Phytoconstituents as modulators of NF-κB signalling: Investigating therapeutic potential for diabetic wound healing.

The NF-κB pathway plays a pivotal role in impeding the diabetic wound healing process, contributing to prolonged inflammation, diminished angiogenesis, and reduced proliferation. In contrast to modern synthetic therapies, naturally occurring phytoconstituents are well-studied inhibitors of the NF-κB pathway that are now attracting increased attention in the context of diabetic wound healing because of lower toxicity, better safety and efficacy, and cost-effectiveness. This study explores recent research on phytoconstituent-based therapies and delve into their action mechanisms targeting the NF-κB pathway and potential for assisting effective healing of diabetic wounds. For this purpose, we have carried out surveys of recent literature and analyzed studies from prominent databases such as Science Direct, Scopus, PubMed, Google Scholar, EMBASE, and Web of Science. The classification of phytoconstituents into various categorie such as: alkaloids, triterpenoids, phenolics, polyphenols, flavonoids, monoterpene glycosides, naphthoquinones and tocopherols. Noteworthy phytoconstituents, including Neferine, Plumbagin, Boswellic acid, Genistein, Luteolin, Kirenol, Rutin, Vicenin-2, Gamma-tocopherol, Icariin, Resveratrol, Mangiferin, Betulinic acid, Berberine, Syringic acid, Gallocatechin, Curcumin, Loureirin-A, Loureirin-B, Lupeol, Paeoniflorin, and Puerarin emerge from these studies as promising agents for diabetic wound healing through the inhibition of the NF-κB pathway. Extensive research on various phytoconstituents has revealed how they modulate signalling pathways, including NF-κB, studies that demonstrate the potential for development of therapeutic phytoconstituents to assist healing of chronic diabetic wounds.

Phyto-Fabrication of Moringa Oleifera Peel-Sourced Silver Nanoparticles: A Promising Approach for Combating Hepatic Cancer by Targeting Proinflammatory Cytokines and Mitigating Cytokine Storms.

Hepatocellular carcinoma (HCC) arises from precancerous nodules, leading to liver damage and inflammation, which triggers the release of proinflammatory cytokines. Dysregulation of these cytokines can escalate into a cytokine storm, causing severe organ damage. Interestingly, Moringa oleifera (M. oleifera) fruit peel, previously discarded as waste, contains an abundance of essential biomolecules and high nutritional value. This study focuses on the eco-friendly synthesis of silver nanoparticles infused with M. oleifera peel extract biomolecules and their impact on regulating proinflammatory cytokines, as well as their potential anticancer effects against Wistar rats. The freshly synthesized nanoformulation underwent comprehensive characterization, followed by antihepatic cancer evaluation using a diethyl nitrosamine-induced model (at a dose of 200 mg kg-1 BW). The study demonstrates a significant reduction in proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, interleukin-1ß, and nuclear factor kappa beta (NF-κB). Furthermore, it confirms that the newly biosynthesized silver nanoparticles exhibit additional potential against hepatic cancer due to their capped biomolecules.

Epigenetic Impact of Curcumin and Thymoquinone on Cancer Therapeutics.

Today, one of the most prevalent reasons for death among people is carcinoma. Because it is still on the increase throughout the world, there is a critical need for in- -depth research on the pathogenic mechanisms behind the disease as well as for efficient treatment. In the field of epigenetics, gene expression alterations that are inherited but not DNA sequence changes are investigated. Three key epigenetic changes, histone modifications, DNA methylation and non-coding RNA (ncRNA) expression, are principally responsible for the initiation and progression of different tumors. These changes are interconnected and constitute many epigenetic changes. A form of polyphenolic chemical obtained from plants called curcumin has great bioactivity against several diseases, specifically cancer. A naturally occurring substance called thymoquinone is well-known for its anticancer properties. Thymoquinone affects cancer cells through a variety of methods, according to preclinical studies. We retrieved information from popular databases, including PubMed, Google Scholar, and CNKI, to summarize current advancements in the efficiency of curcumin against cancer and its epigenetic regulation in terms of DNA methylation, histone modifications, and miRNA expression. The present investigation offers thorough insights into the molecular processes, based on epigenetic control, that underlie the clinical use of curcumin and thymoquinone in cancerous cells.

ABCG2 polymorphisms and susceptibility to ARV-associated hepatotoxicity.

BACKGROUND: The ABCG2 421C/A polymorphism contributes significantly to the distribution and absorption of antiretroviral (ARV) regimens and is associated with the undesirable side effects of efavirenz. METHODS: To investigate this, we examined ABCG2 34G/A (rs2231137) and 421C/A (rs2231142) genetic variations in 149 HIV-infected patients (116 without hepatotoxicity, 33 with ARV-induced hepatotoxicity) and 151 healthy controls through the PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS AND DISCUSSION: The ABCG2 34GA genotype and 34A allele indicated a risk for antiretroviral therapy-associated hepatotoxicity development (p = 0.09, OR = 1.58, 95% CI: 0.93-2.69; p = 0.06, OR = 1.50, 95% CI: 0.98-2.30). The haplotype GA was associated with hepatotoxicity (p = 0.042, OR = 2.37, 95% CI: 1.04-5.43; p = 0.042, OR = 2.49, 95% CI: 1.04-5.96). Moreover, when comparing HIV patients with hepatotoxicity to healthy controls, the haplotype GA had an association with an elevated risk for the development of hepatotoxicity (p = 0.041, OR = 1.73, 95% CI: 1.02-2.93). Additionally, the association of the ABCG2 34GA genotype with the progression of HIV (p = 0.02, OR = 1.97, 95% CI: 1.07-3.63) indicated a risk for advanced HIV infection. Furthermore, the ABCG2 421AA genotype was linked to tobacco users and featured as a risk factor for the progression of HIV disease (p = 0.03, OR = 11.07, 95% CI: 1.09-270.89). CONCLUSION: The haplotype GA may enhance the risk of hepatotoxicity development and its severity. Individuals with the ABCG2 34A allele may also be at risk for the development of hepatotoxicity. Additionally, individuals with an advanced stage of HIV and the ABCG2 34GA genotype may be at risk for disease progression.

Design, Virtual Screening, Molecular Docking, ADME and Cytotoxicity Studies of 1,3,5-Triazine Containing Heterocyclic Scaffolds as Selective BRAF Monomeric, Homo and Heterodimeric Inhibitors.

BACKGROUND: v-RAF murine sarcoma viral homolog B1 (BRAF) is one of the most frequently mutated kinases in human cancers. BRAF exhibits three classes of mutations: Class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). METHOD: In this manuscript, the protein-ligand interaction site of all three mutants: BRAF monomer, BRAF homodimer BRAF2:14-3-32, and BRAF heterodimer BRAF:14-3-32:MEK (Mitogen extracellular Kinase) has been discussed. FDA-approved drugs still have limitations against all three classes of mutants, especially against the second and third classes. Using the DesPot grid model, 1114 new compounds were designed. Using virtual screening, the three PDB Ids 4XV2 for monomers, 7MFF for homodimers, and 4MNE for heterodimers were used for 1114 newly designed compounds. RESULT: Dabrafenib, encorafenib, sorafenib and vemurafenib were included as standard drugs. The top 10 hit molecules were identified for each protein. Additional binding studies were performed using molecular docking studies on the protein-ligand site of each PDB identifier. Absorption, distribution, metabolism, excretion (ADME) and toxicity studies were also performed. CONCLUSION: It was identified that top-hit molecules had better binding and interaction activity than standard in all three classes of mutants.

Ferroptosis: A Frontier in Osteoporosis.

Reduced bone mass and degeneration of the microarchitecture of bone tissue are the hallmarks of osteoporosis, a bone metabolic disease that increases skeletal fragility and fracture susceptibility. Osteoporosis is primarily caused by unbalanced bone remodeling, in which bone synthesis is outpaced by bone resorption caused by osteoclasts. Along with the bone-building vitamins calcium and vitamin D, typical medications for treating osteoporosis include bisphosphonates and calcitonin. The present therapies effectively stop osteoclast activation that is too high, however they come with varying degrees of negative effects. Numerous factors can contribute to osteoporosis, which is characterized by a loss of bone mass and density due to the deterioration of the bone's microstructure, which makes the bone more fragile. As a result, it is a systemic bone condition that makes patients more likely to fracture. Interest in the function of ferroptosis in the pathophysiology of osteoporosis is developing. In this review, we go through the shape of the cell, the fundamental mechanisms of ferroptosis, the relationship between osteoclasts and osteoblasts, the association between ferroptosis and diabetic osteoporosis, steroid-induced osteoporosis, and the relationship between ferroptosis and postmenopausal osteoporosis. The functions of ferroptosis and osteoporosis in cellular function, signaling cascades, pharmacological inhibition, and gene silencing have been better understood thanks to recent advances in biomedical research.

Insights into the mechanisms of diabetic wounds: pathophysiology, molecular targets, and treatment strategies through conventional and alternative therapies.

Diabetes mellitus is a prevalent cause of mortality worldwide and can lead to several secondary issues, including DWs, which are caused by hyperglycemia, diabetic neuropathy, anemia, and ischemia. Roughly 15% of diabetic patient's experience complications related to DWs, with 25% at risk of lower limb amputations. A conventional management protocol is currently used for treating diabetic foot syndrome, which involves therapy using various substances, such as bFGF, pDGF, VEGF, EGF, IGF-I, TGF-ß, skin substitutes, cytokine stimulators, cytokine inhibitors, MMPs inhibitors, gene and stem cell therapies, ECM, and angiogenesis stimulators. The protocol also includes wound cleaning, laser therapy, antibiotics, skin substitutes, HOTC therapy, and removing dead tissue. It has been observed that treatment with numerous plants and their active constituents, including Globularia Arabica, Rhus coriaria L., Neolamarckia cadamba, Olea europaea, Salvia kronenburgii, Moringa oleifera, Syzygium aromaticum, Combretum molle, and Myrtus communis, has been found to promote wound healing, reduce inflammation, stimulate angiogenesis, and cytokines production, increase growth factors production, promote keratinocyte production, and encourage fibroblast proliferation. These therapies may also reduce the need for amputations. However, there is still limited information on how to prevent and manage DWs, and further research is needed to fully understand the role of alternative treatments in managing complications of DWs. The conventional management protocol for treating diabetic foot syndrome can be expensive and may cause adverse side effects. Alternative therapies, such as medicinal plants and green synthesis of nano-formulations, may provide efficient and affordable treatments for DWs.

Navigating the dementia landscape: Biomarkers and emerging therapies.

The field of dementia research has witnessed significant developments in our understanding of neurodegenerative disorders, with a particular focus on Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). Dementia, a collection of symptoms arising from the degeneration of brain cells, presents a significant healthcare challenge, especially as its prevalence escalates with age. This abstract delves into the complexities of these disorders, the role of biomarkers in their diagnosis and monitoring, as well as emerging neurophysiological insights. In the context of AD, anti-amyloid therapy has gained prominence, aiming to reduce the accumulation of amyloid-beta (Aß) plaques in the brain, a hallmark of the disease. Notably, Leqembi recently received full FDA approval, marking a significant breakthrough in AD treatment. Additionally, ongoing phase 3 clinical trials are investigating novel therapies, including Masitinib and NE3107, focusing on cognitive and functional improvements in AD patients. In the realm of FTD, research has unveiled distinct neuropathological features, including the involvement of proteins like TDP-43 and progranulin, providing valuable insights into the diagnosis and management of this heterogeneous condition. Biomarkers, including neurofilaments and various tau fragments, have shown promise in enhancing diagnostic accuracy. Neurophysiological techniques, such as transcranial magnetic stimulation (TMS), have contributed to our understanding of AD and FTD. TMS has uncovered unique neurophysiological signatures, highlighting impaired plasticity, hyperexcitability, and altered connectivity in AD, while FTD displays differences in neurotransmitter systems, particularly GABAergic and glutamatergic circuits. Lastly, ongoing clinical trials in anti-amyloid therapy for AD, such as Simufilam, Solanezumab, Gantenerumab, and Remternetug, offer hope for individuals affected by this devastating disease, with the potential to alter the course of cognitive decline. These advancements collectively illuminate the evolving landscape of dementia research and the pursuit of effective treatments for these challenging conditions.

Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors.

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).

MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives.

MEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the αC-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition.

Challenges and Opportunities in the Crusade of BRAF Inhibitors: From 2002 to 2022.

Serine/threonine-protein kinase B-Raf (BRAF; RAF = rapidly accelerated fibrosarcoma) plays an important role in the mitogen-activated protein kinase (MAPK) signaling cascade. Somatic mutations in the BRAF gene were first discovered in 2002 by Davies et al., which was a major breakthrough in cancer research. Subsequently, three different classes of BRAF mutants have been discovered. This class includes class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600). Cancers caused by these include melanoma, thyroid cancer, ovarian cancer, colorectal cancer, nonsmall cell lung cancer, and others. In this study, we have highlighted the major binding pockets in BRAF protein, their active and inactive conformations with inhibitors, and BRAF dimerization and its importance in paradoxical activation and BRAF mutation. We have discussed the first-, second-, and third-generation drugs approved by the Food and Drug Administration and drugs under clinical trials with all four different binding approaches with DFG-IN/OUT and αC-IN/OUT for BRAF protein. We have investigated particular aspects and difficulties with all three generations of inhibitors. Finally, this study has also covered recent developments in synthetic BRAF inhibitors (from their discovery in 2002 to 2022), their unique properties, and importance in inhibiting BRAF mutants.

STAT3 Signaling Axis and Tamoxifen in Breast Cancer: A Promising Target for Treatment Resistance.

Signal transducers and activators of transcription 3 (STAT 3) have been proposed to be responsible for breast cancer development. Moreover, evidence depicted that upregulation of STAT3 is responsible for angiogenesis, metastasis, and chemo-resistance of breast cancer. Tamoxifen (TAM) resistance is a major concern in breast cancer management which is mediated by numerous signaling pathways such as STAT3. Therefore, STAT3 targeting inhibitors would be beneficial in breast cancer treatment. The information on the topic in this review was gathered from scientific databases such as PubMed, Scopus, Google Scholar, and ScienceDirect. The present review highlights STAT3 signaling axis discoveries and TAM targeting STAT3 in breast cancer. Based on the results of this study, we found that following prolonged TAM treatment, STAT3 showed overexpression and resulted in drug resistance. Moreover, it was concluded that STAT3 plays an important role in breast cancer stem cells, which correlated with TAM resistance.

Targeting autophagy with tamoxifen in breast cancer: From molecular mechanisms to targeted therapy.

BACKGROUND: Tamoxifen (TAM) is often recommended as a first-line treatment for estrogen receptor-positive breast cancer (BC). However, TAM resistance continues to be a medical challenge for BC with hormone receptor positivity. The function of macro-autophagy and autophagy has recently been identified to be altered in BC, which suggests a potential mechanism for TAM resistance. Autophagy is a cellular stress-induced response to preserve cellular homeostasis. Also, therapy-induced autophagy, which is typically cytoprotective and activated in tumor cells, could sometimes be non-protective, cytostatic, or cytotoxic depending on how it is regulated. OBJECTIVE: This review explored the literature on the connections between hormonal therapies and autophagy. We investigated how autophagy could develop drug resistance in BC cells. METHODS: Scopus, Science Direct, PubMed, and Google Scholar were used to search articles for this study. RESULTS: The results demonstrated that protein kinases such as pAMPK, BAX, and p-p70S6K could be a sign of autophagy in developing TAM resistance. According to the study's findings, autophagy plays an important role in BC patients' TAM resistance. CONCLUSION: Therefore, by overcoming endocrine resistance in estrogen receptor-positive breast tumors, autophagy inhibition may improve the therapeutic efficacy of TAM.

Correction: Ameliorative effect of biofabricated ZnO nanoparticles of Trianthema portulacastrum Linn. on dermal wounds via removal of oxidative stress and inflammation.

[This corrects the article DOI: 10.1039/C8RA03500H.].

Green Synthesis of Genistein-Fortified Zinc Ferrite Nanoparticles as a Potent Hepatic Cancer Inhibitor: Validation through Experimental and Computational Studies.

In hepatic cancer, precancerous nodules account for damage and inflammation in liver cells. Studies have proved that phyto-compounds based on biosynthetic metallic nanoparticles display superior action against hepatic tumors. This study targeted the synthesis of genistein-fortified zinc ferrite nanoparticles (GENP) trailed by anticancer activity assessment against diethylnitrosamine and N-acetyl-2-aminofluorene induced hepatic cancer. The process of nucleation was confirmed by UV/VIS spectrophotometry, X-ray beam diffraction, field-emission scanning electron microscopy, and FT-IR. An in vitro antioxidant assay illustrated that the leaves of Pterocarpus mildbraedii have strong tendency as a reductant and, in the nanoformulation synthesis, as a natural capping agent. A MTT assay confirmed that GENP have a strong selective cytotoxic potential against HepG2 cancer cells. In silico studies of genistein exemplified the binding tendency towards human matrix metalloproteinase comparative to the standard drug marimastat. An in vivo anticancer evaluation showed that GENP effectively inhibit the growth of hepatic cancer by interfering with hepatic and non-hepatic biochemical markers.

Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective.

Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, ß-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets.

Virtual screening, structure based pharmacophore mapping, and molecular simulation studies of pyrido[2,3-d]pyrimidines as selective thymidylate synthase inhibitors.

Human thymidylate synthase is the rate-limiting enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate. dUMP (pyrimidine) and folate binding site hTS inhibitors showed resistance in colorectal cancer (CRC). In the present study, we have performed virtual screening of the pyrido[2,3-d]pyrimidine database, followed by binding free energy calculations, and pharmacophore mapping to design novel pyrido[2,3-d]pyrimidine derivatives to stabilize inactive confirmation of hTS. A library of 42 molecules was designed. Based on the molecular docking studies, four ligands (T36, T39, T40, and T13) were identified to have better interactions and docking scores with the catalytic sites [dUMP (pyrimidine) and folate binding sites] of hTS protein than standard drug, raltitrexed. To validate efficacy of the designed molecules, we performed molecular dynamics simulation studies at 1000 ns with principal component analysis and binding free energy calculations on the hTS protein, also drug likeness properties of all hits were in acceptable range. Compounds T36, T39, T40, and T13 interacted with the catalytic amino acid (Cys195), an essential amino acid for anticancer activity. The designed molecules stabilized the inactive conformation of hTS, resulting in the inhibition of hTS. The designed compounds will undergo synthesis and biological evaluation, which may yield selective, less toxic, and highly potent hTS inhibitors.Communicated by Ramaswamy H. Sarma.