Emerging In Vitro and In Vivo Models: Hope for the Better Understanding of Cancer Progression and Treatment.

Various cancer models have been developed to aid the understanding of the underlying mechanisms of tumor development and evaluate the effectiveness of various anticancer drugs in preclinical studies. These models accurately reproduce the critical stages of tumor initiation and development to mimic the tumor microenvironment better. Using these models for target validation, tumor response evaluation, resistance modeling, and toxicity comprehension can significantly enhance the drug development process. Herein, various in vivo or animal models are presented, typically consisting of several mice and in vitro models ranging in complexity from transwell models to spheroids and CRISPR-Cas9 technologies. While in vitro models have been used for decades and dominate the early stages of drug development, they are still limited primary to simplistic tests based on testing on a single cell type cultivated in Petri dishes. Recent advancements in developing new cancer therapies necessitate the generation of complicated animal models that accurately mimic the tumor's complexity and microenvironment. Mice make effective tumor models as they are affordable, have a short reproductive cycle, exhibit rapid tumor growth, and are simple to manipulate genetically. Human cancer mouse models are crucial to understanding the neoplastic process and basic and clinical research improvements. The following review summarizes different in vitro and in vivo metastasis models, their advantages and disadvantages, and their ability to serve as a model for cancer research.

Quality by design fostered fabrication of cabazitaxel loaded pH-responsive Improved nanotherapeutics against prostate cancer.

Cabazitaxel has been approved for the treatment of prostate cancer since 2010. However, its poor solubility and permeability pitfalls prevent its accumulation at the target site and promote severe adverse effects. About 90% of prostate cancer (PCa) patients suffer from bone metastasis. This advent reports the development of CBZ-loaded pH-responsive polydopamine nanoparticles (CBZ NP) against metastatic PCa cells. Quality by design (QbD) and multivariate analysis tools were employed for the optimization of CBZ NP. Amorphisation of CBZ along with metastatic microenvironment responsive release was observed thereby imparting spatial release and circumventing solubility pitfalls. CBZ NP retained its cytotoxic potential, with a significant increase in quantitative cellular uptake. Apoptotic markers observed from nuclear staining with elevated reactive oxygen species (ROS) and mitochondrial damage revealed by JC-1 staining demonstrated the efficacy of CBZ NP against PC-3 cells with good serum stability and diminished hemolysis. Cell cycle analysis revealed substantial S and G2/M phase arrest with enhancement in apoptosis was observed. Western blot studies revealed an elevation in caspase-1 and suppression in Bcl-2 indicating enhanced apoptosis compared to the control group. Substantial reduction in the diameter of 3D-Tumoroid and enhanced cell proliferation inhibition indicated the efficacy of CBZ NP in PCa. Thus, we conclude that CBZ NP could be a promising Nanotherapeutic approach for PCa.

Computational quality-by-design strategy to validate high-performance liquid chromatography method for the estimation of meloxicam in bulk dosage forms and milk samples.

Bovine clinical mastitis has significant repercussions for farmers across the globe. Meloxicam, a COX-2 inhibitor, attenuates mastitis symptoms and is also approved for veterinary use. An RP-HPLC (Reverse Phase-High Performance Liquid Chromatography) method development and validation is essential in the pharmaceutical industry to assess API (Active Pharmaceutical Ingredient) quantity present in the pharmaceutical dosage forms. RP-HPLC method of meloxicam was developed and optimized with the aid of QbD (Quality by Design) using Box-Behnken design (BBD). The pH of the aqueous mobile phase, acetonitrile (ACN) percentage, and column temperature were chosen as influence variables, and retention time (RT) and tailing factor (Tf) were selected as response variables. The optimum experimental conditions were selected as pH ~ 3 of the aqueous mobile phase, 65% v/v ACN, and 30˚C as column temperature. The drug was eluted at 6.02 min RT with 1.18 as Tf. The method was subjected to validation for accuracy, linearity, precision, range, sensitivity, and robustness and was found to comply with ICH Q2 (R1) guidelines. The in vitro bioequivalent studies were performed in hydrochloric acid, pH ~ 1.2; acetate buffer, pH ~ 4.5; and phosphate buffer, pH ~ 6.8 for two veterinary brands of meloxicam tablets, and their release profiles were compared by mathematical models. Both the brands, brand 1 and 2 exhibited significant (Unpaired t-test, P < 0.05) differences in dissolution efficiency (DE) and mean dissolution time (MDT) except DE at pH 1.2. However, brands 1 and 2 showed similarity (f2 > 50) in terms of release of meloxicam except at pH 6.8 (f2 = 47.01). The in vitro release of meloxicam followed Peppas kinetics except for brand 2 at pH 6.8, where it followed the Higuchi model. Moreover, the recovery of meloxicam extracted with ACN in the milk sample was estimated to be 99.67 ± 0.58% significantly (Unpaired t-test, P < 0.05) higher than 90.34 ± 6.77% extracted with methanol. In conclusion, the optimized and validated RP-HPLC method of meloxicam may further be used for the analysis of drug content in pharmaceutical dosage forms in addition to biological fluids.

Oxyberberine an oxoderivative of berberine confers neuroprotective effects in controlled-cortical impact mouse model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is known as a silent epidemic that causes many deaths and disabilities worldwide. We examined the response of oxyberberine (OBB) in lipopolysaccharide-stimulated BV2 microglial cells and a controlled-cortical impact (CCI) mouse model of TBI. METHODS: We synthesized OBB from berberine, and also prepared OBB-nanocrystals (OBB-NC). Male C57BL/6 mice were used for CCI surgery, and post-CCI neurobehavioral deficits were assessed from 1 h after injury through 21 days post-injury (dpi). RESULTS: OBB treatment reduced the lipopolysaccharide-triggered elevated levels of reactive oxygen species, nitric oxide, and nuclear factor kappa B (NF-κB) in BV2 microglial cells, indicating a neuroprotective potential. CCI-operated mice exhibited significant neurological deficits on 1, 3, and 5 dpi in neurological severity scoring and rotarod assay. OBB (25 and 50 mg/kg/day) and OBB-NC (3 mg/kg/day) ameliorated these neurological aberrations. Mice subjected to CCI surgery also displayed anxiogenic- and depression-like behaviours, and cognitive impairments in forced-swimming test and elevated-zero maze, and novel object recognition task, respectively. Administration of OBB reduced these long-term neuropsychiatric complications, and also levels of toll-like receptor 4 (TLR4), high-motility group protein 1 (HMGB1), NF-κB, tumour necrosis factor-alpha and interleukin 6 cytokines in the ipsilateral cortex of mice. CONCLUSION: We suggest that the administration of OBB offers neuroprotective effects via inhibition of HMGB1-mediated TLR4/NFκB pathway.

Delivery of gene editing therapeutics.

For the past decades, gene editing demonstrated the potential to attenuate each of the root causes of genetic, infectious, immune, cancerous, and degenerative disorders. More recently, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9 (CRISPR-Cas9) editing proved effective for editing genomic, cancerous, or microbial DNA to limit disease onset or spread. However, the strategies to deliver CRISPR-Cas9 cargos and elicit protective immune responses requires safe delivery to disease targeted cells and tissues. While viral vector-based systems and viral particles demonstrate high efficiency and stable transgene expression, each are limited in their packaging capacities and secondary untoward immune responses. In contrast, the nonviral vector lipid nanoparticles were successfully used for as vaccine and therapeutic deliverables. Herein, we highlight each available gene delivery systems for treating and preventing a broad range of infectious, inflammatory, genetic, and degenerative diseases. STATEMENT OF SIGNIFICANCE: CRISPR-Cas9 gene editing for disease treatment and prevention is an emerging field that can change the outcome of many chronic debilitating disorders.

Colloidal therapeutics in the management of traumatic brain injury: Portray of biomarkers and drug-targets, preclinical and clinical pieces of evidence and future prospects.

Complexity associated with the aberrant physiology of traumatic brain injury (TBI) makes its therapeutic targeting vulnerable. The underlying mechanisms of pathophysiology of TBI are yet to be completely illustrated. Primary injury in TBI is associated with contusions and axonal shearing whereas excitotoxicity, mitochondrial dysfunction, free radicals generation, and neuroinflammation are considered under secondary injury. MicroRNAs, proinflammatory cytokines, and Glial fibrillary acidic protein (GFAP) recently emerged as biomarkers in TBI. In addition, several approved therapeutic entities have been explored to target existing and newly identified drug-targets in TBI. However, drug delivery in TBI is hampered due to disruption of blood-brain barrier (BBB) in secondary TBI, as well as inadequate drug-targeting and retention effect. Colloidal therapeutics appeared helpful in providing enhanced drug availability to the brain owing to definite targeting strategies. Moreover, immense efforts have been put together to achieve increased bioavailability of therapeutics to TBI by devising effective targeting strategies. The potential of colloidal therapeutics to efficiently deliver drugs at the site of injury and down-regulate the mediators of TBI are serving as novel policies in the management of TBI. Therefore, in present manuscript, we have illuminated a myriad of molecular-targets currently identified and recognized in TBI. Moreover, particular emphasis is given to frame armamentarium of repurpose drugs which could be utilized to block molecular targets in TBI in addition to drug delivery barriers. The critical role of colloidal therapeutics such as liposomes, nanoparticles, dendrimers, and exosomes in drug delivery to TBI through invasive and non-invasive routes has also been highlighted.

Meloxicam emulgel potently suppressed cartilage degradation in knee osteoarthritis: Optimization, formulation, industrial scalability and pharmacodynamic analysis.

BACKGROUND AND OBJECTIVE: Meloxicam (MLX) is prescribed for the management of pain and inflammation allied with osteoarthritis (OA). However, MLX causes intestinal damage in long term administration. Hence, meloxicam loaded emulgel (MLX-emulgel) was optimized, formulated and examined under stringent parameters in monosodium-iodoacetate (MIA) induced knee OA in Wistar rats. METHODS AND RESULTS: Nanoemulsion of MLX was fabricated by ultrasonication and microfluidization method with a droplet size of 66.81 ± 5.31-nm and zeta potential of -24.6 ± 0.72-mV. Further, MLX nanoemulsion was optimized with centrifugation, heating-cooling cycles and transmittance parameters in addition to scale-up feasibility with microfluidizer. Post optimization, MLX-nanoemulsion was tailored as emulgel with Carbopol Ultrez 10 NF and assessed for pH, rheology, textural properties, assay and stability features. The in-vitro release study revealed the Korsmeyer-Peppas release kinetics and ex-vivo skin permeation was improved by 6.71-folds. The skin distribution of MLX-emulgel evinced the transfollicular mode of permeation. In-vivo study indicated the protective action of MLX-emulegl expressed in terms of inflammatory cyctokines level, X-ray analysis of knee joints of rats, histopathology and OARSI (Osteoarthritis Research Society International) scoring. MLX-emulgel treated group displayed lower (P < 0.001) level of COX-2 intensity as compared to positive control group. However, it was comparable (P > 0.05) to the normal control group, MLX oral dispersion, i.v. solution and etoricoxib gel groups. MLX-emulgel showcased an alternative to the long term usage of analgesics for relieving the symptoms of knee OA. CONCLUSION: MLX-emulgel may be a potential candidate for translating in to a clinically viable dosage form in the management of knee OA.

Multifunctional targetable liposomal drug delivery system in the management of leukemia: Potential, opportunities, and emerging strategies.

The concern impeding the success of chemotherapy in leukemia treatment is descending efficacy of drugs because of multiple drug resistance (MDR). The previous failure of traditional treatment methods is primarily responsible for the present era of innovative agents to treat leukemia effectively. The treatment option is a chemotherapeutic agent in most available treatment strategies, which unfortunately leads to high unavoidable toxicities. As a result of the recent surge in marketed products, theranostic nanoparticles, i.e., multifunctional targetable liposomes (MFTL), have been approved for improved and more successful leukemia treatment that blends therapeutic and diagnostic characteristics. Since they broadly offer the required characteristics to get past the traditional/previous limitations, such as the absence of site-specific anti-cancer therapeutic delivery and ongoing real-time surveillance of the leukemia target sites while administering therapeutic activities. To prepare MFTL, suitable targeting ligands or tumor-specific antibodies are required to attach to the surface of the liposomes. This review exhaustively covered and summarized the liposomal-based formulation in leukemia treatment, emphasizing leukemia types; regulatory considerations, patents, and clinical portfolios to overcome clinical translation hurdles have all been explored.

Naringenin-Capped Silver Nanoparticles Amalgamated Gel for the Treatment of Cutaneous Candidiasis.

The current research was aimed to synthesize a phytomolecule, naringenin (NRG)-mediated silver nanoparticles (NRG-SNPs) to study their antifungal potential against Candida albicans (C. albicans) and Candida glabrata (C. glabrata). The NRG-SNPs were synthesized by using NRG as a reducing agent. The synthesis of NRG-SNPs was confirmed by a color change and surface plasmon resonance (SPR) peak at 425 nm. Furthermore, the NRG-SNPs were analyzed for size, PDI, and zeta potential, which were found to be 35 ± 0.21 nm, 0.19 ± 0.03, and 17.73 ± 0.92 mV, respectively. In silico results demonstrated that NRG had a strong affinity towards the sterol 14α-demethylase. The docking with ceramide revealed the skin permeation efficiency of the NRG-SNPs. Next, the NRG-SNPs were loaded into the topical dermal dosage form (NRG-SNPs-TDDF) by formulating a gel using Carbopol Ultrez 10 NF. The MIC50 of NRG solution and TSC-SNPs against C. albicans was found to be 50 µg/mL and 4.8 µg/mL, respectively, significantly (P < 0.05) higher than 0.3625 µg/mL of NRG-SNPs-TDDF. Correspondingly, MIC50 results were calculated against C. glabrata and the results of NRG, TSC-SNPs, NRG-SNPs-TDDF, and miconazole nitrate were found to be 50 µg/mL, 9.6 µg/mL, 0.3625 µg/mL, and 3-µg/mL, respectively. Interestingly, MIC50 of NRG-SNPs-TDDF was significantly (P < 0.05) lower than MIC50 of miconazole nitrate against C. glabrata. The FICI (fractional inhibitory concentration index) value against both the C. albicans and C. glabrata was found to be 0.016 and 0.011, respectively, which indicated the synergistic antifungal activity of NRG-SNPs-TDDF. Thus, NRG-SNPs-TDDF warrants further in depth in vivo study under a set of stringent parameters for translating in to a clinically viable antifungal product.

Acute and sub-acute dermal toxicity of meloxicam emulgel: Analysis of biochemical, hematological, histopathological and immunohistochemical expression.

Meloxicam, a non-steroidal anti-inflammatory drug (NSAID) for the treatment of osteoarthritis. Despite being more effective against pain mediated by inflammation, it is associated with gastrointestinal, cardiovascular, and renal toxicity. In the current study, acute single-dose (2000 mg/kg) and subacute (500, 1000, and 2000 mg kg-1 for 28 days) dermal toxicity analyses of meloxicam emulgel were conducted in Wistar rats. Various biochemical, hematological, histopathological and immunohistochemical parameters were evaluated. The dermal LD50 (lethal dose) of meloxicam emulgel was found to be > 2000 mg/kg. No significant adverse effects of meloxicam emulgel following topical administration in subacute toxicity studies were noticed. IL-1ß was not expressed post treatment with meloxicam emulgel. IL-1ß is an influential pro-inflammatory cytokine that is decisive for host-defence consequence to injury and infection. Therefore, using data gleaned from the extant study, topical administration of meloxicam emulgel may be regarded as safe as the "no observed adverse effect level" (NOAEL) was >2000 mg/kg in experimental animals.

Hyaluronate decorated polyethylene glycol linked poly(lactide-co-glycolide) nanoparticles encapsulating MUC-1 peptide augmented mucosal immune response in Balb/c mice through inhalation route.

BACKGROUND AND OBJECTIVES: NSCLC (Non-Small Cell Lung Cancer) clutches highest mortality rate in man and women globally. The present study was conducted to target MUC-1 peptide (M-1) into antigen presenting cells by cargo the peptide into hyaluronic acid decorated polyethylene glycol linked poly (D, l-lactide-co-glycolide) nanoparticles (M-1-PL-co-GA-PEG-sHA-NPs) for generating mucosal immunity through inhalation (i.h.) route. METHODOLOGY AND RESULTS: The mean particle size and surface charge of M-1-PL-co-GA-PEG-sHA-NPs was measured to be 136.2 ± 18.38-nm and - 28.34 ± 6.77-mV, respectively, prepared by non-aggregated emulsion-diffusion evaporation method. The 28.42% percentage release of M-1 peptide from M-1-PL-co-GA-PEG-NPs was observed to be at 2 h and 95.29% at 8 h while the percentage release of M-1 peptide from M-1-PL-co-GA-PEG-sHA-NPs was observed to be 26.02% at 4 h and 97.95% at 24 h that proved the prolonged release of antigen. M-1-PL-co-GA-PEG-sHA-NPs demonstrated higher (P < 0.05) cellular uptake of 86.2% in RAW 264.7 cells in comparison to 27.6% of M-1-PL-co-GA-PEG-NPs. In addition, M-1-PL-co-GA-PEG-sHA-NPs induced remarkably (P < 0.05) elevated release of 80.6-pg/ml of TNF-α in comparison to 5-pg/ml by culture medium and 57.9-pg/ml of TNF-α by M-1-PL-co-GA-PEG-NPs. Similarly, M-1-PL-co-GA-PEG-sHA-NPs persuade remarkably (P < 0.05) elevated release of 225-pg/ml of IL-1ß in comparison to 47-pg/ml by culture medium and 161.9-pg/ml of IL-1ß by M-1-PL-co-GA-PEG-NPs. M-1-PL-co-GA-PEG-sHA-NPs might have been endocytosed through receptor mediated pathway owing to presence of sHA. Mice immunized through i.h. route with M-1-PL-co-GA-PEG-sHA-NPs induced strong (P < 0.05) IgA antibody titre as compared to M-1-PL-co-GA-PEG-NPs and M-1 peptide in dose-dosage regimen. CONCLUSION: M-1-PL-co-GA-PEG-sHA-NPs nanovaccine warrants further analysis in xenograft model of NSCLC to showcase its antitumor capability.

Andrographolide-Soya-L-α-Phosphatidyl Choline Complex Augmented Solubility and Drug Delivery in Leishmania donovani, a Causative Agent for Cutaneous and Visceral Leishmaniasis.

The utility of andrographolide (AN) in visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) is limited owing to poor solubility, hindered permeation, and unstable structure under physiological conditions. The present study mainly focuses on synthesizing of andrographolide-Soya-L-α-phosphatidyl choline (ANSPC) complex in ethanol and its characterization using various spectral and analytical techniques. Results from FT-IR, 1H NMR, ROSEY, and in silico docking techniques suggest ANSPC complex formation due to inter-molecular interaction between the hydrophilic head of SPC and hydroxyl group of AN present at 24th position. ANSPC complex demonstrated the solubility of 113.93 ± 6.66 µg/mL significantly (P < 0.05) greater than 6.39 ± 0.47 µg/mL of AN. The particle size of ANSPC complex was found to be 182.2 ± 2.69 nm. The IC50 value of AN suspension (PBS, pH ~ 7.4) at 24, 48, and 72 h against Leishmania donovani (L. donovani) was noticed to be 32.76 ± 4.53, 20.87 ± 2.37, and 17.71 ± 3.06 µM/mL, respectively. Moreover, augmented aqueous solubility of ANSPC complex led to significant (P < 0.05) reduction in IC50 value, i.e., 25.02 ± 4.35, 11.31 ± 0.60, and 8.33 ± 2.71 µM/mL at 24, 48, and 72 h, respectively. The IC50 values for miltefosine were noted to be 9.84 ± 2.65, 12.13 ± 7.26, and 6.56 ± 0.61 µM/mL at similar time periods. Moreover, ANSPC complex demonstrated augmented cellular uptake at 24 h as compared to 6 h in L. donovani. We suppose that submicron size and phospholipid-mediated complexation might have endorsed the permeation of ANSPC complex across the plasma membrane of L. donovani parasite by transport mechanisms such as P-type ATPase. ANSPC complex warrants further in-depth in vivo studies under a set of stringent parameters for translating the product into a clinically viable form.

Computational and experimental therapeutic efficacy analysis of andrographolide phospholipid complex self-assembled nanoparticles against Neuro2a cells.

BACKGROUND: Neuroblastoma is one of the most common malignancies in childhood, accounts for approximately 7% of all malignancies. Andrographolide (AN) inhibits cancer cells progression via multiple pathways like cell cycle arrest, mitochondrial apoptosis, NF-κß inhibition, and antiangiogenesis mechanism. Despite multiple advantages, application of AN is very limited due to its low aqueous solubility (6.39 ± 0.47 µg/mL), high lipophilicity (log P âˆ¼ 2.632 ± 0.135), and reduced stability owing to pH sensitive lactone ring. OBJECTIVES AND RESULTS: In present investigation, a molecular complex of AN with soya-L-α-phosphatidyl choline (SPC) was synthesized as ANSPC and characterized by FT-IR and1H NMR spectroscopy. Spectral and molecular simulation techniques confirmed the intermolecular interactions between the 14-OH group of AN and the N+(CH3)3part of SPC. In addition, molecular dynamics (MD) simulation was used to determine the degree of interaction between various proteins such as TNF-α, caspase-3, and Bcl-2. Later, ANSPC complex was transformed in to self-assembled soft nanoparticles of size 201.8 ± 1.48 nm with PDI of 0.092 ± 0.004 and zeta potential of -21.7 ± 0.85 mV. The IC50 offree AN (8.319 µg/mL) and the self-assembled soft ANSPC nanoparticles (3.406 µg/mL âˆ¼ 1.2 µg of AN) against Neuro2a cells was estimated with significant (P < 0.05) difference. Interestingly, the self-assembled soft ANSPC nanoparticles showed better endocytosis compared to free AN in Neuro2a cells. In-vitrobiological assays confirmed that self-assembled soft ANSPC nanoparticles induces apoptosis in Neuro2a cells by declining the MMP (Δψm) and increasing the ROS generation. CONCLUSION: Self-assembled soft ANSPC nanoparticles warrant further in-depth antitumor study in xenograft model of neuroblastoma to establish the anticancer potential.

Potential of Phytomolecules in Alliance with Nanotechnology to Surmount the Limitations of Current Treatment Options in the Management of Osteoarthritis.

Osteoarthritis (OA), a chronic degenerative musculoskeletal disorder, progressively increases with age. It is characterized by progressive loss of hyaline cartilage followed by subchondral bone remodeling and inflammaging. To counteract the inflammation, synovium releases various inflammatory and immune mediators along with metabolic intermediates, which further worsens the condition. However, even after recognizing the key molecular and cellular factors involved in the progression of OA, only disease-modifying therapies are available such as oral and topical NSAIDs, opioids, SNRIs, etc., providing symptomatic treatment and functional improvement instead of suppressing OA progression. Long-term use of these therapies leads to various life-threatening complications. Interestingly, mother nature has numerous medicinal plants containing active phytochemicals that can act on various targets involved in the development and progression of OA. Phytochemicals have been used for millennia in traditional medicine and are promising alternatives to conventional drugs with a lower rate of adverse events and efficiency frequently comparable to synthetic molecules. Nevertheless, their mechanism of action in many cases is elusive and uncertain. Even though many in vitro and in vivo studies show promising results, clinical evidence is scarce. Studies suggest that the presence of carbonyl group in the 2nd position, chloro in the 6th and an electron- withdrawing group at the 7th position exhibit enhanced COX-2 inhibition activity in OA. On the other hand, the presence of a double bond at the C2-C3 position of C ring in flavonoids plays an important role in Nrf2 activation. Moreover, with the advancements in the understanding of OA progression, SARs (structure-activity relationships) of phytochemicals and integration with nanotechnology have provided great opportunities for developing phytopharmaceuticals. Therefore, in the present review, we have discussed various promising phytomolecules, SAR as well as their nano-based delivery systems for the treatment of OA to motivate the future investigation of phytochemical-based drug therapy.

Pathological and Therapeutic Advances in Parkinson's Disease: Mitochondria in the Interplay.

Parkinson's disease (PD) is the second most common neurodegenerative illness majorly affecting the population between the ages of 55 to 65 years. Progressive dopaminergic neuronal loss and the collective assemblage of misfolded alpha-synuclein in the substantia nigra, remain notable neuro-pathological hallmarks of the disease. Multitudes of mechanistic pathways have been proposed in attempts to unravel the pathogenesis of PD but still, it remains elusive. The convergence of PD pathology is found in organelle dysfunction where mitochondria remain a major contributor. Mitochondrial processes like bioenergetics, mitochondrial dynamics, and mitophagy are under strict regulation by the mitochondrial genome and nuclear genome. These processes aggravate neurodegenerative activities upon alteration through neuroinflammation, oxidative damage, apoptosis, and proteostatic stress. Therefore, the mitochondria have grabbed a central position in the patho-mechanistic exploration of neurodegenerative diseases like PD. The management of PD remains a challenge to physicians to date, due to the variable therapeutic response of patients and the limitation of conventional chemical agents which only offer symptomatic relief with minimal to no disease-modifying effect. This review describes the patho-mechanistic pathways involved in PD not only limited to protein dyshomeostasis and oxidative stress, but explicit attention has been drawn to exploring mechanisms like organelle dysfunction, primarily mitochondria and mitochondrial genome influence, while delineating the newer exploratory targets such as GBA1, GLP, LRRK2, and miRNAs and therapeutic agents targeting them.

Meloxicam in Combating Clinical Mastitis: Nanotechnology-Driven Hope and Opportunities.

Mastitis has well-recognized harmful effects on dairy farm profitability. Furthermore, mastitis impairs the milk component synthesizing ability of secretary tissues. Various therapies are available for the treatment of clinical mastitis. Meloxicam exhibits preferential binding to Cyclooxygenase-2 (COX-2) receptor and consequently generates fewer negative gastrointestinal side effects than nonspecific COX inhibitors such as flunixin meglumine and ketoprofen. Toward this end, research efforts directed at understanding the use of meloxicam alone and in combination with other antibiotics to improve milk quality and production. Therefore, in this review, we have highlighted the mechanism, biopharmaceutical challenges, and merits of meloxicam usage in dairy cattle mastitis. In addition, we also presented the integration of artificial neural network, in silico docking, and nanotechnology-driven topical drug delivery cargo as future opportunity for efficient delivery of meloxicam in the management of clinical mastitis.

Engineered upconversion nanocarriers for synergistic breast cancer imaging and therapy: Current state of art.

Breast cancer is the most common type of cancer in women and is the second leading cause of cancer-related deaths worldwide. Early diagnosis and effective therapeutic interventions are critical determinants that can improve survival and quality of life in breast cancer patients. Nanotheranostics are emerging interventions that offer the dual benefit of in vivo diagnosis and therapeutics through a single nano-sized carrier. Rare earth metal-doped upconversion nanoparticles (UCNPs) with their ability to convert near-infrared light to visible light or UV light in vivo settings have gained special attraction due to their unique luminescence and tumor-targeting properties. In this review, we have discussed applications of UCNPs in drug and gene delivery, photothermal therapy (PTT), photodynamic therapy (PDT) and tumor targeting in breast cancer. Further, present challenges and future opportunities for UCNPs in breast cancer treatment have also been mentioned.

Bergenin ameliorates cognitive deficits and neuropathological alterations in sodium azide-induced experimental dementia.

Background: Bergenin, 4-O-methyl gallic acid glucoside, is a bioactive compound found in the cortex of Mallotus japonicus (L.f.) Müll.Arg. along with many other natural resources including that from Bergenia species. The present study delineates the neuroprotective potential of bergenin through the modulation of PPAR-γ receptors. Method: Dementia was induced in the Wistar rats by intraperitoneal (i.p.) administration of sodium azide (12.5 mg/kg for the first 5 days followed by 10 mg/kg for the next 9 days). The rats were then exposed to the Morris water maze test to assess the effect on cognitive abilities followed by a series of biochemical and histopathological evaluations. Results: Sodium azide-treated rats exhibited a severe deterioration of memory as suggested by poor performance in the spatial learning task in addition to the enhancement of brain acetylcholinesterase potential, oxidative stress, inflammation, and amyloid-ß (Aß) accumulation. Administration of bergenin to sodium azide-treated rats significantly recovered cognition and related biochemical variations. Further, co-administration of Bisphenol A diglycidyl ether (BADGE), a PPAR-γ antagonist with bergenin challenged its neuroprotective effects. Conclusions: The findings of our study exhibit that the cognitive restoration potential of bergenin may be attributed to its modulatory effects against cholinesterase, oxidative stress, and inflammatory markers, as well as its neuroprotective actions, thus aligning it as a possible therapy for Alzheimer's disease-related dementia. The study also fortifies the significance of PPAR-γ receptors in dementia.

Luliconazole Topical Dermal Drug Delivery for Superficial Fungal Infections: Penetration Hurdles and Role of Functional Nanomaterials.

Luliconazole is the first and only anti-fungal agent approved for the short-term treatment of superficial fungal infections. However, commercially available conventional topical dermal drug delivery cargo of luliconazole is associated with certain limitations, like lower skin permeation and shorter skin retention of drug. Therefore, the present review is an attempt to unravel the penetration hurdles in luliconazole topical dermal drug delivery. Moreover, we have also summarized the activity of functional nanomaterials-based drug delivery systems employed by the scientific fraternity to improve luliconazole efficacy in superficial fungal infections on a case-to-case basis. In addition, efforts have also been made to unveil the critically acclaimed mechanism of action of luliconazole against fungal cells. Under the framework of future prospects, we have analyzed the combination of luliconazole with isoquercetin using the in-silico docking technique for offering synergistic antifungal activity. Isoquercetin exhibited a good affinity for superoxide dismutase (SOD), a fungal target, owing to the formation of hydrogen bonds with Glu132, Glu133, and Arg143, in addition to a few hydrophobic interactions. On the other hand, luliconazole inhibited lanosterol-14α-demethylase, and consequently blocked ergosterol. In addition, nanotechnology and artificial neural network (ANN) derived integrated drug delivery systems may also be explored for augmenting the luliconazole therapeutic efficacy in topical fungal infections. Synergy of ANN models along with topical nanoscaled drug delivery may help to achieve critical quality attributes (CQA), leading to commercial success of luliconazole.