for the treatment of kidney problems and sexual dysfunctions of patients. The toxicological studies revealed that higher doses of fruit juice (4,000 or 5,000 mg/kg) of M. citrifolia for 2 or more months cause toxic effects on liver and kidneys. M. officinalis root extracts (ethanolic and aqueous) are found fully safe during treatment of diseases. A large number of reviews are available on M. citrifolia but very few studies are conducted on other Indian Morinda species. This review reports the comprehensive knowledge on state-wise distribution, botany, ethnomedicinal uses, phytochemistry, pharmacological activities, clinical applications and toxicological evaluations of 11 species of Morinda found in India.

Glycyrrhizic Acid Prevents Oxidative Stress Mediated DNA Damage Response through Modulation of Autophagy in Ultraviolet-B-Irradiated Human Primary Dermal Fibroblasts.

BACKGROUND/AIMS: Excessive exposure to UV radiation negatively affects the human skin, characterized by photo-damage (premature aging & carcinogenesis). UV-B radiation causes about 90% of non-melanoma skin cancers by damaging de-oxy ribonucleic acids (DNA). We have previously reported that UV-B radiation induces skin photodamage through oxidative & Endoplasmic Reticulum (ER) stresses and Glycyrrhizic acid (GA), a natural triterpene, protects skin cells against such stresses. UV-B radiation elicits signalling cascade by activation of proteins involved in sensing, signalling, and repair process of DNA damage. In this study, we explored the effects & mechanisms of Glycyrrhizic acid (GA) against UV-B -induced photodamage using a well established cellular model. METHODS: We used primary human dermal fibroblasts as a cellular model. The cells were cultured in the presence or absence of GA for 3,6, & 24 h. Effect of UV-B was assessed by examining cell viability, cell morphology, oxidative stress, ER stress, DNA damage & cellular autophagy levels through biochemical assays, microscopy & protein expression studies. RESULTS: In this study, we have determined the effect of GA on autophagy mediated DNA damage response system as the main mechanism in preventing photodamage due to UV-B -irradiation to primary human dermal fibroblasts (HDFs). GA treatment to UV-B exposed HDFs, significantly inhibited cell death, oxidative & ER stress responses, prevented Cyclobutane Pyrimidine dimer (CPD) DNA adduct formation, and DNA fragmentation via modulation of UV-B induced autophagic flux. Present results showed that GA treatment quenched reactive oxygen species (ROS), relieved ER stress response, improved autophagy (6 hr's post-UV-B -irradiation) and prevented UV-B induced DNA damage. CONCLUSION: The present study links autophagy induction by GA as the main mechanism in the prevention of DNA damage and provides a mechanistic basis for the photoprotective effect of GA and suggests that GA can be potentially developed as a promising agent against UV-B induced skin photo-damage.

Introducing Oxo-Phenylacetyl (OPAc) as a Protecting Group for Carbohydrates.

A series of oxo-phenylacetyl (OPAc)-protected saccharides, with divergent base sensitivity profiles against benzoyl (Bz) and acetyl (Ac) were synthesized, and KHSO5/AcCl in methanol was identified as an easy, mild, selective, and efficient deprotecting reagent for their removal in the perspective of carbohydrate synthesis. Timely monitoring of AcCl reagent was supportive in both sequential and simultaneous deprotecting of OPAc, Bz, and Ac. The salient feature of our method is the orthogonal stability against different groups, its ease to generate different valuable acceptors using designed monosaccharides, and use of OPAc as a glycosyl donar.