Design and Evaluation of Inorganic/Organic Hybrid Bio-composite for Site-Specific Oral Delivery of Darifenacin.

Benign hyperplasia (BHP) is a common disorder that affects men over the age of 60 years. Transurethral resection of the prostate (TURP) is the gold standard for operative treatment, but a range of drugs are also available to improve quality of life and to reduce BHP-associated urinary tract infections and complications. Darifenacin, an anti-muscarinic agent, has been found effective for relieving symptoms of overactive bladder associated with BHP, but the drug has poor solubility and bioavailability, which are major challenges in product development. An inorganic/organic bio-composite with gastric pH-resistant property was synthesized for the targeted oral delivery of Darifenacin to the lower gastrointestinal tract (GIT). This development was accomplished through co-precipitation of calcium carbonate in quince seed-based mucilage. The FTIR, XRD, DSC, and TGA results showed good drug-polymer compatibility, and the SEM images showed calcite formation in the quince hydrogel system. After 72 h, the drug release of 34% and 75% were observed in acidic (0.1N HCl) and 6.8 pH phosphate buffer, respectively. A restricted/less drug was permeated through gastric membrane (21.8%) as compared to permeation through intestinal membrane (65%.) The developed composite showed significant reduction in testosterone-induced prostatic hyperplasia (2.39 ± 0.12***) as compared to untreated diseased animal group. No sign of organ toxicity was observed against all the developed composites. In this study, we developed an inorganic-organic composite system that is highly biocompatible and effective for targeting the lower GIT, thereby avoiding the first-pass metabolism of darifenacin.

TGF-ß1 signaling can worsen NAFLD with liver fibrosis backdrop.

Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by the accumulation of fats in the liver. Relatively benign NAFLD often progresses to fibrosis, cirrhosis, and liver malignancies. Although NAFLD precedes fibrosis, continuous lipid overload keeps fueling fibrosis and the process of disease progression remains unhindered. It is well known that TGF-ß1 plays its part in liver fibrosis, yet its effects on liver lipid overload remain unknown. As TGF-ß1 signaling has been increasingly attempted to manage liver fibrosis, its actions on the primary suspect (NAFLD) are easily ignored. The complex interaction of inflammatory stress and lipid accumulation aided by mediators scuh as pro-inflammatory interleukins and TGF-ß1 forms the basis of NAFLD progression. Anticipatorily, the inhibition of TGF-ß1 signaling during anti-fibrotic treatment should reverse the NAFLD though the data remain scattered on this subject to date. TGF-ß1 signaling pathway is an important drug target in liver fibrosis and abundant literature is available on it, but its direct effects on NAFLD are rarely studied. This review aims to cover the pathogenesis of NAFLD focusing on the role of the TGF-ß1 in the disease progression, especially in the backdrop of liver fibrosis.

Role of Adaptor Protein Myeloid Differentiation 88 (MyD88) in Post-Subarachnoid Hemorrhage Inflammation: A Systematic Review.

Myeloid differentiation 88 (MyD88) is a well-established inflammatory adaptor protein. It is one of the essential downstream proteins of the toll-like receptor 4 (TLR4) signaling pathway. TLRs are pattern recognition receptors that are usually activated by the damage-associated molecular pattern molecules (DAMPs). Sterile inflammation is triggered by the endogenous DAMPs released in response to global cerebral ischemia and from extravasated blood after subarachnoid hemorrhage (SAH). In this review, we highlight the importance of the neuroinflammatory role of the MyD88 in the SAH. We also explore a few possible pharmacological agents that can be used to decrease SAH-associated neuroinflammation by modulating the MyD88 dependent functions. Pharmacological agents such as flavonoids, melatonin, fluoxetine, pentoxifylline and progesterone have been investigated experimentally to reduce the SAH-associated inflammation. Inhibition of the MyD88 not only reduces the expression of pro-inflammatory cytokines, but also potentially inhibits other processes that can augment the SAH associated inflammation. Further investigations are required to translate these findings in the clinical setting.

Abutilon indicum Exhibits Anxiolytic and Antidepressant Effects in Mice Models.

Abutilon indicum Linn (A. indicum) is native to tropical and subtropical zones and traditionally used in ulcer, diabetes, piles, jaundice, gonorrhoea and leprosy. Erstwhile phytochemical analysis showed the presence of flavonoids, sesquiterpenes, gallic acid, ß-sitosterols, geraniol, and caryophyllene. The study identifies the antidepressant potential of the crude methanolic extract of A. indicum (Ai.Cr). Crude methanolic extract of leaves and bark was prepared using maceration and freeze-drying. Forty Swiss-albino mice were divided into five groups containing eight mice each. Designated groups were administered with normal saline, Ai.Cr (30, 50, and 100 mg/kg) and diazepam (1 mg/kg) or fluoxetine (10 mg/kg) intra-peritoneally. Light and Dark Exploration (LDE), Elevated Plus Maze (EPM) and Hole Board (HB) test were used for anxiolytic activity testing, while forced swim and tail suspension model were used for the evaluation of antidepressant potential of Ai.Cr. Results showed that mice spent more time in light; passed more duration in open arms and raised number of head poking in respective anxiolytic LDE, EPM, and HB tests. Similarly, mobility time was raised in forced swim and tail suspension antidepressant testing. Ai.Cr has significant dose dependent antidepressant and anxiolytic potential, which peaks at highest dose (100 mg/kg) used in this study. A. indicum has significant pharmacological potential against anxiety and depression.

Evaluation of cytokines expression in the phytoflavonoids treated epileptic rats: An in vivo study.

Seizure are basic characteristic of epilepsy; these initiate due to irregular, excessive and synchronous electrical discharges. We aimed to determine the antiepileptic potential of phyto-flavonoids on the evaluation of the mRNA expression of TNF-α, IL-6, IL-1 Beta, IL-10, IL-1Ra, IL 4 and NF-κB. We induced chronic epilepsy in rats by administering sub-convulsive dose of pentylenetetrazole (25 mg/kg/day for 28 days). We observed intensity and frequency of seizures. Levetiracetam was used as a standard drug and divided all the subjects into 6 groups. All experimental animals were trained to acclimatize the behaviour tests. Food and water intake, changes in the body weight and WBC levels were assessed. Using qPCR, we assessed mRNA expression levels of, TNF α, IL-6, IL1 beta, NF-κB, IL1Ra, IL-4, and IL-10. qPCR confirmed the down regulation of the pro- and up-regulation of the anti-inflammatory cytokines. Significant reduction in seizure frequency, neutrophil counts and improvement in behaviour were observed when compared treatment group to control groups. PF exerts their antiepileptic activity by the downregulation of pro- and upregulation of anti-inflammatory cytokines respectively.

Lauric acid: Its role in behavioral modulation, neuro-inflammatory and oxidative stress markers in haloperidol induced Parkinson's disease.

The study was designed to investigate the neuro-protection of lauric acid (LA) on haloperidol (HPD) induced Parkinson's disease (PkD) rat model. Rats were divided into group A (normal), group B (diseased, by HPD 1mg/kg i.p. for 14 days), group C (standard treatment, levodopa 30 mg/kg), group D (vehicle coconut oil 1ml/kg), group E (LA 0.66mg/kg) and group F (LA 1.32mg/kg) for 35 days after induction of PkD. The study displayed a state of oxidative stress in the striatum of rat model of PkD as shown from the increased MDA, NO levels and the decreased superoxide dismutase levels. HPD caused an increase in tumor necrosis factor-α level, NF-κB, IL-8 mRNA expression and suppress IL-4 expression. Neuro-protection with LA attenuated the oxidative stress and changes in pro-inflammatory cytokines induced due to PkD induction. The LA treatment also showed improvement in the histo-pathology of the rats' brain. LA also improved behavioral performances, food intake, weight gain as compared to animal of diseased group and prevented decline in motor activities (assessed Rotarod, and Beam walking test). LA showed significant neuro-protection against oxidative stress, inflammatory cytokines and behavioral changes in HPD induced rat model of PkD.

Review-Medicinal plants and management of Diabetes Mellitus: A review.

Diabetes is a metabolic disorder characterized by chronic hyperglycemia and associated with dysfunction and failure of various body organs. Alarming increase in prevalence rate has made this disorder a major health problem globally. The available treatment modalities are not sufficient to combat diabetes and associated complications. A number of medicinal plants have a significant antidiabetic potential against diabetes mellitus. We have listed the use of important medicinal herbs for the treatment and management of diabetes in this review.

Metasurface for Engineering Superimposed Ince-Gaussian Beams.

Ince-Gaussian beams (IGBs) are the third complete family of exact and orthogonal solutions of the paraxial wave equation and have been applied in many fields ranging from particle trapping to quantum optics. IGBs play a very important role in optics as they represent the exact and continuous transition modes connecting Laguerre-Gaussian and Hermite-Gaussian beams. The method currently in use suffers from the high cost, complexity, and large volume of the optical system. The superposition of IGBs can generate complicated structured beams with multiple phase and polarization singularities. A metasurface approach is proposed to realizing various superpositions of IGBs without relying on a complicated optical setup. By superimposing IGBs with even and odd modes, multiple phase, and polarization singularities are observed in the resultant beams. The phase and polarization singularities are modulated by setting the initial phase in the design and controlling the incident linear polarization. The compactness of the developed metasurface devices and the unique properties of the generated beams have the potential to impact many practical applications such as particle manipulation, orbital angular momentum spectrum manipulation, and optical communications.

Exploring the Significance of Vitamin D Levels as a Biomarker in Ear Diseases: A Narrative Review.

This narrative review examines the role of vitamin D as a biomarker in ear disorders, including benign paroxysmal positional vertigo (BPPV), otitis media, bell's palsy, Meniere's disease, and hearing loss. PubMed, The Cochrane Library, and Google Scholar were utilized to conduct a comprehensive literature search, and findings were combined from studies from 2014 to 2024. As highlighted in this review, there is a consistent association between vitamin D deficiency and an increased risk and recurrence of disease especially in BPPV and otitis media. Its importance as a prognostic biomarker is emphasized in Bell's palsy, where higher levels of deficiencies in vitamin D are associated with higher grades of severity on the House Brackmann grading system. Vitamin D deficiency can also lead to sensorineural hearing loss due to its receptors present in the inner ear or its effect on calcium metabolism. Serum levels of vitamin D have also been shown to influence treatment outcome of sensorineural hearing loss. The role of vitamin D in Meniere's disease is unclear as no cause has been identified for the increase in endolymphatic fluid. The findings of this review emphasize the importance of serum vitamin D as a biomarker in ear disorders and advocate for more studies to be conducted to assess the importance of optimal dosing of vitamin D for the progression and outcome of these diseases.

Mortality Audit in the Head and Neck Surgery Ward: A Retrospective Study in a Tertiary Care Hospital of Pakistan.

Background Mortality audit is important for healthcare workers, but this data is lacking in developing countries. It helps to provide material about the cause of death, mortality rate, age, and gender. In a surgical department, such information can help identify key public health challenges that are contributing to morbidity and mortality, and this information can help healthcare workers better tackle those pathologies and focus on their prevention and treatment. Materials and methods A retrospective study was conducted at the Department of ENT - Head and Neck Surgery, Pakistan Institute of Medical Sciences Hospital, Islamabad. Five-year data was collected from the mortality register of the ward from January 2019 to December 2023, including the age, gender, surgical diagnosis, course of hospital stay, and cause of death. The collected data was statistically analyzed and presented in the form of tables and figures. Results A total of 53 deaths in 3890 admissions were found on record, with an overall mortality rate of 1.4%. The median age of participants was 61.5 years, with a preponderance of the male gender (n=34; 64.2%). The most common cause of death was head and neck malignancy (n=39; 73.6%), followed by head and neck abscesses (n=9; 17%). The least common cause of death was diphtheria (n=2; 3.8%). Conclusion Death was more common in old-age patients, with more prevalence in the male population. The most common cause of mortality was head and neck malignancy. The total death count almost remained constant through the years.

Phloroglucinol inhibited glycation via entrapping carbonyl intermediates.

Advanced glycation end products (AGEs) play an important role in the pathogenesis of age-linked disorders and diabetes mellitus. The aim of this study was to assess the repurposing potential of Phloroglucinol (PHL the antispasmodic drug), as an anti-glycation agent using Fructose-BSA model. The ability of PHL to inhibit AGE formation was evaluated using AGEs formation (Intrinsic fluorescence), fructosamine adduct (NBT) and free lysine availability (TNBSA) assays. The BSA protein conformation was assessed through Thioflavin-T, Congo-Red and Circular Dichroism assays. The lysine blockade and carbonyl entrapment were explored as possible mode of action. Our data showed that PHL significantly decreased the formation of AGEs with an IC50 value of 0.3mM. The fructosamine adducts and free lysine load was found to be reduced. Additionally, the BSA conformation was preserved by PHL. Mechanistic assays did not reveal involvement of lysine blockade as underlying reason for reduction in AGEs load. This was also supported by computational data whereby PHL failed to engage any catalytic residue involved in early fructose-BSA interaction. However, it was found to entrap the carbonyl moieties. In conclusion, the PHL demonstrated anti-glycation potential, which can be attributed to its ability to entrap carbonyl intermediates. Hence, the clinically available antispasmodic drug, presents itself as a promising candidate to be repurposed as anti-glycation agent.

Synthesis of quercetin derivatives as cytotoxic against breast cancer MCF-7 cell line in vitro and in silico studies.

Background: Quercetin being antioxidant and antiproliferative agent acts by inhibiting CDK2, with an increase in cancer prevalence there is a need to profile quercetin derivatives as CDK2 inhibitors. Materials & method: Schiff bases of quercetin were synthesized as cytotoxic agents against the MCF7 cell line. FTIR, 1H-NMR and 13C-NMR, CHNS/O analysis were employed along with in vivo and in silico activities. Results & conclusion: 2q, 4q, 8q and 9q derivatives have maximum cytotoxic effect with IC50 values 39.7 ± 0.7, 36.65 ± 0.25, 35.49 ± 0.21 and 36.99 ± 0.45, respectively. Molecular docking also confirmed these results 8q has the highest binding potential of -9.165 KJ/mole making it a potent inhibitor of CDK2. These derivatives can be used as lead compounds as potent CDK2 inhibitors.

[Box: see text].

Multifaceted control of focal points along an arbitrary 3D curved trajectory.

Metalenses can integrate the functionalities of multiple optical components thanks to the unprecedented capability of optical metasurfaces in light control. With the rapid development of optical metasurfaces, metalenses continue to evolve. Polarization and color play a very important role in understanding optics and serve as valuable tools for gaining insights into our world. Benefiting from the design flexibility of metasurfaces, we propose and experimentally demonstrate a super metalens that can realize multifaceted control of focal points along any 3D curved trajectory. The wavelengths and polarization states of all focal points are engineered in a desirable manner. The super metalens can simultaneously realize customized 3D positioning, polarization states, and wavelengths of focal points, which are experimentally demonstrated with incident wavelengths ranging from 501 to 700 nm. We further showcase the application of the developed super metalenses in 3D optical distance measurement. The compact nature of metasurfaces and unique properties of the proposed super metalenses hold promise to dramatically miniaturize and simplify the optical architecture for applications in optical metrology, imaging, detection, and security.

Phloroglucinol ameliorated methylglyoxal induced harmful effects in rats.

Glycation is among the underlying mechanisms attributed to ageing and associated morbidities. There is no drug available to combat this deleterious phenomenon. The present study aimed to explore phloroglucinol (PHL) for its anti-glycation potential at preclinical level. The rats were treated with methylglyoxal (MGO, 17.25 mg/kg, i.p. for 14 days) to induce glvcative stress. The treatment groups received additional administration of test drug (PHL; 0.25mg/kg, 0.5mg/kg, and 1mg/kg) or standard aminoguanidine (AG, 50 mg/kg) or saline (control, 5ml/kg). During 14 days, the weight and food intake was noted. Afterwards, the cognitive function was evaluated using Morris Water Maze (MWM) while hepatic and renal functions were assessed through liver function test (bilirubin, alkaline phosphatase, SGPT, and SGOT) and creatinine respectively, using chemical analyzer. The carboxymethyllysine (CML) levels were quantified in the blood using ELISA technique. Histopathological study was performed on the brain, liver, and kidney using H&E staining. Additionally, the qPCR was used to quantify the expression of TNF-α, RAGE and BACE-1 (brain), RAGE, TNF-α, and glyoxalase-I (liver) and RAGE, TNF-α, and VEGF (kidney), while glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as a reference housekeeping gene. The data regarding weight and food intake did not reveal significant alterations. In MWM, the MGO treatment caused significant increase in the time to reach target quadrant, while decrease in the time spent in target quadrant and number of crossings through platform position. All these effects were inhibited by both AG and PHL. The navigation maps also exhibit that the retention of spatial memory. Additionally, the MGO-induced alteration in hepatic and renal function indicators was ameliorated by both AG and PHL treatments. The plasma CML levels were found to be elevated following MGO treatment, while the concomitant administration of AG and PHL has resisted this raise. Histopathological assessment revealed no specific pathology in liver kidney and brain tissues. The qPCR data revealed enhanced expression of all genes, especially TNF-α and BACE, which were found to be reduced following both AG and PHL treatments. PHL prevented the brain, hepatic, and renal impairments caused by MGO induced glycative stress. Hence, the PHL, a clinically used anti-spasmodic drug, presents itself as a potential candidate to be repurposed as anti-glycation drug.

Longitudinally variable 3D optical polarization structures.

Generation and manipulation of three-dimensional (3D) optical polarization structures have received considerable interest because of their distinctive optical features and potential applications. However, the realization of multiple 3D polarization structures in a queue along the light propagation direction has not yet been reported. We propose and experimentally demonstrate a metalens to create longitudinally variable 3D polarization knots. A single metalens can simultaneously generate three distinct 3D polarization knots, which are indirectly validated with a rotating polarizer. The 3D polarization profiles are dynamically modulated by manipulating the linear polarization direction of the incident light. We further showcase the 3D image steganography with the generated 3D polarization structures. The ultrathin nature of metasurfaces and unique properties of the developed metalenses hold promise for lightweight polarization systems applicable to areas such as 3D image steganography and virtual reality.

Metasurface-Enabled 3-in-1 Microscopy.

Edge enhancement and polarization detection are critical to image transparent or low-contrast samples. However, currently available systems are limited to performing only a single functionality. To meet the requirement of system integration, there is a pressing need for a microscope with multiple functionalities. Here, we propose and develop a microscope with three different functionalities based on spatial multiplexing and polarization splitting. A novel geometric metasurface (MS) is used to realize a spiral phase profile and two phase gradient profiles along two vertical directions, which can perform such an extremely challenging optical task. This is the first demonstration of a 3-in-1 microscope that can simultaneously obtain five images with different optical properties in an imaging plane for the same sample. Imaging experiments with different samples verify its capability to simultaneously perform edge imaging, polarimetric imaging, and conventional microscope imaging. Benefiting from the compactness and multifunctionality of the optical MS device, the integration does not increase the volume of the microscope. This approach can enable users to visualize the multiple facets of samples in real-time.

Dynamic control of hybrid grafted perfect vector vortex beams.

Perfect vector vortex beams (PVVBs) have attracted considerable interest due to their peculiar optical features. PVVBs are typically generated through the superposition of perfect vortex beams, which suffer from the limited number of topological charges (TCs). Furthermore, dynamic control of PVVBs is desirable and has not been reported. We propose and experimentally demonstrate hybrid grafted perfect vector vortex beams (GPVVBs) and their dynamic control. Hybrid GPVVBs are generated through the superposition of grafted perfect vortex beams with a multifunctional metasurface. The generated hybrid GPVVBs possess spatially variant rates of polarization change due to the involvement of more TCs. Each hybrid GPVVB includes different GPVVBs in the same beam, adding more design flexibility. Moreover, these beams are dynamically controlled with a rotating half waveplate. The generated dynamic GPVVBs may find applications in the fields where dynamic control is in high demand, including optical encryption, dense data communication, and multiple particle manipulation.

Compact multi-foci metalens spectrometer.

A lightweight and portable spectrometer is desirable for miniaturization and integration. The unprecedented capability of optical metasurfaces has shown much promise to perform such a task. We propose and experimentally demonstrate a compact high-resolution spectrometer with a multi-foci metalens. The novel metalens is designed based on wavelength and phase multiplexing, which can accurately map the wavelength information into its focal points located on the same plane. The measured wavelengths in the light spectra agree with simulation results upon the illumination of various incident light spectra. The uniqueness of this technique lies in the novel metalens that can simultaneously realize wavelength splitting and light focusing. The compactness and ultrathin nature of the metalens spectrometer render this technology have potential applications in on-chip integrated photonics where spectral analysis and information processing can be performed in a compact platform.

Oral Brincidofovir Therapy for Monkeypox Outbreak: A Focused Review on the Therapeutic Potential, Clinical Studies, Patent Literature, and Prospects.

The monkeypox disease (MPX) outbreak of 2022 has been reported in more than one hundred countries and is becoming a global concern. Unfortunately, only a few treatments, such as tecovirimat (TCV), are available against MPX. Brincidofovir (BCV) is a United States Food and Drug Administration (USFDA)-approved antiviral against smallpox. This article reviews the potential of BCV for treating MPX and other Orthopoxvirus (OPXVs) diseases. The literature for this review was collected from PubMed, authentic websites (USFDA, Chimerix), and freely available patent databases (USPTO, Espacenet, and Patentscope). BCV (a lipophilic derivative of cidofovir) has been discovered and developed by Chimerix Incorporation, USA. Besides smallpox, BCV has also been tested clinically for various viral infections (adenovirus, cytomegalovirus, ebola virus, herpes simplex virus, and double-stranded DNA virus). Many health agencies and reports have recommended using BCV for MPX. However, no health agency has yet approved BCV for MPX. Accordingly, the off-label use of BCV is anticipated for MPX and various viral diseases. The patent literature revealed some important antiviral compositions of BCV. The authors believe there is a huge opportunity to create novel, inventive, and patentable BCV-based antiviral therapies (new combinations with existing antivirals) for OPXVs illnesses (MPX, smallpox, cowpox, camelpox, and vaccinia). It is also advised to conduct drug interaction (food, drug, and disease interaction) and drug resistance investigations on BCV while developing its combinations with other medications. The BCV-based drug repurposing options are also open for further exploration. BCV offers a promising opportunity for biosecurity against OPXV-based bioterrorism attacks and to control the MPX outbreak of 2022.

Study of trioleoylglycerol two-layer and adiposome cross-section mimicking four-layer systems through atomic-level simulations.

Adiposomes are artificially prepared lipid droplet (LD)-mimetic structures, which, unlike LDs, do not harbor proteins. The dynamics of interaction between triacylglycerols (TAGs), drug molecule, and phospholipids in adiposomes is currently not well-established. Trioleoylglycerol (TOG) molecule was divided into three parts: two oleoyl tails and one 2-monooleoylglycerol (MOG). Forcefield parameters for two oleoyl tails were adopted from the AMBER18 repository while that of the MOG forcefield was taken from the literature. Charge correction was performed on the MOG forcefield before its utilization. After charge correction, the resulting TOG molecule had zero charge. TOG bilayer (2L) and tetralayer (4L) systems were prepared and simulated. TOG bilayer (2L) systems-modeled from two different initial conformations, the TOG3 conformation and the TOG2:1 conformation-showed that TOG2:1 conformation was more prevailing irrespective of the starting conformation and was subsequently used in further simulations. The hydrated TOG 2L system showed TOG-water solution solubility of 0.051 mol L-1 which is near experimental values. This validated the correct parameterization of the TOG molecule. The simulations of 4L systems showed stable membrane behaviors toward the end of simulations. It was also observed that in the 4L system, the TOG molecules showed the formation of micelles with the drug molecule. Almost six TOGs remained continuously in contact with the drug molecule throughout the simulation. The availability of charge-corrected TOG parameterization is expected to equip future studies with a framework for molecular dynamics simulations of adiposomes and/or LDs at the atomic level.