Fisetin-Loaded Nanostructured Lipid Carriers: Formulation and Evaluations against Advanced and Metastatic Melanoma.

Fisetin (Fis), a natural flavonoid with anticancer effects, suffers from delivery constraints. Fisetin-nanostructured lipid carriers (NLCs) were developed for better efficacy against metastatic melanoma, employing the design of experiment (DoE) approach. The optimized NLCs depict a particle diameter of 135.0 ± 5.5 nm, a polydispersity index (PDI) of 0.176 ± 0.035, and an entrapment efficiency of 78.16 ± 1.58%. The formulation was stable over a period of 60 days and demonstrated sustained release of the drug (74.79 ± 3.75%) over 96 h. Fis-NLCs depicted at least ∼3.2 times lower IC50 value and ∼1.8 times higher drug uptake at 48 h in A-375 and B16F10 cells compared to that of Fis. It also inhibited the mobility of melanoma cells and induced cell cycle arrest at the G1/S phase. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot results show enhanced expression of Nrf2/NQO1 genes and an apoptotic effect by the upregulation of BAX mRNA expression. The protein levels of BAX and p53 were ∼2-fold higher compared with that of pure Fis. In-vivo studies demonstrated 5.9- and 10.7-fold higher inhibition in melanoma-associated metastasis in the lungs and liver, respectively. The outcomes from this study demonstrated Fis-NLCs as an effective tool against melanoma.

Dual role of Nrf2 in cancer: molecular mechanisms, cellular functions and therapeutic interventions.

BACKGROUND: Nrf2 regulates oxidative stress, which is essential for cellular function. Fundamental initiation of Nrf2 in many malignancies increases prosurvival genes & endorses tumour cell propagation via metabolic reprogramming, suppression of tumour programmed cell death, & increased cancer stem cell self-renewal potential. More specifically, Nrf2 has been associated with cancer cell chemoresistance, radioresistance & inflammation-induced carcinogenesis.  METHODS AND RESULTS: Many Nrf2 inhibitors have been revealed for tumour treatment and targeting Nrf2 could be an effective cancer therapeutic method. Before spreading, cancer cells adapt to their surroundings. Cancer cells usually have mutations in tumor suppressor genes. In a variety of malignancies, somatic mutations & other anomalies in the Nrf2 genes, as well as renowned cancer suppressor genes including TP53, CDKN2A, PTEN & PIK3CA, have been found. In tumour cells, somatic mutations in the Nrf2 genes, as well as additional mechanisms that affect Nrf2 binding, and produce aberrant Nrf2 activation. Uncontrolled Nrf2 causes tumour cells to become resistant to antineoplastic drugs & reactive oxygen species (ROS), as well as guiding them toward metabolic reprogramming.  CONCLUSIONS: As a result, Nrf2 has been studied as potential malignancy treatment target. We covered the pathways, mechanisms, and dual characteristics of Nrf2 in malignancy in this article. We also discussed how Nrf2 inhibitors are targeted against cancer in this review.

A Concise Review on Natural Products and Their Derivatives for Breast Cancer Treatment.

Cancer is a leading cause of death worldwide. Among other cancers, breast cancer has been found to produce maximum number of cases in 2020. Different factors including geographical, genetic, hormonal, oral contraceptives and modern lifestyle could be responsible for the development of breast cancer and different pathways can be targeted for breast cancer treatment. The various conventional approaches used for the treatment of breast cancer including radiotherapy, chemotherapy, hormone and immunotherapy. But due to the side effects associated with these conventional treatments such as non-selectivity, multidrug resistance and bioavailability, there is a need for the development of better therapeutic agents for breast cancer treatment. Several natural products have been explored for breast cancer treatment. However, many of these natural products suffered from the limitations of poor water solubility and possess toxic side effects. To overcome these limitations, several structural analogs of natural products have been synthesized and possess potent anti-breast cancer effects with less side effects over their precursor molecules. In the present manuscript, we describe the pathogenesis of breast cancer, some potent natural products used in the treatment of breast cancer and their selected structural analogs possessing potent anti-breast cancer effects. Database such as Science direct, Pubmed and Google scholar were searched using keywords 'risk factors', 'screening methods','receptors', and 'natural products and derivatives', Registered clinical trials on selected natural products were also analyzed. Present study concludes that eight selected natural products and their derivatives possess wide potential to exhibit anti-breast cancer effects and could be explored further to develop better chemotherapeutic agents against breast cancer.

5d CIDR-Heatsynch improves the circulatory estradiol levels, estrus expression and conception rate in anestrus buffalo (Bubalus bubalis).

The present study aimed to investigate whether increasing estradiol (E2) during preovulatory period would increase estrous expression, luteal profiles and conception rate in 5d CIDR based timed AI protocol. A total 156 anestrus buffalo allocated (78 per group) to either 5d CIDR-Cosynch (d-5: CIDR + GnRH; d0: PGF2α+CIDR removal; 72 h post-CIDR removal: GnRH) or 5d CIDR-Heatsynch (d-5: CIDR + GnRH; d0: PGF2α+CIDR removal; 24 h post-CIDR removal: estradiol benzoate) group. All the buffaloes inseminated at 72 and 84 h post-CIDR removal. A subset of buffalo (n = 58) were subjected to examination of the follicle diameter and luteal profile during protocol, post-AI on days 5 and 12. The buffalo in 5d CIDR-Heatsynch had greater (p < .05) E2 concentrations, estrus induction and increasing trend (p < .08) for conception rate (57.7% vs. 43.6%) than 5d CIDR-Cosynch. The percentage of pregnant buffalo that exhibited estrus signs was greater (p < .01) in 5d CIDR-Heatsynch than 5d CIDR-Cosynch. Positive correlation (p < .01) was observed between POF and E2 concentrations; POF and CL diameter, CL diameter and P4 concentrations. Estrus response and P4 concentrations were indicators of probability of pregnancy. In conclusion, 5d CIDR-Heatsynch tended to improve conception rate. The estrus expression and P4 concentrations (d5 and 12 post-first-AI) is the indicator of probability of pregnancy in buffalo.

Incidence, Risk Factors and Outcome of COVID-19 Associated AKI- A Study from South India.

BACKGROUND: Acute Kidney Injury (AKI) is a dreaded complication of Covid-19 infection with high morbidity and mortality. Limited data exists on Indian experience. In a tertiary care hospital situated in South India, we analysed the incidence, clinical profile and outcomes of patients diagnosed with AKI due to COVID-19. METHODS: Retrospective data of Adult cases admitted with COVID-19 over a 8 month period from April - November 2020 was collected. Incidence, Demographics, Clinical profile, Management and Outcomes of COVID-19 associated AKI were analysed. Primary outcome was In- hospital mortality. Secondary outcomes were Dialysis Requirement and Renal Recovery. RESULTS: 52 (7%) out of a total 718 patients with COVID-19 developed AKI. Mean Age was 58 years (IQR 51-69) with a striking male predominance of 92%.(Male:Female -9.4:1) (P< 0.001). Co morbidities seen were Diabetes in 38 (73%) and Hypertension in 31(59%) and Coronary Artery Disease in 17(32%). Fever with myalgia was seen in 29 (46%), Respiratory symptoms in 31(59%), Oliguria in 26(50%) and Diarrhea in 2 (3%) patients. At admission, Hypoxemia and Hypotension were seen in 27 (51%) and 16 (30%) patients respectively. Urinalysis revealed > 2+ dipstick Proteinuria in 24 (46%) and Microscopic hematuria in 16(34%) patients. 25 (48%) were admitted in Stage 3 AKI with a mean S.Creatinine level of 4.4 + 3.4 mg/dl. CT chest showed > 50% lung involvement in 23 patients (44%). Mechanical ventilation was required in 20(38%). Hemodialysis was required in 12 (23%). The median duration of hospitalisation was 10 + 5 days. Primary Outcome of Mortality occurred in 44% of AKI cohort in comparison to 7% in Non AKI cohort (Relative Risk[RR]6.2; 95% Confidence Interval[CI], 4.1 to 9.4) (P= 0.001). Hypoxemia [RR,3.76;95% CI,1.4-9.5], Hypotension [RR 2.54; CI,1.5-4 ], Low Serum albumin [RR1.6;CI,1.1 - 2.3] and Requirement for mechanical ventilation [RR,11.3; CI, 2.9 - 23 ] were significant risk factors for mortality. All 5 patients who required both mechanical ventilation and Dialysis died. 31 patients (59%) were treated with Remdesivir therapy without survival benefit. Significantly higher C-Reactive Protein, Interleukin -6, D-Dimer levels and lower serum albumin levels were seen in those who died. Among the 29 patients who survived, the estimated GFR (e GFR) had recovered in 12 (41%) at discharge. After further followup of 4-6 weeks, the total number of patients who recovered renal function rose to 21 (72%). CONCLUSION: Mortality in COVID associated AKI stood at 44%. Multiple factors contributed to high mortality such as Severe disease with hypotension and extensive pulmonary involvement, High Neutrophil to Lymphocyte Ratio, Absolute Monocyte Count, inflammatory markers, d-Dimer and low serum albumin. It was encouraging to note that 72% of survivors recovered renal function by 4-6 weeks after discharge from hospital which means that it is worth the struggle to treat AKI in COVID-19.

Lactoferrin Coupled Lower Generation PAMAM Dendrimers for Brain Targeted Delivery of Memantine in Aluminum-Chloride-Induced Alzheimer's Disease in Mice.

Lower generation PAMAM dendrimers have an immense potential for drug delivery with lower toxicity, but these dendrimers yet need certain basic ameliorations. In this study, the brain delivery potential of the synthesized PAMAM-Lf (lower generation PAMAM and lactoferrin conjugate) loaded with memantine (MEM) was explored and evaluated in vitro and in vivo in the disease-induced mouse model. The developed nanoscaffolds were characterized for size, zeta potential and in vitro release. Increase in the average size from 11.54 ± 0.91 to 131.72 ± 4.73 nm, respectively, was observed for drug-loaded PAMAM (i.e., PAMAM-MEM) and PAMAM-Lf (i.e., MEM-PAMAM-Lf).  Release profile of MEM from MEM-PAMAM-Lf was slow and sustained up to 48 h. In vivo biodistribution in the Sprague-Dawley rat model revealed that the brain uptake of MEM-PAMAM-Lf was significantly higher than that of MEM alone. The behavioral response study in the healthy rats did not result in any significant changes. The in vivo study in an AlCl3-induced Alzheimer's (AD) mice model showed a significant improvement in behavioral responses. Optical density, which reflects the acetylcholinesterase (AChE) activity, was highest in the AL group 0.16 ± 0.01 (higher than the CON group, 0.09 ± 0.02; p < 0.05). No significant suppression of AChE activity was recorded in all the other treated groups. Similarly, the DOPAmine and 3,4 dihydroxyphenylacetic acid (DOPAC) levels were unaffected by the developed formulations. The study reported improved brain bioavailability of MEM in AlCl3-induced Alzheimer's mice leading to improved memory, with the resultant mechanism behind in a descriptive manner. This study is among the preliminary studies reporting the memory improvement aspect of PAMAM-Lf conjugates for MEM in AlCl3-AD induced mice. The formulation developed was beneficial in AD-induced mice and had a significant impact on the memory aspects.

The autoimmune basis of hypopituitarism in traumatic brain injury: fiction or reality?

Post-traumatic hypopituitarism has remained as an obscured cause of worsening morbidity and mortality in head injury patients. Researchers have for decades been puzzled by the mechanism of pituitary dysfunction in these cases. Amongst other causes like direct injury, vascular injury etc, an immunological basis of hypopituitarism has been suggested in some animal studies as well as human research. In this article, we have reviewed the latest articles and compiled the evidence which suggests for or against the role of autoimmunity in post-traumatic hypopituitarism or which defines the strength to which autoimmunity has been established as a cause of head-injury induced pituitary dysfunction.

Craniovertebral junction evaluation by computed tomography in asymptomatic individuals in the Indian population.

BACKGROUND: The available literature on the anatomy and imaging of the craniovertebral junction (CVJ) focusses on the osteometric indices described for the detection of abnormal relationships between the components of CVJ. However, a knowledge of the normal osteometry of this region in the Indian population is critically important for the operating surgeon as it may influence the surgical technique as well as the choice, size and configurations of the implants. It is also important to determine whether critical differences exist between the osteometric data of Indians and the rest of the world for this part of the anatomy. Accordingly, the present study is an attempt to quantitate the osteometric indices for the anatomically normal CVJ in Indian subjects. MATERIALS AND METHODS: We retrospectively studied the imaging data of 49 consecutive adult patients (31 males, 18 females) who underwent a computed tomographic (CT) angiogram for suspected vascular conditions unrelated to the craniovertebral junction. Several parameters related to the atlanto-dental relationship, foramen magnum, atlas and axis vertebrae were recorded, including the dimensions of the commonly instrumented bony regions and also the indices related to the CVJ bony relationships. The data was also compared between the two genders, statistically through the Student's t-test using the statistical program "R". RESULTS: No patient had an atlanto dens interval >2.5 mm. The mean distance of the odontoid tip from the McRae line in this series was 5.11 mm and no patient had the odontoid tip above the McRae line. Female subjects had significantly smaller diameters of C1 lateral masses and odontoid screw trajectory length when compared to males. Additionally, in the Indian population, the length range of odontoid screw trajectory and the thickness of the narrowest part of the C2 pedicles was smaller with respect to similar data from other geographical regions. However, the rest of the parameters resembled the data from studies conducted on populations with other ethnicities. CONCLUSION: The osteometric parameters of the CVJ in the Indian population are largely similar to those described globally. However, there are some important differences too which can influence the design of surgical implants suited to the Indian population.

Galactose-Anchored Gelatin Nanoparticles for Primaquine Delivery and Improved Pharmacokinetics: A Biodegradable and Safe Approach for Effective Antiplasmodial Activity against P. falciparum 3D7 and in Vivo Hepatocyte Targeting.

Primaquine phosphate (PQ) is mainly used as a radical cure therapy to eradicate relapse of malaria at the liver stage, which is particularly caused by P. falciparum and P. vivax. In the present study, PQ-loaded galactosylated gelatin nanoparticles (Gel-LA-PQ-NPs) were formulated using a one-step desolvation technique. The mean particle size of Gel-LA-PQ-NPs was found to be 93.48 ± 6.36 nm with a zeta potential of 4.80 ± 0.20 mV having 69.90 ± 1.53% encapsulation efficiency. Electron microscopy demonstrated that the NPs were spherical in shape and uniformly distributed without any cluster formation. The in vitro release of PQ from Gel-LA-PQ-NPs has been facilitated in sustained manner, and the release was three times slower than the naïve drug. The prepared nanoparticles (Gel-LA-PQ-NPs) were significantly (p < 0.0001) less hemolytic than the pure drug PQ. The hematological ex vivo study further supported that the developed Gel-LA-PQ-NPs were safer than PQ. The in vitro antiplasmodium assay revealed that the IC50 value against the blood stage of asexual P. falciparum 3D7 strains was significantly (p < 0.01) less (2.862 ± 0.103 µM) for Gel-LA-PQ-NPs than naïve PQ (3.879 ± 0.655 µM). In vivo pharmacokinetic parameters of Gel-LA-PQ-NPs such as half-life and AUC were significantly higher for Gel-LA-PQ-NPs, i.e., with higher bioavailability. Galactosylation of the NPs led to liver targeting of the PQ in animal studies. Approximately eight-fold higher accumulation of PQ was observed in liver compared to pure drug (i.e., PQ). Conclusively, the prepared galactosylated gelatin nanocarrier holds the promising potential and hepatic targetability of an antimalarial, maintaining its safety and biocompatibility.

Assessment of striatal & postural deformities in patients with Parkinson's disease.

BACKGROUND & OBJECTIVES: Though striatal and postural deformities are known to occur commonly in atypical Parkinsonism patients, these may also be seen in patients with Parkinson's disease (PD). These are frequently misdiagnosed as joint or orthopaedic pathology leading to unnecessary investigations. This study was conducted to observe the various striatal and postural deformities among patients with PD in India. METHODS: This study was conducted at a tertiary care teaching institute in north# India. Seventy consecutive patients with PD diagnosed as per the modified UK Brain Bank criteria were included. Various striatal (hand & foot) and postural (antecollis, camptocormia, scoliosis & Pisa syndrome) deformities and their relation with the duration of disease, severity [measured by the Unified Parkinson's Disease Rating Scale (UPDRS)] and levodopa intake were analyzed. RESULTS: Of the 70 patients with PD, 34 (48.57%) had either striatal or postural deformities. Striatal foot was the most common deformity observed (25.71%). Camptocormia was the second most common deformity (20%). Striatal and postural deformities were seen in more advanced PD as suggested by significantly higher UPDRS and Hoehn and Yahr scale (P<0.001). Striatal deformities were more ipsilateral to PD symptom onset side (agreement 94.44%). Pisa and scoliosis concavity were more on contralateral side to PD symptoms onset side (66.67%). INTERPRETATION & CONCLUSIONS: Our results showed that striatal and postural deformities were common and present in about half of the patients with PD. These deformities we more common in patients with advanced stage of PD.

Population structure and breeding value of a new type of Brassica juncea created by combining A and B genomes from related allotetraploids.

KEY MESSAGE: Derived amphiploidy helped to resynthesize agronomically superior B. juncea germplasm which showed high heterosis in crosses with natural B. juncea . This new procedure facilitates a seamless flow of variation across Brassica digenomics. Brassica digenomics, artificially resynthesized by hybridizing extant genome donor diploids, show poor breeding value due to the linkage drag associated with diploid donors. We recently developed a method that involves resynthesis through hybridization between related allotetraploids. Derived B. juncea was created by combining A and B genomes extant in B. napus and B. carinata, respectively. Large genomic and agronomic modifications resulted. Population structure analysis based on the DNA polymorphism generated using 108 locus-specific SSR primers helped to identify three pools of allelic diversity. Thirteen progenies with determinate plant growth habit were discovered, and these aligned closely with B genome of the donor species like B. nigra and B. carinata. The indeterminate group showed greater genetic affinity with extant B. juncea. Derived genotypes possessed high agronomic potential. Importantly, high heterosis was observed in crosses between derived and natural B. juncea. Some derived juncea progenies figured in heterotic combinations during both the years of F 1 hybrid evaluation. In essence, the hybrids between derived B. juncea and natural B. juncea can be considered as interspecific hybrids between B. juncea and B. napus for A genome and between B. juncea and B. carinata for B genome. This possibly explains their high heterosis-inducing potential. Integrating genetic diversity with the inherent breeding value allowed more efficient prediction of heterosis. Besides generation of new novel variability of huge economic importance and operational simplicity, the method of derived amphiploidy allows a seamless flow of heritable variation across Brassica digenomics.

Reshaping the zygomatic complex: A "small step" in frontotemporal craniotomy and a "big leap" in exposure.

CONTEXT: Pterional or fronto-temporal craniotomy, developed by Prof. M. G. Yasargil, is among the most familiar skull base surgery techniques. The cranio-orbito zygomatic (COZ) approach evolved to address the significant limitations of the pterional exposure in excising some parasellar lesions. Although extremely versatile, the COZ technique involves extensive dissection of the cranio-facial soft tissue and reconstruction towards the end of the procedure. The zygomatic reshaping is a minor modification of the pterional approach, which enhances the exposure possible through the classical approach and often circumvents the need for an orbito-zygomatic osteotomy. AIMS: To demonstrate the technique of reshaping of the zygomatic complex for an optimum surgical exposure and cosmetic results. MATERIALS AND METHODS: Between April 2013 and December 2014, 8 patients with various middle and anterior skull base lesions were operated using this technique. These patients form the clinical material for this study. The clinical details, radiological images and follow-up data of these patients were collected for this clinical series. RESULTS: No mortality or significant morbidity were noted in this series. The post-operative cosmetic results were also acceptable. CONCLUSIONS: A quick and easy modification of the classical pterional approach through zygomatic reshaping has the potential to provide a significantly enhanced surgical exposure for parasellar lesions. Using this approach, it might be possible to avoid an extensive orbito-zygomatic osteotomy in suitable lesions.

Virtual screening of acetylcholinesterase inhibitors through pharmacophore-based 3D-QSAR modeling, ADMET, molecular docking, and MD simulation studies.

Alzheimer's disease (AD) is a leading cause of dementia in elderly patients. The pathophysiology of AD includes various pathways, such as the degradation of acetylcholine, amyloid-beta deposition, neurofibrillary tangle formation, and neuroinflammation. Many studies showed that targeting acetylcholinesterase enzyme (AChE) to improve acetylcholine can be an effective option to treat AD. In the current work, we employed a 3D QSAR-based approach to generate a pharmacophore to screen a chemical library of compounds that may inhibit AChE. Data from experimental studies were collected and used for the generation of pharmacophores. More than 1 million compounds were screened, and further drug-like properties were determined via in-silico ADMET studies. Techniques like molecular docking and molecular dynamics simulation were performed to analyze the binding of novel AChE inhibitors. A novel AChE inhibitor ligand-1 was identified as best with a docking score of -13.560 kcal/mol with RMSD of 1.71 Å during a 100 ns MD run. Further biological studies can give an insight into the potential of ligand-1 as a therapeutic agent for AD. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00189-1.

Deciphering Physio-Biochemical Basis of Tolerance Mechanism for Sesame (Sesamum indicum L.) Genotypes under Waterlogging Stress at Early Vegetative Stage.

Waterlogging represents a substantial agricultural concern, inducing harmful impacts on crop development and productivity. In the present study, 142 diverse sesame genotypes were examined during the early vegetative phase to assess their response under waterlogging conditions. Based on the severity of symptoms observed, 2 genotypes were classified as highly tolerant, 66 as moderately tolerant, 69 as susceptible, and 5 as highly susceptible. Subsequent investigation focused on four genotypes, i.e., two highly tolerant (JLT-8 and GP-70) and two highly susceptible (R-III-F6 and EC-335003). These genotypes were subjected to incremental stress periods (0 h, 24 h, 48 h, 72 h, and 96 h) to elucidate the biochemical basis of tolerance mechanisms. Each experiment was conducted as a randomized split-plot design with three replications, and the statistical significance of the treatment differences was determined using the one-way analysis of variance (ANOVA) followed by the Fisher least significant difference (LSD) test at p ≤ 0.05. The influence of waterlogging stress on morphological growth was detrimental for both tolerant and susceptible genotypes, with more severe consequences observed in the latter. Although adventitious roots were observed in both sets of genotypes above flooding levels, the tolerant genotypes exhibited a more rapid and vigorous development of these roots after 48 h of stress exposure. Tolerant genotypes displayed higher tolerance coefficients compared to susceptible genotypes. Furthermore, tolerant genotypes maintained elevated antioxidant potential, thereby minimizing oxidative stress. Conversely, susceptible genotypes exhibited higher accumulation of hydrogen peroxide (H2O2) and malondialdehyde content. Photosynthetic efficiency was reduced in all genotypes after 24 h of stress treatment, with a particularly drastic reduction in susceptible genotypes compared to their tolerant counterparts. Tolerant genotypes exhibited significantly higher activities of anaerobic metabolism enzymes, enabling prolonged survival under waterlogging conditions. Increase in proline content was observed in all the genotypes indicating the cellular osmotic balance adjustments in response to stress exposure. Consequently, the robust antioxidant potential and efficient anaerobic metabolism observed in the tolerant genotypes served as key mechanisms enabling their resilience to short-term waterlogging exposure. These findings underscore the promising potential of specific sesame genotypes in enhancing crop resilience against waterlogging stress, offering valuable insights for agricultural practices and breeding programs.

Directional molecular transport in iron redox flow batteries by interfacial electrostatic forces.

The mounting global energy demand urges surplus electricity generation. Due to dwindling fossil resources and environmental concerns, shifting from carbon-based fuels to renewables is vital. Though renewables are affordable, their intermittent nature poses supply challenges. In these contexts, aqueous flow batteries (AFBs), are a viable energy storage solution. This study tackles AFBs' energy density and efficiency challenges. Conventional strategies focus on altering molecule's solubility but overlook interface's transport kinetics. We show that triggering electrostatic forces at the interface can significantly enhance the mass transport kinetics of redox active molecules by introducing a powerful electrostatic flux over the diffusional flux, thereby exerting a precise directionality on the molecular transport. This approach of controlling the directionality of molecular flux in an all iron redox flow battery amplifies the current and power rating with approximately 140 % enhancement in the energy density.

Angiopep-2 Grafted PAMAM Dendrimers for the Targeted Delivery of Temozolomide: In Vitro and In Vivo Effects of PEGylation in the Management of Glioblastoma Multiforme.

The present study was aimed to synthesize, characterize, and evaluate the angiopep-2 grafted PAMAM dendrimers (Den, G 3.0 NH2) with and without PEGylation for the targeted and better delivery approach of temozolomide (TMZ) for the management of glioblastoma multiforme (GBM). Den-ANG and Den-PEG2-ANG conjugates were synthesized and characterized by 1H NMR spectroscopy. The PEGylated (TMZ@Den-PEG2-ANG) and non-PEGylated (TMZ@Den-ANG) drug loaded formulations were prepared and characterized for particle size, zeta potential, entrapment efficiency, and drug loading. An in vitro release study at physiological (pH 7.4) and acidic pH (pH 5.0) was performed. Preliminary toxicity studies were performed through hemolytic assay in human RBCs. MTT assay, cell uptake, and cell cycle analysis were performed to evaluate the in vitro efficacy against GBM cell lines (U87MG). Finally, the formulations were evaluated in vivo in a Sprague-Dawley rat model for pharmacokinetics and organ distribution analysis. The 1H NMR spectra confirmed the conjugation of angiopep-2 to both PAMAM and PEGylated PAMAM dendrimers, as the characteristic chemical shifts were observed in the range of 2.1 to 3.9 ppm. AFM results revealed that the surface of Den-ANG and Den-PEG2-ANG conjugates were rough. The particle size and zeta potential of TMZ@Den-ANG were observed to be 229.0 ± 17.8 nm and 9.06 ± 0.4 mV, respectively, whereas the same for TMZ@Den-PEG2-ANG were found to be 249.6 ± 12.9 nm and 10.9 ± 0.6 mV, respectively. The entrapment efficiency of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were calculated to be 63.27 ± 5.1% and 71.48 ± 4.3%, respectively. Moreover, TMZ@Den-PEG2-ANG showed a better drug release profile with a controlled and sustained pattern at PBS pH 5.0 than at pH 7.4. The ex vivo hemolytic study revealed that TMZ@Den-PEG2-ANG was biocompatible in nature as it showed 2.78 ± 0.1% hemolysis compared to 4.12 ± 0.2% hemolysis displayed by TMZ@Den-ANG. The outcomes of the MTT assay inferred that TMZ@Den-PEG2-ANG possessed maximum cytotoxic effects against U87MG cells with IC50 values of 106.62 ± 11.43 µM (24 h) and 85.90 ± 9.12 µM (48 h). In the case of TMZ@Den-PEG2-ANG, the IC50 values were reduced by 2.23-fold (24 h) and 1.36-fold (48 h) in comparison to pure TMZ. The cytotoxicity findings were further confirmed by significantly higher cellular uptake of TMZ@Den-PEG2-ANG. Cell cycle analysis of the formulations suggested that the PEGylated formulation halts the cell cycle at G2/M phase with S-phase inhibition. In the in vivo studies, the half-life (t1/2) values of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were enhanced by 2.22 and 2.76 times, respectively, than the pure TMZ. After 4 h of administration, the brain uptake values of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were found to be 2.55 and 3.35 times, respectively, higher than that of pure TMZ. The outcomes of various in vitro and ex vivo experiments promoted the use of PEGylated nanocarriers for the management of GBM. Angiopep-2 grafted PEGylated PAMAM dendrimers can be potential and promising drug carriers for the targeted delivery of antiglioma drugs directly to the brain.

The multifaceted role of extracellular vesicles in prostate cancer-a review.

Prostate cancer is the second most prominent form of cancer in men and confers the highest mortality after lung cancer. The term "extracellular vesicles" refers to minute endosomal-derived membrane microvesicles and it was demonstrated that extracellular vesicles affect the environment in which tumors originate. Extracellular vesicles' involvement is also established in the development of drug resistance, angiogenesis, stemness, and radioresistance in various cancers including prostate cancer. Extracellular vesicles influence the general environment, processes, and growth of prostate cancer and can be a potential area that offers a significant lead in prostate cancer therapy. In this review, we have elaborated on the multifaceted role of extracellular vesicles in various processes involved in the development of prostate cancer, and their multitude of applications in the diagnosis and treatment of prostate cancer through the encapsulation of various bioactives.

Nanoconstructs for theranostic application in cancer: Challenges and strategies to enhance the delivery.

Nanoconstructs are made up of nanoparticles and ligands, which can deliver the loaded cargo at the desired site of action. Various nanoparticulate platforms have been utilized for the preparation of nanoconstructs, which may serve both diagnostic as well as therapeutic purposes. Nanoconstructs are mostly used to overcome the limitations of cancer therapies, such as toxicity, nonspecific distribution of the drug, and uncontrolled release rate. The strategies employed during the design of nanoconstructs help improve the efficiency and specificity of loaded theranostic agents and make them a successful approach for cancer therapy. Nanoconstructs are designed with a sole purpose of targeting the requisite site, overcoming the barriers which hinders its right placement for desired benefit. Therefore, instead of classifying modes for delivery of nanoconstructs as actively or passively targeted systems, they are suitably classified as autonomous and nonautonomous types. At large, nanoconstructs offer numerous benefits, however they suffer from multiple challenges, too. Hence, to overcome such challenges computational modelling methods and artificial intelligence/machine learning processes are being explored. The current review provides an overview on attributes and applications offered by nanoconstructs as theranostic agent in cancer.

Fisetin in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics.

Cancer is one of the major causes of mortality, globally. Cancerous cells invade normal cells and metastasize to distant sites with the help of the lymphatic system. There are several mechanisms involved in the development and progression of cancer. Several treatment strategies including the use of phytoconstituents have evolved and been practiced for better therapeutic outcomes against cancer. Fisetin is one such naturally derived flavone that offers numerous pharmacological benefits, i.e., antioxidant, anti-inflammatory, antiangiogenic, and anticancer properties. It inhibits the rapid growth, invasiveness, and metastasis of tumors by hindering the multiplication of cancer cells, and prompts apoptosis by avoiding cell division related to actuation of caspase-9 and caspase-8. However, its poor bioavailability associated with its extreme hydrophobicity hampers its clinical utility. The issues related to fisetin delivery can be addressed by adapting to the developmental aspects of nanomedicines, such as formulating it into lipid or polymer-based systems, including nanocochleates and liposomes. This review aims to provide in-depth information regarding fisetin as a potential candidate for anticancer therapy, its properties and various formulation strategies.

F3 peptide functionalized liquid crystalline nanoparticles for delivering Salinomycin against breast cancer.

Salinomycin (Sal) is a potent veterinary antibiotic known to offer significant toxicity to the variety of neoplastic cells. Its therapeutic utility is limited due to its higher lipophilicity (logP 7.5) and poor hydrophilicity. Liquid crystalline nanoparticles (LCNPs) known to offer a suitable delivery platform for these kinds of drugs. The overexpressed nucleolin receptor on the cell surface and cytoplasm, could be selected as a target in cancer therapy. The present study involves the development and characterization of the F3 peptide functionalized LCNPs for delivering Sal (F3-Sal-NPs) for selectively targeting to the nucleolin receptor. The optimized LCNPs were characterized for particle size, zeta potential, surface morphology, drug release kinetics and stability. The LCNPs have a structure similar to nematic phases. In vitro drug release studies revealed sustained drug release characteristics (89.5 ± 1.5% at 120 h) with F3-Sal-NPs. The cytotoxicity results demonstrated that F3-Sal-NPs were 4.8, 2.6 and 5.5 folds more effective than naïve drug in MDA-MB-468, MDA-MB-231 and MCF-7 cells, respectively and the cell cycle was arrested in the S and G2/M phases. The expression of the gene responsible for the stemness (CD44 gene), apoptosis (BAX/Bcl-2 ration) and angiogenesis (LCN-2) was reduced by F3-Sal-NPs treatment. Ex vivo hemolytic toxicity was reduced (6.5 ± 1.5%) and the pharmacokinetics and bioavailability of Sal was improved with F3-Sal-NPs. The in vivo antitumor efficacy was tested in EAC bearing mice, where F3-Sal-NPs significantly reduced the tumor growth by 2.8-fold compared to pure Sal and induced necrosis of tumor cells. The results clearly demonstrate the outstanding performance of F3 peptide functionalized LCNPs for delivering Sal against breast cancer.