Targeting of S-phase kinase associated protein 2 stabilized tumor suppressors leading to apoptotic cell death in squamous skin cancer cells.

S-phase kinase-associated protein 2 (Skp2) is an F-box protein overexpressed in human cancers and linked with poor prognosis. It triggers cancer pathogenesis, including stemness and drug resistance. In this study, we have explored the potential role of Skp2 targeting in restoring the expression of tumor suppressors in human cutaneous squamous cell carcinoma (cSCC) cells. Our results showed that genetic and pharmacological Skp2 targeting markedly suppressed cSCC cell proliferation, colony growth, spheroid formation, and enhanced sensitization to chemotherapeutic drugs. Further, western blot results demonstrated restoration of tumor suppressor (KLF4) and CDKI (p21) and suppression of vimentin and survivin in Skp2-knocked-down cSCC cells. Importantly, we also explored that Skp2 targeting potentiates apoptosis of cSCC cells through MAPK signaling. Moreover, co-targeting of Skp2 and PI3K/AKT resulted in increased cancer cell death. Interestingly, curcumin, a well-known naturally derived anticancer agent, also inhibits Skp2 expression with concomitant CDKI upregulation. In line, curcumin suppressed cSCC cell growth through ROS-mediated apoptosis, while the use of N-acetyl cysteine (NAC) reversed curcumin-induced cell death. Curcumin treatment also sensitized cSCC cells to conventional anticancer drugs, such as cisplatin and doxorubicin. Altogether, these data suggest that Skp2 targeting restores the functioning of tumor suppressors, inhibits the expression of genes associated with cell proliferation and stemness, and sensitizes cancer cells to anticancer drugs. Thus, genetic, and pharmacological ablation of Skp2 can be an important strategy for attenuating cancer pathogenesis and associated complications in skin squamous cell carcinoma.

Highly Biocompatible Smart Injectable Hydrogel for the Management of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that severely affects joints and restricts locomotion. Various treatment regimens are available for RA, providing short-term relief from pain, but long-term relief from the disease is still not available. Evidently, cytokines play a crucial role in the pathophysiology of the disease. However, aberrant immune responses, genetic dispositions, viral infections, or toxicants are some possible causative mediators of RA. The synovial fluid of rheumatoid arthritis patients encompass cytokines, especially osteoclastogenic cytokines, and invasion factors such as macrophage colony-stimulating factor (M-CSF) and the receptor activator of NF-κB ligand (RANKL). Moreover, tumor necrosis factor-α (TNF-α) and interleukins (IL-1, 6, and 17) intensify osteoclast differentiation and activation. Therefore, in order to restrict the cytokine expression, we used budesonide as a therapeutic lead and encapsulated it into a highly biocompatible hydrogel system. The hydrogel system developed by us is enzyme-responsive and provides sustained drug release flow over an extended period of time. This hydrogel is characterized by ζ-potential analysis, field-emission scanning electron microscopy (FE-SEM), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, and it is further encapsulated with budesonide (glucocorticoids) for therapeutic purposes. Evidently, Bud-loaded ER-hydrogel showed improvement in joint physiology compared to the disease group and downregulated the inflammatory markers.

Insight into the transcription factors regulating Ischemic stroke and glioma in response to shared stimuli.

Cerebral ischemic stroke and glioma are the two leading causes of patient mortality globally. Despite physiological variations, 1 in 10 people who have an ischemic stroke go on to develop brain cancer, most notably gliomas. In addition, glioma treatments have also been shown to increase the risk of ischemic strokes. Stroke occurs more frequently in cancer patients than in the general population, according to traditional literature. Unbelievably, these events share multiple pathways, but the precise mechanism underlying their co-occurrence remains unknown. Transcription factors (TFs), the main components of gene expression programmes, finally determine the fate of cells and homeostasis. Both ischemic stroke and glioma exhibit aberrant expression of a large number of TFs, which are strongly linked to the pathophysiology and progression of both diseases. The precise genomic binding locations of TFs and how TF binding ultimately relates to transcriptional regulation remain elusive despite a strong interest in understanding how TFs regulate gene expression in both stroke and glioma. As a result, the importance of continuing efforts to understand TF-mediated gene regulation is highlighted in this review, along with some of the primary shared events in stroke and glioma.

NLRP3 Inflammasome-Targeting Nanomicelles for Preventing Ischemia-Reperfusion-Induced Inflammatory Injury.

Ischemia-reperfusion (I/R) injury is a disease process that affects several vital organs. There is widespread agreement that the NLRP3 inflammasome pathway plays a crucial role in the development of I/R injury. We have developed transferrin-conjugated, pH-responsive nanomicelles for the entrapment of MCC950 drug. These nanomicelles specifically bind to the transferrin receptor 1 (TFR1) expressed on the cells of the blood-brain barrier (BBB) and thus help the cargo to cross the BBB. Furthermore, the therapeutic potential of nanomicelles was assessed using in vitro, in ovo, and in vivo models of I/R injury. Nanomicelles were injected into the common carotid artery (CCA) of a middle cerebral artery occlusion (MCAO) rat model to achieve maximum accretion of nanomicelles into the brain as blood flows toward the brain in the CCA. The current study reveals that the treatment with nanomicelles significantly alleviates the levels of NLRP3 inflammasome biomarkers which were found to be increased in oxygen-glucose deprivation (OGD)-treated SH-SY5Y cells, the I/R-damaged right vitelline artery (RVA) of chick embryos, and the MCAO rat model. The supplementation with nanomicelles significantly enhanced the overall survival of MCAO rats. Overall, nanomicelles exerted therapeutic effects against I/R injury, which might be due to the suppression of the activation of the NLRP3 inflammasome.

MCC950 Regulates Stem Cells Destiny Through Modulating SIRT3-NLRP3 Inflammasome Dynamics During Oxygen Glucose Deprivation.

Ischemic stroke is the major cause of death and morbidity worldwide. Stem cell treatment is at the forefront of ischemic therapeutic interventions. However, the fate of these cells following transplantation is mostly unknown. The current study examines the influence of oxidative and inflammatory pathological events associated with experimental ischemic stroke (oxygen glucose deprivation (OGD)) on the stem cell population (human Dental Pulp Stem Cells, and human Mesenchymal Stem Cells) through the involvement of the NLRP3 inflammasome. We explored the destiny of the above-mentioned stem cells in the stressed micro (-environment) and the ability of MCC950 to reverse the magnitudes. An enhanced expression of NLRP3, ASC, cleaved caspase1, active IL-1ß and active IL-18 in OGD-treated DPSC and MSC was observed. The MCC950 significantly reduced NLRP3 inflammasome activation in the aforementioned cells. Further, in OGD groups, oxidative stress markers were shown to be alleviated in the stem cells under stress, which was effectively relieved by MCC950 supplementation. Interestingly, whereas OGD increased NLRP3 expression, it decreased SIRT3 levels, implying that these two processes are intertwined. In brief, we discovered that MCC950 inhibits NLRP3-mediated inflammation by inhibiting the NLRP3 inflammasome and increasing SIRT3. To conclude, according to our findings, inhibiting NLRP3 activation while enhancing SIRT3 levels with MCC950 reduces oxidative and inflammatory stress in stem cells under OGD-induced stress. These findings shed light on the causes of hDPSC and hMSC demise following transplantation and point to strategies to lessen therapeutic cell loss under ischemic-reperfusion stress.

Nanomedicine as potential cancer therapy via targeting dysregulated transcription factors.

Cancer as a disease possess quite complicated pathophysiological implications and is among the prominent causes of morbidity and mortality on global scales. Anti-cancer chemotherapy, surgery, and radiation therapy are some of the present-day conventional treatment options. However, these therapeutic paradigms own several retreats, including lack of specificity, non-targeted toxicological implications, inefficient drug delivery to targeted cells, and emergence of cancer resistance, ultimately causing ineffective cancer management. Owing to the advanced and better biophysical characteristic features and potentiality for the tailoring and customizations and in several fashions, nanotechnology can entirely transubstantiate the cancer identification and its managements. Additionally, nanotechnology also renders several answers to present-day mainstream limitations springing-up in anti-cancer therapeutics. Nanocarriers, owing to their outstanding physicochemical features including but not limited to their particle size, surface morphological features viz. shape etc., have been employed in nanomedicinal platforms for targeting various transcription factors leading to worthy pharmacological outcomes. This transcription targeting activates the wide array of cellular and molecular events like antioxidant enzyme-induction, apoptotic cell death, cell-cycle arrest etc. These outcomes are obtained after the activation or inactivation of several transcription factors and cellular pathways. Further, nanoformulations have been precisely calibrated and functionalized with peculiar targeting groups for improving their efficiency to deliver the drug-payload to specified and targeted cancerous cells and tissues. This review undertakes an extensive, across-the-board and all-inclusive approach consisting of various studies encompassing different types of tailored and customized nanoformulations and nanomaterials designed for targeting the transcription factors implicated in the process of carcinogenesis, tumor-maturation, growth and metastasis. Various transcription factors viz. nuclear factor kappa (NF-κB), signal transducer and activators of transcription (STAT), Cmyc and Twist-related protein 1 (TWIST1) along with several types of nanoparticles targeting these transcription factors have been summarized here. A section has also been dedicated to the different types of nanoparticles targeting the hypoxia inducing factors. Efforts have been made to summarize several other transcription factors implicated in various stages of cancer development, growth, progression and invasion, and their targeting with different kinds of nanomedicinal agents.

Transcriptional factors targeting in cancer stem cells for tumor modulation.

Cancer Stem Cells (CSCs) are now considered the primary "seeds" for the onset, development, metastasis, and recurrence of tumors. Despite therapeutic breakthroughs, cancer remains the leading cause of death worldwide. This is because the tumor microenvironment contains a key population of cells known as CSCs, which promote tumor aggression. CSCs are self-renewing cells that aid tumor recurrence by promoting tumor growth and persisting in patients after many traditional cancer treatments. According to reports, numerous transcription factors (TF) play a key role in maintaining CSC pluripotency and its self-renewal property. The understanding of the functions, structures, and interactional dynamics of these transcription factors with DNA has modified the hypothesis, paving the way for novel transcription factor-targeted therapies. These TFs, which are crucial and are required by cancer cells, play a vital function in the etiology of human cancer. Such CSC TFs will help with gene expression profiling, which provides crucial data for predicting the prognosis of patients. To overcome anti-cancer medication resistance and completely eradicate cancer, a potent therapy combining TFs-based CSC targets with traditional chemotherapy may be developed. In order to develop therapies that could eliminate CSCs, we here concentrated on the effect of TFs and other components of signalling pathways on cancer stemness.

Nanoparticle-Mediated PRDX2 Inhibition for Specific Targeting of CHK2-Null Colorectal Cancer.

Synthetic lethality is a pragmatic targeted cancer therapy approach in which cancer cells harboring genetic alterations are exploited for the specific killing of cancer cells. Earlier, we have established a synthetic lethal (SL) interaction between two genes that are CHK2 and PRDX2 in colorectal cancer (CRC) cells. The SL interaction between CHK2 and PRDX2 resulted in selective targeting of CHK2-defective CRC cells. N-Carbamoyl alanine (NCA) is a PRDX2 inhibitor and is a peptide-like organic compound, which degrades after oral administration in harsh gastric pH. To overcome the limitations of NCA, a chitosan-based nanocarrier was developed for the entrapment of NCA. In this study, we targeted the SL interaction between PRDX2 and CHK2 using NCA-loaded chitosan nanoparticles (NCA-Chit NPs) to selectively inhibit the CHK2-null HCT116 cells. NCA-Chit NPs were assessed for various physicochemical characterizations such as the hydrodynamic diameter (size), zeta potential, and polydispersity index using a Zetasizer. Additionally, morphological studies for the shape and size of NPs were confirmed by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. Cellular uptake of NPs was confirmed using confocal microscopy, which exhibited that nanoparticles were able to internalize into the HCT116 cells. Blank Chit NPs were found to be cytocompatible as they did not exert any cytotoxic effects on hTERT, L929, and Caco-2 cells (intestinal epithelial cells). Importantly, NCA-Chit NPs were quite hemocompatible also. In the form of an NCA-chitosan nanoformulation, the efficacy was enhanced by about 8 times compared to free form of NCA towards selective killing of CHK2-null HCT116 cells as compared to HCT116 cells. The chitosan-based nanoformulation for NCA was developed to augment the efficacy of the NCA for enhanced cell death of colorectal cancer cells having CHK2 defects.

Pristimerin mediated anticancer effects and sensitization of human skin cancer cells through modulation of MAPK signaling pathways.

Squamous cell carcinoma is a frequent skin cancer still demanding to understand the underlying mechanisms for better clinical outcomes. Pristimerin, a natural quinonemethide triterpenoid, has shown promising therapeutic outcome due to its anti-cancer activity and multi-targeting potential. We explored the underlying mechanisms of pristimerin-induced programmed cell death of primary (A431) and metastatic (A388) cutaneous squamous cell carcinoma (cSCC) cells. Our results show that pristimerin inhibits growth and proliferation of cSCC through JNK activation. Moreover, pristimerin causes cell cycle arrest and induces cell death via apoptosis and autophagy. Interestingly, use of apoptosis (z-VAD-FMK) and autophagy (3-methyladenine) inhibitors confirmed vital role of programmed cell death in pristimerin-mediated anti-cancer actions. JNK inhibitor, SP600125, also mitigated pristimerin-induced apoptotic and autophagic actions. Moreover, pristimerin-mediated anti-cancer activity acts by generating reactive oxygen species (ROS) thereby inducing JNK signaling. Use of N-acetyl cystine (NAC), a universal ROS scavenger, significantly reversed pristimerin-induced programmed cell death through downregulation of JNK. Pristimerin sensitized skin cancer cells to conventional anticancer drugs cisplatin, azacytidine and doxorubicin through JNK activation, as confirmed by SP600125. Our results indicate that pristimerin mediates programmed cell death and sensitized skin cancer cells to conventional anti-cancer drugs via ROS-mediated JNK activation.

Enhanced Antioxidant Effects of Naringenin Nanoparticles Synthesized using the High-Energy Ball Milling Method.

Naringenin, one of the flavonoid components, is majorly found in and obtained from grapefruits and oranges. Naringenin also acts as a potent antioxidant, which possesses hypolipidemic as well as anti-inflammatory potential. Naringenin reduces the expressions of several inflammatory mediators, viz., NF-κB, cycloxygenase-2, and other cytokine mediators. In spite of having various biological effects, the clinical application of naringenin is restricted due to its very poor aqueous solubility. In the present study, the high-energy ball milling method was employed for the preparation of naringenin nanoparticles without using any chemical with an aim to enhance the anti-oxidant potential of naringenin. The milled naringenin nanoparticles were characterized for their physicochemical properties using scanning electron microscopy (SEM) and X-ray diffraction. Additionally, the effects of milling time and temperature were further assessed on the solubility of crude and milled naringenin samples. The antioxidant potential of milled naringenin was evaluated with various assays such as DHE, DCFDA, and cleaved caspase-3 using SH-SY5Y human neuroblastoma cells. The nanoparticle size of naringenin after milling was confirmed using SEM analysis. Crystalline peaks for milled and crude samples of naringenin also established that both the naringenin forms were in the crystalline form. The solubility of naringenin was enhanced depending on the milling time and temperature. Moreover, crude and milled naringenin were found to be cytocompatible up to doses of 120 µM each for the duration of 24 and 48 h. It was also observed that milled naringenin at the doses of 1, 2, and 5 µM significantly reduced the levels of reactive oxygen species (ROS) generated by H2O2 and exhibited superior ROS scavenging effects as compared to those of crude or un-milled forms of naringenin. Furthermore, milled naringenin at the doses of 1 and 2 µM inhibited H2O2-induced cell death, as shown by immunofluorescence staining of cleaved caspase-3 and Annexin-V PI flow cytometry analysis. Conclusively, it could be suggested that the size reduction of naringenin using high-energy ball milling techniques substantially enhanced the antioxidant potential as compared to naïve or crude naringenin, which may be attributed to its enhanced solubility due to reduced size.

Mesenchymal stem cells: a new front emerges in coronavirus disease 2019 treatment.

Currently, treating coronavirus disease 2019 (COVID-19) patients, particularly those afflicted with severe pneumonia, is challenging, as no effective pharmacotherapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists. Severe pneumonia is recognized as a clinical syndrome characterized by hyper-induction of pro-inflammatory cytokine production, which can induce organ damage, followed by edema, dysfunction of air exchange, acute respiratory distress syndrome, acute cardiac injury, secondary infection and increased mortality. Owing to the immunoregulatory and differentiation potential of mesenchymal stem cells (MSCs), we aimed to outline current insights into the clinical application of MSCs in COVID-19 patients. Based on results from preliminary clinical investigations, it can be predicted that MSC therapy for patients infected with SARS-CoV-2 is safe and effective, although multiple clinical trials with a protracted follow-up will be necessary to determine the long-term effects of the treatment on COVID-19 patients.

Cellulose-Conjugated Copper-Oxide Nanoparticles for the Treatment of Ethanol-Induced Gastric Ulcers in Wistar Rats.

Gastric ulcer (GU) is the most common and chronic inflammatory condition mediated by multiple immune cells like neutrophils, macrophages, and lymphocytes with multiple pro-inflammatory cytokine interleukins such as IL-8, IL-10, IL-ß, and interferon-γ (IFN-γ). Copper (Cu) is one of the essential micronutrients mainly found in the liver and brain. It plays a major role in metabolism, enzyme conversion, free radical scavenging, trafficking agents, and many others. Due to its various roles in the biological system, it can also be used as a therapeutic agent in many diseases like colon cancer, bone fracture healing, angiogenesis, as an antibacterial, wound-healing and radiotherapeutic agents. In this study, we used thiol-functionalized cellulose-conjugated copper-oxide nanoparticles (CuI/IIO NPs) synthesized under environmentally friendly conditions. We have evaluated the effects of cellulose-conjugated CuI/IIO NPs against ethanol-induced gastric ulcer in Wistar rats. The cellulose-conjugated CuI/IIO NPs were evaluated against different physical, histochemical, and inflammatory parameters. The NPs promoted mucosal healing by ameliorating ulcerative damage, restoring the histoarchitecture of gastric mucosa, and inhibiting pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1ß), and other inflammatory biomarkers such as myeloperoxidase (MPO) activity and nitric oxide (NO) levels. The current study's findings suggest that cellulose-conjugated CuI/IIO NPs exerted antiulcer effects on the preclinical rat model and have promising potential as a novel therapeutic agent for the treatment of gastric ulcers.

N-Carbamoyl Alanine-Mediated Selective Targeting for CHEK2-Null Colorectal Cancer.

Colorectal cancer (CRC) is one of the major causes of cancer-linked mortality worldwide. Selective therapeutic approaches toward cancer are the need of the hour to combat cancer. Synthetic lethality is a pragmatic targeted cancer therapy in which cancer cell-specific vulnerabilities such as genetic defects/somatic mutations are exploited for selective cancer therapy by targeting genetic interactors (synthetic lethal interactors) of such mutation/defects present in cancer cells. In this study, we investigated the synthetic lethal interaction between checkpoint kinase 2 (CHEK2) and peroxiredoxin-2 (PRDX2) in CRC cells to precisely target CRC cells having CHEK2 defects. We have performed siRNA-mediated silencing and n-carbamoyl alanine (NCA)-mediated inhibition of PRDX2 in CHEK2-null HCT116 cells to confirm the synthetic lethal (SL) interaction between PRDX2 and CHEK2 as the cell population reduced significantly after silencing/inhibition of PRDX2. Additionally, treatment with NCA resulted in an increased level of total ROS in both cell types (HCT116 and CHEK2-null HCT116 cells), which further confirms that inhibition of PRDX2 results in an increased ROS level, which are mainly responsible for DNA double-strand breaks (DSBs). ROS-induced DNA DSBs get repaired in HCT116 cells, in which CHEK2 is in the normal functional state, but these DNA DSBs persist in CHEK2-null HCT116 cells as confirmed by the immunofluorescence analysis of 53BP1 and γ-H2AX. Finally, CHEK2-null HCT116 cells undergo apoptosis due to persistent DNA damage as confirmed by immunofluorescence analysis of cleaved caspase-3. The findings of this study suggest that PRDX2 has a SL interaction with CHEK2, and this interaction can be exploited for the targeted cancer therapy using NCA as a drug inhibitor of PRDX2 for the therapy of colorectal cancer having CHEK2 defects. Further studies are warranted to confirm the interaction in the preclinical model.

Oxidative Stress-induced Autophagy Compromises Stem Cell Viability.

Stem cell therapies have emerged as a promising treatment strategy for various diseases characterized by ischemic injury such as ischemic stroke. Cell survival after transplantation remains a critical issue. We investigated the impact of oxidative stress, being typically present in ischemically challenged tissue, on human dental pulp stem cells (hDPSC) and human mesenchymal stem cells (hMSC). We used oxygen-glucose deprivation (OGD) to induce oxidative stress in hDPSC and hMSC. OGD-induced generation of O2•- or H2O2 enhanced autophagy by inducing the expression of activating molecule in BECN1-regulated autophagy protein 1 (Ambra1) and Beclin1 in both cell types. However, hDPSC and hMSC pre-conditioning using reactive oxygen species (ROS) scavengers significantly repressed the expression of Ambra1 and Beclin1 and inactivated autophagy. O2•- or H2O2 acted upstream of autophagy, and the mechanism was unidirectional. Furthermore, our findings revealed ROS-p38-Erk1/2 involvement. Pre-treatment with selective inhibitors of p38 and Erk1/2 pathways (SB202190 and PD98059) reversed OGD effects on the expression of Ambra1 and Beclin1, suggesting that these pathways induced oxidative stress-mediated autophagy. SIRT3 depletion was found to be associated with increased oxidative stress and activation of p38 and Erk1/2 MAPKs pathways. Global ROS inhibition by NAC or a combination of polyethylene glycol-superoxide dismutase (PEG-SOD) and polyethylene glycol-catalase (PEG-catalase) further confirmed that O2•- or H2O2 or a combination of both impacts stems cell viability by inducing autophagy. Furthermore, autophagy inhibition by 3-methyladenine (3-MA) significantly improved hDPSC viability. These findings contribute to a better understanding of post-transplantation hDPSC and hMSC death and may deduce strategies to minimize therapeutic cell loss under oxidative stress.

Role of non-coding RNAs in the progression and resistance of cutaneous malignancies and autoimmune diseases.

Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.

Sanguinarine mediated apoptosis in Non-Small Cell Lung Cancer via generation of reactive oxygen species and suppression of JAK/STAT pathway.

Effective treatment of lung cancer remains a significant clinical challenge due to its multidrug resistance and side effects of the current treatment options. The high mortality associated with this malignancy indicates the need for new therapeutic interventions with fewer side effects. Natural compounds offer various benefits such as easy access, minimal side effects, and multi-molecular targets and thus, can prove useful in treating lung cancer. Sanguinarine (SNG), a natural compound, possesses favorable therapeutic potential against a variety of cancers. Here, we examined the underlying molecular mechanisms of SNG in Non-Small Cell Lung Cancer (NSCLC) cells. SNG suppressed cell growth and induced apoptosis via downregulation of the constitutively active JAK/STAT pathway in all the NSCLC cell lines. siRNA silencing of STAT3 in NSCLC cells further confirmed the involvement of the JAK/STAT signaling cascade. SNG treatment increased Bax/Bcl-2 ratio, which contributed to a leaky mitochondrial membrane leading to cytochrome c release accompanied by caspase activation. In addition, we established the antitumor effects of SNG through reactive oxygen species (ROS) production, as inhibiting ROS production prevented the apoptosis-inducing potential of SNG. In vivo xenograft tumor model further validated our in vitro findings. Overall, our study investigated the molecular mechanisms by which SNG induces apoptosis in NSCLC, providing avenues for developing novel natural compound-based cancer therapies.

Dose dependent safety implications and acute intravenous toxicity of aminocellulose-grafted-polycaprolactone coated gelatin nanoparticles in mice.

Polymeric nanoparticles (NPs) are the most widely researched nanoformulations and gained broad acceptance in nanotherapeutics for targeted drug delivery and theranostics. However, lack of regulations, guidelines, harmonized standards, and limitations with their employability in clinical circumstances necessitates an in-depth understanding of their toxicology. Here, we examined the in-vivo toxicity of core-shell polymeric NPs made up of gelatin core coated with an outer layer of aminocellulose-grafted polycaprolactone (PCL-AC) synthesized for drug delivery purposes in inflammatory disorders. Nanoparticles were administered intravenously in Swiss albino mice, in multiple dosing (10, 25, and 50 mg/kg body weight) and outcomes of serum biochemistry analysis and histopathology evaluation exhibited that the highest 50 mg/kg administration of NPs altered biochemistry and histopathology aspects of vital organs, while doses of 10 and 25 mg/kg were safe and biocompatible. Further, mast cell (toluidine blue) staining confirmed that administration of the highest dose enhanced mast cell infiltration in tissues of vital organs, while lower doses did not exhibit any of these alterations. Therefore, the results of the present study establish that the NPs disposal in-vivo culminates into alterations in organ structure and function consequences such that lower doses are quite biocompatible and do not demonstrate any structural or functional toxicity while some toxicological effects start appearing at the highest dose.

Oxidative Stress Enhances Autophagy-Mediated Death Of Stem Cells Through Erk1/2 Signaling Pathway - Implications For Neurotransplantations.

Stem cell therapies are becoming increasingly popular solutions for neurological disorders. However, there is a lower survival rate of these cells after transplantation. Oxidative stress is linked to brain damage, and it may also impact transplanted stem cells. To better understand how transplanted cells respond to oxidative stress, the current study used H2O2. We briefly illustrated that exogenous H2O2 treatment exaggerated oxidative stress in the human dental pulp and mesenchymal stem cells. 2',7'-Dichlorofluorescin diacetate (DCFDA), MitoSOX confirms the reactive oxygen species (ROS) involvement, which was remarkably subsided by the ROS inhibitors. The findings showed that H2O2 activates autophagy by enhancing pro-autophagic proteins, Beclin1 and Atg7. Increased LC3II/I expression (which co-localized with lysosomal proteins, LAMP1 and Cathepsin B) showed that H2O2 treatment promoted autophagolysosome formation. In the results, both Beclin1 and Atg7 were observed co-localized in mitochondria, indicating their involvement in mitophagy. The evaluation of Erk1/2 in the presence and absence of Na-Pyruvate, PEG-Catalase, and PD98059 established ROS-Erk1/2 participation in autophagy regulation. Further, these findings showed a link between apoptosis and autophagy. The results conclude that H2O2 acts as a stressor, promoting autophagy and mitophagy in stem cells under oxidative stress. The current study may help understand better cell survival and death approaches for transplanted cells in various neurological diseases. The current study uses human Dental Pulp and Mesenchymal Stem cells to demonstrate the importance of H2O2-driven autophagy in deciding the fate of these cells in an oxidative microenvironment. To summarise, we discovered that exogenous H2O2 treatment causes oxidative stress. Exogenous H2O2  treatment also increased ROS production, especially intracellular H2O2. H2O2 stimulated the ErK1/2 signaling pathway and autophagy. Erk1/2 was found to cause autophagy. Further, the function of mitophagy appeared to be an important factor in the H2O2-induced regulation of these two human stem cell types. In a nutshell, by engaging in autophagy nucleation, maturation, and terminal phase proteins, we elucidated the participation of autophagy in cell dysfunction and death.

Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids.

Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy.

Aminocellulose-grafted-polycaprolactone coated gelatin nanoparticles alleviate inflammation in rheumatoid arthritis: A combinational therapeutic approach.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder and serious cause of disability. Despite considerable advances in RA management, challenges like extensive drug metabolism and rapid clearance causes poor bioavailability. Core-shell nanocarriers for co-delivery of glycyrrhizic acid (GA) and budesonide against RA were developed. GA-loaded gelatin nanoparticles (NPs) were synthesized and coated with budesonide encapsulated aminocellulose-grafted polycaprolactone (PCL-AC). GA- and budesonide-loaded PCL-AC-gel NPs had diameter of 200-225 nm. Dual drug-loaded (DDL) NPs reduced joint swelling and erythema in rats while markedly ameliorating bone erosion evidenced by radiological analysis, suppressed collagen destruction, restored synovial tissue, bone and cartilage histoarchitecture with reduced inflammatory cells infiltration. NPs also reduced various inflammatory biomarkers such as TNF-α, IL-1ß, COX-2, iNOS. Results of this study suggest that dual NPs exerted superior therapeutic effects in RA compared to free drugs which may be attributed to slow and sustained drug release and NPs' ability to inhibit inflammatory mediators.