Boron-Salphen Conjugate based Molecular Probe Exhibiting Fluorescence On-Off-On Response in Detection of Cu2+ and ATP through Displacement Approach.

Synthesis and photophysical properties of a fluorescent probe HBD is described. Probe upon interaction with metal ions, anions and nucleoside pyrophosphates (NPPs) showed fluorescence quenching with Cu2+ due to chelation enhanced quenching effect (CHEQ). Moreover, interaction of ensemble HBD.Cu2+ with anions and NPPs showed fluorescence "turn-On" response with ATP selectively. "On-Off-On" responses observed with Cu2+ and ATP is attributed to an interplay between ESIPT and TICT processes. Cyclic voltammogram of probe exhibited quasi-reversible redox behaviour with three oxidation and two reduction potentials and the change in band gaps of probe suggested the interaction with Cu2+ and ATP. The 2:1 and 1:1 binding stoichiometry for an interaction between probe and Cu2+ (LOD, 62 nM) and ensemble, HBD.Cu2+ with ATP (LOD, 0.4 µM) respectively are realised by Job's plot and HRMS data. Cell imaging studies carried out to detect Cu2+ and ATP in HeLa cells. Also, the output emission observed with Cu2+ and ATP is utilized to construct an implication (IMP) logic gate. Test paper strips showed naked-eye visible color responses to detect Cu2+ and ATP. In real water samples probe successfully detected copper (0.03 µM) between 5-6.5 ppb level (ICP-MS method).

Development and Optimization of Proniosomal Formulation of Irbesartan Using a Box-Behnken Design to Enhance Oral Bioavailability: Physicochemical Characterization and In Vivo Assessment.

This research work aimed to develop and evaluate proniosomes for the oral delivery of the lipophilic drug Irbesartan (IRB) to improve its solubility and bioavailability. Proniosomes of Irbesartan were formulated using a lipid, surfactant, and carrier by a slurry method. Based on the prepared preliminary trial batches and their evaluation, the formulation was optimized by employing a Box-Behnken design (BBD) in which concentrations of span 60 (X1), cholesterol (X2), and mannitol (X3) were used as three independent variables and the vesicular size (VS) (Y1), % entrapment efficiency (% EE) (Y2), and % cumulative drug release (% CDR) (Y3) were used as dependent variables. The optimized batch B1 was obtained from the BBD experiment after validation of checkpoint analysis, and their characterization was done for VS, % EE, % CDR, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) analysis. The optimized batch showed a VS of 199 ± 5.4 nm, a % EE of 99.25 ± 2.24%, and a % CDR of 97.36 ± 1.13% at 24 h. Scanning electron microscopy (SEM) study showed a smooth surface of batch B1. DSC and XRD studies indicated the amorphous nature of the proniosomal formulation. The proniosomal formulation showed increased solubility (2.65 ± 0.2 mg/mL) in phosphate buffer, pH 6.8, as compared to water (0.059 ± 0.02 mg/mL). The pharmacokinetic study in rats confirmed the increased bioavailability of the drug in optimized proniosomal formulation compared with its pure drug suspension. Cmax, Tmax, and AUC0-t of the drug also increased by 2-fold compared to those of drug suspension. Thus, in conclusion, the proniosomal formulation proved to be an efficient carrier for improved oral delivery of Irbesartan by improving the solubility and bioavailability of the drug.

A Comprehensive Review of Various Therapeutic Strategies for the Management of Skin Cancer.

Skin cancer (SC) poses a global threat to the healthcare system and is expected to increase significantly over the next two decades if not diagnosed at an early stage. Early diagnosis is crucial for successful treatment, as the disease becomes more challenging to cure as it progresses. However, identifying new drugs, achieving clinical success, and overcoming drug resistance remain significant challenges. To overcome these obstacles and provide effective treatment, it is crucial to understand the causes of skin cancer, how cells grow and divide, factors that affect cell growth, and how drug resistance occurs. In this review, we have explained various therapeutic approaches for SC treatment via ligands, targeted photosensitizers, natural and synthetic drugs for the treatment of SC, an epigenetic approach for management of melanoma, photodynamic therapy, and targeted therapy for BRAF-mutated melanoma. This article also provides a detailed summary of the various natural drugs that are effective in managing melanoma and reducing the occurrence of skin cancer at early stages and focuses on the current status and future prospects of various therapies available for the management of skin cancer.

Anticancer Drug Discovery Based on Natural Products: From Computational Approaches to Clinical Studies.

Globally, malignancies cause one out of six mortalities, which is a serious health problem. Cancer therapy has always been challenging, apart from major advances in immunotherapies, stem cell transplantation, targeted therapies, hormonal therapies, precision medicine, and palliative care, and traditional therapies such as surgery, radiation therapy, and chemotherapy. Natural products are integral to the development of innovative anticancer drugs in cancer research, offering the scientific community the possibility of exploring novel natural compounds against cancers. The role of natural products like Vincristine and Vinblastine has been thoroughly implicated in the management of leukemia and Hodgkin's disease. The computational method is the initial key approach in drug discovery, among various approaches. This review investigates the synergy between natural products and computational techniques, and highlights their significance in the drug discovery process. The transition from computational to experimental validation has been highlighted through in vitro and in vivo studies, with examples such as betulinic acid and withaferin A. The path toward therapeutic applications have been demonstrated through clinical studies of compounds such as silvestrol and artemisinin, from preclinical investigations to clinical trials. This article also addresses the challenges and limitations in the development of natural products as potential anti-cancer drugs. Moreover, the integration of deep learning and artificial intelligence with traditional computational drug discovery methods may be useful for enhancing the anticancer potential of natural products.

In Vitro and In Vivo Preventive Effects of Thymoquinone against Breast Cancer: Role of DNMT1.

Breast cancer (BC) is one of the most common cancers in women and is a major cause of female cancer-related deaths. BC is a multifactorial disease caused by the dysregulation of many genes, raising the need to find novel drugs that function by targeting several signaling pathways. The antitumoral drug thymoquinone (TQ), found in black seed oil, has multitargeting properties against several signaling pathways. This study evaluated the inhibitory effects of TQ on the MCF7 and T47D human breast cancer cell lines and its antitumor activity against BC induced by a single oral dose (65 mg/kg) of 7,12-dimethylbenzanthracene (DMBA) in female rats. The therapeutic activity was evaluated in DMBA-treated rats who received oral TQ (50 mg/kg) three times weekly. TQ-treated MCF7 and T47D cells showed concentration-dependent inhibition of cell proliferation and induction of apoptosis. TQ also decreased the expression of DNA methyltransferase 1 (DNMT1) in both cancer cell types. In DMBA-treated animals, TQ inhibited the number of liver and kidney metastases. These effects were associated with a reduction in DNMT1 mRNA expression. These results indicate that TQ has protective effects against breast carcinogens through epigenetic mechanisms involving DNMT1 inhibition.

Comparing the Effectiveness of Role-Play Simulation versus Real Patient Transferal Skills Training in Occupational Therapy Students in Saudi-Arabia- A Quasi-Experimental Study.

Purpose: To compare the effectiveness of using role-play simulation as a possible alternative to real-patient training to teach transferal skills to occupational therapy students. Patients and Methods: Seventy-one occupational therapy students (including those in their second, third and fourth years) participated in a quasi-experimental study. The students were randomly divided into two groups. One group received role-play simulation at the university. The other received training on real patients with mild to moderate stroke and spinal cord injury (one session/week for six weeks) in clinical (inpatient) settings in Jeddah to learn patient transferring skills. Student performance was taken as a measure of teaching method effectiveness, and was evaluated by using a validated OSCE-type assessment tool developed at the end of training. The tool showed good reliability (Cronbach's α was > 0.7) and inter-reliability (Kappa < 0.001). Results: A total number of 71 students participated in the study. The majority of the students were female (66.2%, N=47) and 33.8% (N=24) were male. About 33.8% (N=24) of students were in the second year, 29.6% (N=21) were in the third year and 36.6% (N=26) were in the fourth year. There were 36 (49.3%) students in the simulation group The mean age of the students was 20.70 (SD=1.2). There was no significant difference in the students' performance in both groups with a P-value of 0.139. Conclusion: Role-play simulation can effectively be used for students' training as there was no difference in the outcome of the students' performance in patient transferring skills in both groups. This finding can help in designing and implementing training through simulation, especially in situations where training on severely ill patients may be a safety risk.

Innovative Wound Healing Hydrogel Containing Chicken Feather Keratin and Soy Isoflavone Genistein: In Vivo Studies.

The current study was performed to isolate keratin from chicken feathers with an intention to develop a keratin-genistein wound-healing hydrogel, along with its in vivo analysis. Pre-formulation aspects were analysed by using FTIR; SEM; HPTLC, while gel was characterized for gel strength, viscosity, spreadability, drug content, etc. Additionally, an in vivo study along with biochemical factors against pro-inflammatory factors and histopathological studies were conducted to determine possible wound-healing and anti-inflammatory effects. Pre-formulation studies revealed the presence of amide bonds with region of dense fibrous keratin and an internal porous network in extracted keratin, which corresponds with standard keratin. Evaluation of optimised keratin-genistein hydrogel indicated the development of neutral, non-sticky hydrogel which spread evenly on the skin. In vivo studies in rats indicate higher degrees of wound-healing in combined hydrogel (94.65%) for a duration of 14 days as compared to an individual hydrogel formulation with the development of the epidermis and excessive proliferation of fibrous connective tissue indicating wound repair. Furthermore, the hydrogel inhibited the overexpression of IL-6 gene along with other pro-inflammatory factors, indicating its anti-inflammatory effects. In order to find out the possibility of closure of wounds and anti-inflammatory properties of the novel product, an in vivo investigation into the healing of wounds in laboratory animals was carried out through biochemical (ELISA and qRT-PCR) analyses against inflammatory markers (IL-2, IL-6, IL-1, IL-10, and COX-2) and histopathological (liver, skin, and the kidneys) investigations. Based on the results, we conclude that keratin-genistein hydrogel is a promising therapeutic molecule for the management of wound repair.

DOE-Assisted Formulation, Optimization, and Characterization of Tioconazole-Loaded Transferosomal Hydrogel for the Effective Treatment of Atopic Dermatitis: In Vitro and In Vivo Evaluation.

The present study was performed to determine the therapeutic effects of tioconazole (Tz)-loaded novel transferosome carriers (TFs) for the treatment of atopic dermatitis (AD). METHOD: Tioconazole transferosomes suspension (TTFs) was formulated and optimized using a 32 factorial design. After that, the optimized batch of TTFs loaded into Carbopol 934 and sodium CMC was prepared with hydrogel and noted as TTFsH. Subsequently, it was evaluated for pH, spread ability, drug content, in vitro drug release, viscosity, in vivo scratching and erythema score, skin irritation, and histopathology study. RESULT: The optimized batch of TTFs (B4) showed the values of vesicle size, flux, and entrapment efficiency to be 171.40 ± 9.03 nm, 48.23 ± 0.42, and 93.89 ± 2.41, respectively. All batches of TTFsH showed sustained drug release for up to 24 h. The F2 optimized batch released Tz in an amount of 94.23 ± 0.98% with a flux of 47.23 ± 0.823 and followed the Higuchi kinetic model. The in vivo studies provided evidence that the F2 batch of TTFsH was able to treat atopic dermatitis (AD) by reducing the erythema and the scratching score compared to that of the marketed formulation (Candiderm cream, Glenmark). The histopathology study supported the result of the erythema and scratching score study with intact skin structure. It showed that a formulated low dose of TTFsH was safe and biocompatible to both the dermis and the epidermis layer of skin. CONCLUSION: Thus, a low dose of F2-TTFsH is a promising tool that effectively targeted the skin for the topical delivery of Tz to treat atopic dermatitis symptoms.

An Insight into Molecular Targets of Breast Cancer Brain Metastasis.

Brain metastasis is one of the major reasons of death in breast cancer (BC) patients, significantly affecting the quality of life, physical activity, and interdependence on several individuals. There is no clear evidence in scientific literature that depicts an exact mechanism relating to brain metastasis in BC patients. The tendency to develop breast cancer brain metastases (BCBMs) differs by the BC subtype, varying from almost half with triple-negative breast cancer (TNBC) (HER2- ER- PR-), one-third with HER2+ (human epidermal growth factor receptor 2-positive, and around one-tenth with luminal subclass (ER+ (estrogen positive) or PR+ (progesterone positive)) breast cancer. This review focuses on the molecular pathways as possible therapeutic targets of BCBMs and their potent drugs under different stages of clinical trial. In view of increased numbers of clinical trials and systemic studies, the scientific community is hopeful of unraveling the underlying mechanisms of BCBMs that will help in designing an effective treatment regimen with multiple molecular targets.

Thermosensitive Hydrogels Loaded with Resveratrol Nanoemulsion: Formulation Optimization by Central Composite Design and Evaluation in MCF-7 Human Breast Cancer Cell Lines.

The second most common cause of mortality among women is breast cancer. A variety of natural compounds have been demonstrated to be beneficial in the management of various malignancies. Resveratrol is a promising anticancer polyphenolic compound found in grapes, berries, etc. Nevertheless, its low solubility, and hence its low bioavailability, restrict its therapeutic potential. Therefore, in our study, we developed a thermosensitive hydrogel formulation loaded with resveratrol nanoemulsion to enhance its bioavailability. Initially, resveratrol nanoemulsions were formulated and optimized utilizing a central composite-face-centered design. The independent variables for optimization were surfactant level, homogenization speed, and time, while the size and zeta potential were the dependent variables. The optimized nanoemulsion formulation was converted into a sensitive hydrogel using poloxamer 407. Rheological studies proved the formation of gel consistency at physiological temperature. Drug loading efficiency and in vitro drug release from gels were also analyzed. The drug release mechanisms from the gels were assessed using various mathematical models. The effect of the optimized thermosensitive resveratrol nanoemulsion hydrogel on the viability of human breast cancer cells was tested using MCF-7 cancer cell lines. The globule size of the selected formulation was 111.54 ± 4.16 nm, with a zeta potential of 40.96 ± 3.1 mV. Within 6 h, the in vitro release profile demonstrated a release rate of 80%. According to cell line studies, the produced hydrogel of resveratrol nanoemulsion was cytotoxic to breast cancer cells. Overall, the results proved the developed nanoemulsion-loaded thermosensitive hydrogel is a promising platform for the effective delivery of resveratrol for the management of breast cancer.

Epigenetics of Triple-Negative Breast Cancer via Natural Compounds.

Triple-negative breast cancer (TNBC) is a highly resistant, lethal, and metastatic sub-division of breast carcinoma, characterized by the deficiency of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In women, TNBC shows a higher aggressive behavior with poor patient prognosis and a higher recurrence rate during reproductive age. TNBC is defined by the presence of epithelial- to-mesenchymal-transition (EMT), which shows a significant role in cancer progression. At the epigenetic level, TNBC is characterized by epigenetic signatures, such as DNA methylation, histone remodeling, and a host of miRNA, MiR-193, LncRNA, HIF- 2α, eEF2K, LIN9/NEK2, IMP3, LISCH7/TGF-ß1, GD3s, KLK12, mediated regulation. These modifications either are silenced or activate the necessary genes that are prevalent in TNBC. The review is based on epigenetic mediated mechanistic changes in TNBC. Furthermore, Thymoquinone (TQ), Regorafenib, Fangjihuangqi decoction, Saikosaponin A, and Huaier, etc., are potent antitumor natural compounds extensively reported in the literature. Further, the review emphasizes the role of these natural compounds in TNBC and their possible epigenetic targets, which can be utilized as a potential therapeutic strategy in the treatment of TNBC.

Formulation, Optimization and Evaluation of Cytarabine-Loaded Iron Oxide Nanoparticles: From In Vitro to In Vivo Evaluation of Anticancer Activity.

Innovative drug delivery systems based on iron oxide nanoparticles (INPs) has generated a lot of interest worldwide and have prime biomedical benefits in anticancer therapy. There are still issues reported regarding the stability, absorption, and toxicity of iron oxide nanoparticles (INPs) when administered due to its rapid surface oxidation and agglomeration with blood proteins. To solve this problem, we have synthesized trehalose-coated stabilized iron oxide nanoparticles (TINPs) by a co-precipitation technique. The surface coating of INPs with trehalose helps to improve the stability, prevents protein binding, and increase absorption uptake inside the body. Developed TINPs was then loaded with anticancer drug cytarabine by chemical crosslinking encapsulation method using suitable solvent. Engineered cytarabine-loaded trehalose-coated stabilized iron oxide nanoparticles (CY-TINPs) were optimized for particle size, zeta potential (-13.03 mV), and solid-state characterization such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and transmission electron microscope (TEM) studies. The particle size of 50 nm was achieved for developed CY-TINPs. The developed CY-TINPs was further evaluated for in vitro cell line investigations which confirmed potential cytotoxic activity. Developed CY-TINPs show remarkable enhancement in in vivo pharmacokinetic parameters Cmax as 425.26 ± 2.11 and AUC0-72 as 11,546.64 ± 139.82 as compared to pure drug. Compared to traditional drug delivery, the CY-TINPs formulation can effectively delay release, improve bioavailability, and boost cytotoxic activity against tumors.

Comparative Analysis of the Impact of Urolithins on the Composition of the Gut Microbiota in Normal-Diet Fed Rats.

The gut microbiota consists of a community of microorganisms that inhabit the large intestine. These microbes play important roles in maintaining gut barrier integrity, inflammation, lipid and carbohydrate metabolism, immunity, and protection against pathogens. However, recent studies have shown that dysfunction in the gut microbiota composition can lead to the development of several diseases. Urolithin A has recently been approved as a functional food ingredient. In this study, we examined the potentials of urolithin A (Uro-A) and B (Uro-B) in improving metabolic functions and their impact on gut microbiota composition under a metabolically unchallenged state in normal rats. Male Wistar rats (n = 18) were randomly segregated into three groups, with Group 1 serving as the control group. Groups 2 and 3 were administered with 2.5 mg/kg Uro-A and Uro-B, respectively, for four weeks. Our results showed that both Uro-A and B improved liver and kidney functions without affecting body weight. Metagenomic analysis revealed that both Uro-A and B induced the growth of Akkermansia. However, Uro-A decreased species diversity and microbial richness and negatively impacted the composition of pathogenic microbes in normal rats. Taken together, this study showed the differential impacts of Uro-A and B on the gut microbiota composition in normal rats and would thus serve as a guide in the choice of these metabolites as a functional food ingredient or prebiotic.

Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors.

The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status.

Hemorrhagic fever in Saudi Arabia: challenge to public health, effective management and future considerations.

BACKGROUND: Viral hemorrhagic fevers (VHF) refers to a group of febrile illnesses caused by different viruses that result in high mortality in animals and humans. Many risk factors like increased human-animal interactions, climate change, increased mobility of people and limited diagnostic facility have contributed to the rapid spread of VHF. MATERIALS: The history of VHFs in the Saudi Arabian Peninsula has been documented since the 19th century, in which many outbreaks have been reported from the southwestern region of Saudi Arabia. Despite presence of regional network of experts and technical organizations, which expedite support and respond during outbreaks, there are some more challenges that need to be addressed immediately. Gaps in funding, exhaustive and inclusive response plans and improved surveillance systems are some areas of concern in the region which can be dealt productively. This review primarily focusses on the hemorrhagic fevers that are caused by three most common viruses namely, the Alkhurma hemorrhagic fever virus, Rift valley fever virus, and Dengue fever virus. CONCLUSION: In summary, effective vector control, health education, possible use of vaccine and concerted synchronized efforts between different government organizations and private research institutions will help in planning effective outbreak-prevention and response strategies in future.

Effects of a novel organophosphorus pesticide (RPR-V) on extra hepatic detoxifying enzymes after repeated oral doses in rats.

The effects of a novel organophosphorous pesticide, 2-butenoic acid-3-(diethoxy phosphinothionyl) ethyl ester (RPR-V) on glutathione S-transferases (GST), UDP-glucuronyl transferases (UDPGT) and the level of glutathione (GSH) were evaluated in rats after repeated oral administration at 33 microg kg(-1)day(-1) (low), 66 microg kg(-1)day(-1) (mid) and 99 microg kg(-1)day(-1) (high) for 90 days and at 28 days (withdrawal) post-treatment. GSH level and GST in kidney; GSH level in brain decreased significantly at mid and high doses on 45th and 90th day (P < 0.05). However, UDPGT activity in brain and kidney increased significantly at mid and high doses on 45th and 90th day (P < 0.05). Interestingly, the withdrawal study revealed that the effect was reversible 28 days after the treatment when all the enzymes reverted to levels close to those of controls. These results suggest that RPR-V has the potential to modulate the extrahepatic detoxifying enzymes and thereby interact with other physiological processes in the exposed organisms.