Current studies on the degradation of microplastics in the terrestrial and aquatic ecosystem.

Soil and water are two important basic ecosystems for the survival of different organisms. The excessive microplastic pollutants in soil have been directly discharged into the terrestrial ecosystems. Microplastic pollutants (MPs) constitute a ubiquitous global menace due to their durability, flexibility, and tough nature. MPs posed threat to the sustainability of the ecosystem due to their small size and easy transportation via ecological series resulting in the accumulation of MPs in aquatic and terrestrial ecosystems. After being emitted into the terrestrial ecosystem, the MPs might be aged by oxidative degeneration (photo/thermal), reprecipitation (bioturbation), and hetero-accumulation. The mechanism of adsorption, degradation, and breakdown of MPs into unaffected plastic debris is accomplished by using several biological, physical, and chemical strategies. This review presents the importance of ecosystems, occurrence and sources of MPs, its toxicity, and the alteration in the ecology of the ecosystems. The inhibitory impact of MPs on the ecosystems also documents to unveil the ecological hazards of MPs. Further research is required to study the immobilization and recovery efficiency of MPs on a larger scale.

Effect of vinpocetine alone and in combination with enalapril in experimental model of diabetic cardiomyopathy in rats: possible involvement of PDE-1/TGF-ß/ Smad 2/3 signalling pathways.

OBJECTIVE: Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats. METHODS: Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-ß (TGF-ß) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR. KEY FINDING: Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-ß and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril. CONCLUSIONS: Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-ß/Smad 2/3.

Essential oil nebulization in mild COVID-19(EONCO): Early phase exploratory clinical trial.

Background: Medications studied for therapeutic benefits in coronavirus disease 2019 (COVID-19) have produced inconclusive efficacy results except for steroids. Objective: A prospective randomized open-label, parallel-arm Phase I/II clinical trial was planned to compare essential oil (EO) blend versus placebo nebulization in mild COVID-19. Methods: A Phase I safety evaluation was carried out in a single ascending and multiple ascending dose study designs. We assessed Phase II therapeutic efficacy on COVID-19 and general respiratory symptoms on days 0, 3, 5, 7, 10, and 14 on the predesigned case record form. Viremia was evaluated on day 0, day 5, and day 10. Results: Dose-limiting toxicities were not reached with the doses, frequencies, and duration studied, thus confirming the formulation's preliminary safety. General respiratory symptoms (p < 0.001), anosmia (p < 0.05), and dysgeusia (p < 0.001) benefited significantly with the use of EO blend nebulization compared to placebo. Symptomatic COVID-19 participants with mild disease did not show treatment benefits in terms of symptomatic relief (p = 1.0) and viremia clearance (p = 0.74) compared to the placebo. EO blend was found to be associated with the reduced evolution of symptoms in previously asymptomatic reverse transcription polymerase chain reaction (RT-PCR)-positive study participants (p = 0.034). Conclusion: EO nebulization appears to be a safer add-on symptomatic relief approach for mild COVID-19. However, the direct antiviral action of the EO blend needs to be assessed with different concentrations of combinations of individual phytochemicals in the EO blend.

Hepatoprotective effect of Physalis divaricata in paracetamol induced hepatotoxicity: In vitro, in silico and in vivo analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalis divaricata D. Don. is an erect weed of family Solanaceae. The root extract of this plant is used by the indigenous communities of Sub-Himalayan region of Uttarakhand, India for the treatment of liver disorders. AIM OF THE STUDY: To evaluate hepatoprotective potential of P. divaricata in paracetamol (PCM) induced hepatotoxicity in rats. MATERIALS AND METHODS: The dried roots of P. divaricata were subjected to extraction using different solvents. The chloroform extract, methanol extract and bioactive aqueous fraction of methanol extract were evaluated for hepatoprotective effect. After initial in vitro screening, all extracts were screened for hepatoprotective potential in PCM (3 g/kg p.o) induced hepatotoxicity. Following PCM administration, extracts were administered orally for 7 days in increasing dose concentrations. All the animals were euthanized on eighth day, serum and liver tissues were collected and subjected to various biochemical and histopathological analysis. Aqueous fraction of methanol extract was further analyzed using LC- MS analysis. RESULTS: Methanol extract and its bioactive aqueous fraction exhibited significant and better in vitro antioxidant and antiproliferative activity as compared to chloroform extract. PCM treatment caused hepatotoxicity as assessed by altered levels of various hepatic biomarkers (increase in the levels of ALT, AST, ALP, albumin, triglycerides, cholesterol, TBARS, and AOPPs as well as decrease in GSH and TrxR levels) along with histopathological changes (portal to portal bridging, necrosis, and inflammation). Methanolic extract (200, 400 and 800 mg/kg) and its aqueous fraction treatment (25, 50 and 100 mg/kg) significantly restored elevated hepatic biomarkers, oxidative stress, and protected normal hepato-architecture. LC-MS analysis of aqueous fraction showed presence of rutin and kaempferol. In silico analysis further showed the capability of rutin to make complex with TNF-α and block its interaction with the target site. CONCLUSION: Aqueous fraction showed maximum hepatoprotective potential as conceived through in vitro and in vivo studies. Presence of rutin may explain hepatoprotective potential of P. divaricata.

Ameliorative role of inducible nitric oxide synthase inhibitors against sodium arsenite-induced renal and hepatic dysfunction in rats.

Arsenic exposure causes immense health distress by increasing risk of cardiovascular abnormalities, diabetes mellitus, neurotoxicity, and nephrotoxicity. The present study explored the role of inducible nitric oxide synthase (iNOS) inhibitors against sodium arsenite-induced renal and hepatic dysfunction in rats. Female Sprague Dawley rats were subjected to arsenic toxicity by administering sodium arsenite (5 mg/kg/day, oral) for 4 weeks. The iNOS inhibitors, S-methylisothiourea (10 mg/kg, i.p.) and aminoguanidine (100 mg/kg, i.p.) were given one hour before sodium arsenite administration in rats for 4 weeks. Sodium arsenite led rise in serum creatinine, urea, uric acid, electrolytes (potassium, fractional excretion of sodium), microproteinuria, and decreased creatinine clearance (p < 0.001) indicated renal dysfunction in rats. Arsenic-intoxication resulted in significant oxidative stress in rat kidneys, which was measured in terms of increase in lipid peroxides, superoxide anion generation and decrease in reduced glutathione (p < 0.001) levels. A threefold increase in renal hydroxyproline level in arsenic intoxicated rats indicated fibrosis. Hematoxylin-eosin staining indicated tubular damage, whereas picrosirius red staining highlighted collagen deposition in rat kidneys. S-methylisothiourea and aminoguanidine improved renal function and attenuated arsenic led renal oxidative stress, fibrosis, and decreased the kidney injury score. Additionally, arsenite-intoxication resulted in significant rise in hepatic parameters (serum aspartate aminotransferase, alanine transferase, alkaline phosphatase, and bilirubin (p < 0.001) along with multi-fold increase in oxidative stress, fibrosis and liver injury score in rats, which was significantly (p < 0.001) attenuated by concurrent administration of iNOS inhibitors). Hence, it is concluded that iNOS inhibitors attenuate sodium arsenite-induced renal and hepatic dysfunction in rats.

Betaine attenuates sodium arsenite-induced renal dysfunction in rats.

Exposure to higher levels of arsenic is a serious threat affecting human health worldwide. We investigated the protective role of betaine (N,N,N-trimethylglycine) against sodium arsenite-induced renal dysfunction in rats. Sodium arsenite (5 mg/kg, oral) was given to rats for 4 weeks to induce nephrotoxicity. Betaine (125 and 250 mg/kg, oral) was administered in rats for 4 weeks along with sodium-arsenite feeding. Arsenic-induced renal dysfunction was demonstrated by measuring serum creatinine, creatinine clearance, urea, uric acid, potassium, fractional excretion of sodium, and microproteinuria. Oxidative stress in rat kidneys was determined by assaying thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels. Furthermore, hydroxyproline assay was done to assess renal fibrosis in arsenic intoxicated rats. Hematoxylin-eosin and picrosirius red staining revealed pathological alterations in rat kidneys. Renal endothelial nitric oxide synthase (eNOS) expression was determined by immuno-histochemistry. Concurrent administration of betaine abrogated arsenic-induced renal biochemical and histological changes in rats. Betaine treatment significantly attenuated arsenic-induced decrease in renal eNOS expression. In conclusion, betaine is protective against sodium arsenite-induced renal dysfunction, which may be attributed to its anti-oxidant activity and modulation of renal eNOS expression in rat kidneys.

Ameliorative Role of Diallyl Disulfide Against Glycerol-induced Nephrotoxicity in Rats.

INTRODUCTION: This study investigated the role of diallyl disulfide (DADS) against glycerol-induced nephrotoxicity in rats. Moreover, the role of peroxisome proliferator activated receptor-γ (PPAR-γ) in DADS-mediated renoprotection has been explored. MATERIALS AND METHODS: Male Wistar albino rats were challenged with glycerol (50% w/v, 8 mL/kg intramuscular) to induce nephrotoxicity. Kidney injury was quantified by measuring serum creatinine, creatinine clearance, urea, potassium, fractional excretion of sodium, and microproteinuria in rats. Renal oxidative stress was measured in terms of thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione levels. Hematoxylin-eosin (H&E) and periodic acid Schiff staining of renal samples was done to show histological changes. Glycerol-induced muscle damage was quantified by assaying creatine kinase (CK) levels in rat serum. RESULTS: Administration of glycerol resulted in muscle damage as reflected by significant rise in CK levels in rats. Glycerol intoxication led kidney damage was reflected by significant change in renal biochemical parameters, renal oxidative stress and histological changes in rat kidneys. Administration of DADS attenuated glycerol-induced renal damage. Notably, pretreatment with bisphenol A diglycidyl ether, a PPAR-γ antagonist, abolished DADS renoprotection in rats. CONCLUSION: We conclude that DADS affords protection against glycerol-induced renal damage in rats. Moreover, PPAR-γ plays a key role in DADS-mediated renoprotective effect.

Mechanistic interplay of various mediators involved in mediating the neuroprotective effect of daphnetin.

Daphnetin is a 7, 8 dihydroxy coumarin isolated from different medicinal plants of the Thymelaeaceae family and exhibits copious pharmacological activities including neuroprotection, anti-cancer, anti-malarial, anti-inflammatory, anti-parasitic and anti-arthritic activity. It has been proved to be an effective neuroprotective agent in several preclinical animal studies and cell line examinations. It is found to interact with different cellular mediators and signaling pathways to confer protection against neurodegeneration. The reactive oxygen species and inflammatory mediators are the major culprits of different neurodegenerative diseases. Oxidative stress activates the pro-apoptotic proteins and inhibits anti-apoptotic proteins, leading to neuronal cell death. Daphnetin restores cellular redox balance by upregulating the antioxidants level (GSH and SOD), anti-apoptotic protein (Bcl-2), as well as by reducing the levels of proinflammatory cytokines, executioner caspase-3, pro-apoptotic-Bax, and oxidative stress markers. Furthermore, activation of Nrf-2/HO-1 signaling and upregulation of HSP-70 governs the protection elicited by daphnetin against oxidative stress-induced neuronal apoptosis. Daphnetin modulated inhibition of JNK-MAPK, JAK-STAT, and TLR-4/NF-κB signaling pathways also contributed to its neuroprotective effect. The positive effects of daphnetin have been also related to its AChE, BChE, and BACE-1 inhibitory potential. The present review has been designed to explore the mechanistic interplay of various mediators in mediating the neuroprotective effects of daphnetin.

Daphnetin, a natural coumarin averts reserpine-induced fibromyalgia in mice: modulation of MAO-A.

Fibromyalgia is a common, chronic, and generalized pain syndrome that is often associated with comorbid depression. The etiology of fibromyalgia is complex; most researchers have documented that the hallmark symptoms are due to the central nervous system's abnormal functioning. Neurotransmitters such as serotonin, norepinephrine, and glutamate, have been reported to be key regulators of fibromyalgia syndrome. Daphnetin is a 7, 8 dihydroxy coumarin widely distributed in Thymelaeaceae family plants, possessing various activities such as anti-arthritic, anti-tumor, anti-malarial, and anti-parasitic. The present study was designed to explore the potential of daphnetin against reserpine-induced fibromyalgia in mice. In mice, a fibromyalgia-like state was achieved by injecting reserpine (0.5 mg/kg, s.c) continuously for 3 days. All behavioral tests were conducted on the 4th and 6th day of experimentation. Reserpine administration significantly increased the mechanical hypersensitivity in electronic von Frey (eVF) and pressure application measurement (PAM) tests. It also increased the immobility period and time to reach the platform in force swim test (FST) and Morris water maze (MWM) test, respectively. In the biochemical analysis, reserpine treatment upregulated the monoamine oxidase-A (MAO-A) activity and level of glutamate, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), and thiobarbituric acid reactive substances (TBARS). Whereas, it decreased the level of glutathione (GSH), dopamine, serotonin, and norepinephrine. Daphnetin pretreatment attenuated the behavioral and biochemical changes induced by reserpine. Thus, the current investigation results delineate that daphnetin might exert its protective effect by inhibiting inflammatory stress and MAO-A-mediated neurotransmitter depletion and oxidative stress.

Biological Evaluation of Aegle marmelos Fruit Extract and Isolated Aegeline in Alleviating Pain-Depression Dyad: In Silico Analysis of Aegeline on MAO-A and iNOS.

Pain and depression have been assessed to co-occur in up to 80% of patients, and this comorbidity is more debilitating and pricier for the patients as compared to either of these disorders alone. Aegle marmelos is a well-known medicinal plant with a broad spectrum of pharmacological activities. Aegeline is a relatively unexplored molecule present in Aegle marmelos. Therefore, the current investigation aims to explore the potential of Aegle marmelos fruit extract (AMFE) and isolated aegeline against the reserpine-induced pain-depression dyad. In the current investigation, aegeline was isolated from AMFE, followed by spectroscopic characterization, i.e., using NMR and mass analyses. AMFE (200 mg kg-1 p.o) and aegeline (10 mg kg-1 p.o.) were administered to reserpinized (0.5 mg kg-1 s.c.) mice, and clorgyline (3 mg kg-1 i.p.) was taken as the standard drug. AMFE and aegeline significantly alleviated the reserpine-induced reduction in a pain threshold and an increase in immobility as observed in behavioral tests of pain and depression, respectively. In silico molecular docking studies of aegeline showed a good binding interaction at the active sites of MAO-A and iNOS. The in vivo analysis showed that AMFE and aegeline treatment significantly decreased the monoamine oxidase-A (MAO-A) activity, serum interleukin-6 (IL-6) level, and lipid peroxidation, along with an increase in the reduced glutathione level in comparison to the reserpine-treated group. Immunofluorescence studies also showed that AMFE and aegeline abrogated the reserpine-induced increase in iNOS expression. Conclusively, the results delineate that AMFE and aegeline might exert a protective effect via downregulating the MAO-A hyperactivity, IL-6 level, oxidative and nitrosative stress.

Tinospora cordifolia ameliorates brain functions impairments associated with high fat diet induced obesity.

Obesity is a rapidly growing health problem worldwide and its prevalence has increased markedly in both the developing and developed nations. It is associated with a range of co-morbidities such as cardiovascular disease, type 2 diabetes mellitus, and cognitive dysfunctions. Therefore, the need for a safe and effective treatment has led to the exploration of natural products for the management of obesity. In the present study, we tested the anxiolytic, anti-apoptotic, and anti-neuroinflammatory potential of Tinospora cordifolia in a high fat diet-induced obesity rat model system. Young female Wistar albino rats were divided into three groups: (1) Low fat diet (LFD), fed on normal chow feed; (2) High fat diet (HFD), fed on diet containing 30% fat by weight; and (3) High fat diet containing extract (HFDE), fed on high fat diet supplemented with the stem powder of T. cordifolia (TCP). The rats from each group were kept on their respective feeding regimen for 12 weeks. The body weight and calorie intake were recorded weekly. The elevated plus maze test and rotarod performance test were performed to evaluate the anxiety-like behavior and locomotor coordination, respectively. The levels of serum cytokines (IL-6 and TNF-α) were estimated and various markers for inflammation, synaptic plasticity, apoptosis, and energy homeostasis were studied by western blotting. The HFDE rats showed reduced anxiety-like behavior and improved locomotor behavior as compared to HFD-induced obese rats. The TCP supplementation in high fat diet suppressed the expression of inflammatory molecules, including serum cytokines (IL-6 and TNF-α), and modulated apoptosis and synaptic plasticity. TCP was found to be effective in managing body weight in HFD-fed rats by maintaining energy metabolism and cellular homeostasis. T. cordifolia may be recommended as a potential therapeutic agent to prevent the adverse effects of obesity and obesity-associated brain dysfunctions.

Fenofibrate attenuates ischemia reperfusion-induced acute kidney injury and associated liver dysfunction in rats.

Ischemia/reperfusion (I/R) is one of the common reasons for acute kidney injury (AKI) and we need to develop effective therapies for treating AKI. We investigated the role of fenofibrate against I/R-induced AKI and associated hepatic dysfunction in rats. In male wistar albino rats, renal pedicle occlusion for 40 min and 24 h reperfusion resulted in AKI. I/R-induced AKI was demonstrated by measuring serum creatinine, creatinine clearance, urea, uric acid, potassium, fractional excretion of sodium and urinary microproteins. Oxidative stress in rat kidneys was quantified by assaying superoxide anion generation, thiobarbituric acid reactive substances, and reduced glutathione levels. AKI-induced hepatic damage was quantified by assaying serum aminotransferases, alkaline phosphatase and bilirubin levels. Moreover, serum cholesterol, high density lipoprotein and triglycerides were quantified. Hematoxylin-eosin staining of renal and hepatic tissues was done and the kidney and liver injury scores were determined. Immunohistology of endothelial nitric oxide synthase (eNOS) was done in rat kidneys. Fenofibrate was administered for 1 week before subjecting rats to AKI. In separate group, the nitric oxide synthase inhibitor, L-nitroarginine methyl ester (L-NAME) was administered prior to fenofibrate treatment. In I/R group, significant alteration in the serum/urine parameters indicated AKI and hepatic dysfunction along with marked increase in kidney and liver injury scores. Treatment with fenofibrate attenuated AKI and associated hepatic dysfunction. Moreover, I/R-induced decrease in renal eNOS expression was abrogated by fenofibrate. Pre-treatment with L-NAME abolished fenofibrate mediated reno- and hepato-protective effects. In conclusion, fenofibrate attenuates I/R-induced AKI and associated hepatic dysfunction putatively through modulation of eNOS expression.

Ameliorative role of bosentan, an endothelin receptor antagonist, against sodium arsenite-induced renal dysfunction in rats.

Arsenic exposure is well documented to cause serious health hazards, such as cardiovascular abnormalities, neurotoxicity and nephrotoxicity. In the present study, we intended to explore the role of bosentan, an endothelial receptor antagonist, against sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Sodium arsenite (5 mg/kg, oral) was administered for 4 weeks to induce renal dysfunction in rats. Sodium arsenite intoxicated rats were treated with bosentan (50 and 100 mg/kg, oral) for 4 weeks. Arsenic led renal damage was demonstrated by significant increase in serum creatinine, urea, uric acid, potassium, fractional excretion of sodium, microproteinuria and decreased creatinine clearance in rats. Sodium arsenite resulted in marked oxidative stress in rat kidneys as indicated by profound increase in lipid peroxides, and superoxide anion generation alongwith decrease in reduced glutathione levels. Hydroxyproline assay highlighted arsenic-induced renal fibrosis in rats. Hematoxylin-eosin staining indicated glomerular and tubular changes in rat kidneys. Picrosirius red staining highlighted collagen deposition in renal tissues of arsenic treated rats. Immunohistological results demonstrated the reduction of renal eNOS expression in arsenic treated rats. Notably, treatment with bosentan attenuated arsenic-induced renal damage and resisted arsenic-led reduction in renal eNOS expression. In addition, sodium arsenite-induced alteration in hepatic parameters (serum aspartate aminotransferase, alanine transferase, alkaline phosphatase, bilirubin), oxidative stress and histological changes were abrogated by bosentan treatment in rats. Hence, we conclude that bosentan treatment attenuated sodium arsenite-induced oxidative stress, fibrosis and reduction in renal eNOS expression in rat kidneys. Moreover, bosentan abrogated arsenic led hepatic changes in rats.

Protective Effect of Esculetin, Natural Coumarin in Mice Model of Fibromyalgia: Targeting Pro-Inflammatory Cytokines and MAO-A.

Fibromyalgia is a refractory syndrome characterized by chronic wayward pain and complex co-morbid psychological trepidation. The current treatments have a limited role and proper clinical benefits are far from satisfactory. Naturally occurring coumarins such as osthole are known to have analgesic and anti-inflammatory activities. Therefore, the current investigation was designed to explore the potential of natural coumarin esculetin (2.5, 5, and 10 mg/kg) in mitigating reserpine-induced fibromyalgia in Swiss albino mice. Esculetin is a 6,7 dihydroxy-coumarin obtained from various plant sources such as Aesculus hippocastanum L, Ceratostigma willmottianum, Citrus limonia, etc. Reserpine (0.5 mg/kg/day s.c.) treatment for first 3 days, significantly altered the behavior of mice as evidenced by reduced paw withdrawal threshold in pressure application measurement (PAM) test and electronic von-Frey (eVF) test, increased immobility time in forced swim test (FST), increased latency to reach the platform in Morris water maze (MWM) test and reduced number of square crossed in the open field test (OFT). These behavioral deficits with reserpine treatment were integrated with a reduced level of serotonin (5-HT), reduced glutathione (GSH), along with an increase in monoamine oxidase-A (MAO-A) activity, pro-inflammatory cytokines (IL-1ß, TNF-α), thiobarbituric acid reactive substances (TBARS) and glutamate level. Esculetin (10 mg/kg/day i.p) treatment for 5 days, significantly abrogated reserpine induced behavioral and biochemical alterations. Whereas, no significant improvement was observed with lower doses of esculetin i.e. 2.5 and 5 mg/kg.

Enhanced oral bioavailability and anti-diabetic activity of canagliflozin through a spray dried lipid based oral delivery: a novel paradigm.

AIM: Canagliflozin (CFZ), a novel SGLT II antagonist, exhibits erratic absorption after oral administration. The current study entails development and evaluation of spray dried lipid based formulation (solid SMEDDS) for enhancing oral bioavailability and anti-diabetic activity of CFZ. METHODS: Solid SMEDDS developed through spray drying containing Neusilin US2 as an adsorbent. The formed solid SMEDDS were characterized for physicochemical and solid state attributes. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) were used to confirm the spherical morphology. In vitro dissolution, ex vivo permeability and in vivo pharmacokinetic studies were conducted to determine the release rate, permeation rate and absorption profile of CFZ, respectively. Pharmacodynamic studies were done as per standard protocols. RESULTS: The optimized solid SMEDDS exhibited acceptable practical yield and flow properties and is vouched with enhanced amorphization, nanoparticulate distribution and acceptable drug content. The spherical morphology of solid SMEDDS and reconstituted SMEDDS were confirmed in SEM and TEM, respectively. In vitro dissolution studies revealed multi-fold release behavior in CFZ in various dissolution media, whereas, remarkable permeability was observed in jejunum segment of rat intestine. Pharmacokinetic studies of CFZ in solid SMEDDS demonstrated 2.53 and 1.43 fold enhancement in Cmax and 2.73 and 1.98 fold in AUC 0-24h, as compared to pure API and marketed formulation, respectively. Pharmacological evaluation of solid SMEDDS revealed enhanced anti-diabetic activity of CFZ through predominant SGLT II inhibition in rats, as evident from evaluation of biochemical levels, urinary glucose excretion studies and SGLT II expression analysis. CONCLUSION: The current work describes significant improvement biopharmaceutical properties of CFZ in solid SMEDD formulation. Graphical abstract Graphical Abstract: Enhanced oral bioavailability and anti-diabetic activity of canagliflozin through a spray dried lipid based oral delivery: a novel paradigm.

Pleomorphic adenoma of the upper lip: A rare case report.

Pleomorphic adenoma (PA), also called mixed tumor, is the most common benign tumor of the salivary glands that mostly occurs in the parotid or submandibular glands but may also occur in the minor salivary glands that are distributed throughout the oral cavity. The common sites of PA of the minor salivary glands are the palates followed by lips and cheeks. Surgical removal with adequate margins is the principal treatment. We present a case of PA (arising from the minor salivary gland of the upper lip) - a rare site in a 65-year-old female who presented with a swelling upper lip of 2-year duration. Fine-needle aspiration cytology of the swelling revealed PA which was confirmed by histopathological examination after complete excision of the swelling.

Continuous-wave squeezed states of light via 'up-down' self-phase modulation.

Continuous-wave (cw) squeezed states of light have applications in sensing, metrology and secure communication. In recent decades their efficient generation has been based on parametric down-conversion, which requires pumping by externally generated pump light of twice the optical frequency. Currently, there is immense effort in miniaturizing squeezed-light sources for chip-integration. Designs that require just a single input wavelength are favored since they offer an easier realization. Here we report the first observation of cw squeezed states generated by self-phase modulation caused by subsequent up and down conversions. The wavelengths of input light and of balanced homodyne detection are identical, and 1550 nm in our case. At sideband frequencies around 1.075 GHz, a nonclassical noise reduction of (2.4 ± 0.1) dB is observed. The setup uses a second-order nonlinear crystal, but no externally generated light of twice the frequency. Our experiment is not miniaturized, but might open a route towards simplified chip-integrated realizations.

Amelioration of hepatic function, oxidative stress, and histopathologic damages by Cassia fistula L. fraction in thioacetamide-induced liver toxicity.

Cassia fistula L. (Caesalpinioideae) is a highly admirable medicinal plant and is traditionally recommended for the treatment of rheumatism, liver disorders, jaundice, and other inflammatory diseases. This study was designed to investigate the hepatoprotective properties of ethyl acetate fraction from C. fistula leaves in an animal model. Treatment with thioacetamide significantly elevated the level of serum glutamic-oxaloacetic transaminase (1.75-fold), alkaline phosphatase (4.07-fold), and total bilirubin (2.29-fold) as compared to the control. It was found that pretreatment of fraction followed by consecutive 2 days thioacetamide reduced the conversion of thioacetamide carcinogen to its reactive metabolites by phase I enzymes and increased the level of detoxification phase II along with antioxidative enzymes. The histopathological studies revealed the hepatoprotective nature of the fraction in restoring the normal architecture of thioacetamide-intoxicated damaged liver. The fraction showed downregulation in the expression level of p-PI3K, p-Akt, and p-mTOR pointing towards its chemopreventive potential. The HPLC analysis of the fraction had shown the dominance of three phenolic compounds namely, catechin, epicatechin, and chlorogenic acid. The above studies comprising histopathological, immunohistochemical, and hepatic enzymes are strong indicative of the potential protective ability of ethyl acetate fraction phytoconstituents against thioacetamide-induced toxicity. Graphical abstract.

Elucidating the role of size of hydroxyl apatite particles toward the development of competent antiosteoporotic bioceramic materials: In vitro and in vivo studies.

Osteoporosis caused by overdose of steroids is one of the major concerns for the orthopedic surgeons. Current therapeutic strategies offer limited success due to their inability to regenerate damaged bone at osteoporosis site. Therefore, there is an urgent need to develop a material having bone regeneration ability and also, ability to cure osteoporosis simultaneously. In this work, nanosized and microsized hydroxyl apatite (HAp) particles doped with europium (Eu) were prepared for diagnostic and therapeutic applications in biomedical engineering. Particles were characterized by X-ray diffraction to confirm the formation of HAp phase and transmission electron microscopy technique has been used to explore the size of microparticle and nanoparticle. In vitro release of antibiotic drug and degradation behavior in two different pHs of phosphate buffered saline was checked. Controlled drug release behavior and conversion of degraded ions into HAp is estimated by Higuchi's and 3D diffusion model, respectively. Osteoporosis was induced in 36 female Wistar rats by administering dexamethasone once a week for four consecutive weeks. Rats were treated with different doses of nano-HAp (25, 50, and 100 µg/kg intravenous single dose) and single dose of microsized HAp (100 µg/kg). After treatment, authors have evaluated sensitive biochemical markers of bone in serum. Continuous improvement in ultimate stiffness and Young's modulus of femur shaft of rats was observed with the increase in the dose of nano-HAp from 25 to 100 µg/kg. Results strongly suggest that europium-doped nano-HAp is more effective for treating severe osteoporosis in humans. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1723-1735, 2019.

Inner membrane complex 1l protein of Plasmodium falciparum links membrane lipids with cytoskeletal element 'actin' and its associated motor 'myosin'.

The inner membrane complex (IMC) is a defining feature of apicomplexans comprising of lipid and protein components involved in gliding motility and host cell invasion. Motility of Plasmodium parasites is accomplished by an actin and myosin based glideosome machinery situated between the parasite plasma membrane (PPM) and IMC. Here, we have studied in vivo expression and localization of a Plasmodium falciparum (Pf) IMC protein 'PfIMC1l' and characterized it functionally by using biochemical assays. We have identified cytoskeletal protein 'actin' and motor protein 'myosin' as novel binding partners of PfIMC1l, alongside its interaction with the lipids 'cholesterol' and 'phosphatidyl-inositol 4, 5 bisphosphate' (PIP2). While actin and myosin compete for interaction with PfIMC1l, actin and either of the lipids (cholesterol or PIP2) simultaneously bind PfIMC1l. Interestingly, PfIMC1l showed enhanced binding with actin in the presence of calcium ions, and displayed direct binding with calcium. Based on our in silico analysis and experimental data showing PfIMC1l-actin/myosin and PfIMC1l-lipid interactions, we propose that this protein may anchor the IMC membrane with the parasite gliding apparatus. Considering its binding with key proteins involved in motility viz. myosin and actin (with calcium dependence), we suggest that PfIMC1l may have a role in the locomotion of Plasmodium.