Efficacy and safety of nab-paclitaxel in metastatic gastric cancer: a meta-analysis.

Background: Nab-paclitaxel is formulated to address several limitations of paclitaxel. Methods: A systematic review was done of several databases and a meta-analysis with a random-effects model was conducted to assess the efficacy and safety of nab-paclitaxel in metastatic gastric cancer (MGC). Results: Included studies revealed that nab-paclitaxel provides a 30.4% overall response rate and 65.7% disease control rate in MGC patients. The overall survival was 9.65 months and progression-free survival was 4.48 months, associated with the treatment line and regimen. The highest incidence of grade 3 and higher treatment-related adverse events was for neutropenia (29.9%). Conclusion: Nab-paclitaxel provides better disease response and longer survival with manageable side effects in MGC compared with paclitaxel.

Diabetic retinopathy: a comprehensive update on in vivo, in vitro and ex vivo experimental models.

Diabetic retinopathy (DR), one of the leading causes of visual impairment and blindness worldwide, is one of the major microvascular complications in diabetes mellitus (DM). Globally, DR prevalence among DM patients is 25%, and 6% have vision-threatening problems among them. With the higher incidence of DM globally, more DR cases are expected to be seen in the future. In order to comprehend the pathophysiological mechanism of DR in humans and discover potential novel substances for the treatment of DR, investigations are typically conducted using various experimental models. Among the experimental models, in vivo models have contributed significantly to understanding DR pathogenesis. There are several types of in vivo models for DR research, which include chemical-induced, surgical-induced, diet-induced, and genetic models. Similarly, for the in vitro models, there are several cell types that are utilised in DR research, such as retinal endothelial cells, Müller cells, and glial cells. With the advancement of DR research, it is essential to have a comprehensive update on the various experimental models utilised to mimic DR environment. This review provides the update on the in vitro, in vivo, and ex vivo models used in DR research, focusing on their features, advantages, and limitations.

The effect of palm oil-derived tocotrienol-rich fraction in preserving normal retinal vascular diameter in streptozotocin-induced diabetic rats.

PURPOSE: Angiogenesis in diabetic retinopathy (DR) is associated with increased retinal expression of angiopoietin-2 (Ang-2) and protein kinase C (PKC). Tocotrienol-rich fraction (TRF) has been shown to reduce the expression vascular endothelial growth factor (VEGF) in several experimental models. However, its effect against other angiogenic markers such as Ang-2 and PKC in rat model of diabetes remains unknown. Therefore, we investigated the effect of TRF on the retinal vascular changes and Ang-2 and PKC expressions in rats with streptozotocin (STZ)-induced DR. METHODS: Sprague-Dawley rats were divided into normal control rats (N) which received vehicle, and diabetic rats which either received vehicle (DV) or 100 mg/kg of TRF (DT). Diabetes was induced with intraperitoneal injection of STZ (60 mg/kg body weight). Treatments were given orally, once daily, for 12 weeks after confirmation of hyperglycaemia. Fundus photographs were captured at baseline, 6- and 12-week post-STZ injection and average diameter of retinal veins and arteries were measured. At 12-week post-STZ injection, rats were euthanised, and retinae were collected for measurement of Ang-2 and PKC gene and protein expressions. RESULTS: Retinal venous and arterial diameters were significantly greater in DV compared to DT at week 12 post-STZ injection (p < 0.001 and < 0.05, respectively). The vessel diameter measurements in DT were comparable to N and this effect of TRF was associated with significantly lower Ang-2 and PKC gene and protein expressions compared to DV. CONCLUSION: Oral TRF reduces the expression of retinal angiogenic markers and preserves the retinal vascular diameter of rats with STZ-induced DR.

Nanoparticles for the treatment of glaucoma-associated neuroinflammation.

Recently, a considerable amount of literature has emerged around the theme of neuroinflammation linked to neurodegeneration. Glaucoma is a neurodegenerative disease characterized by visual impairment. Understanding the complex neuroinflammatory processes underlying retinal ganglion cell loss has the potential to improve conventional therapeutic approaches in glaucoma. Due to the presence of multiple barriers that a systemically administered drug has to cross to reach the intraocular space, ocular drug delivery has always been a challenge. Nowadays, studies are focused on improving the current therapies for glaucoma by utilizing nanoparticles as the modes of drug transport across the ocular anatomical and physiological barriers. This review offers some important insights on the therapeutic advancements made in this direction, focusing on the use of nanoparticles loaded with anti-inflammatory and neuroprotective agents in the treatment of glaucoma. The prospect of these novel therapies is discussed in relation to the current therapies to alleviate inflammation in glaucoma, which are being reviewed as well, along with the detailed molecular and cellular mechanisms governing the onset and the progression of the disease.

Targeting Differential Roles of Tumor Necrosis Factor Receptors as a Therapeutic Strategy for Glaucoma.

Glaucoma is an irreversible sight-threatening disorder primarily due to elevated intraocular pressure (IOP), leading to retinal ganglion cell (RGC) death by apoptosis with subsequent loss of optic nerve fibers. A considerable amount of empirical evidence has shown the significant association between tumor necrosis factor cytokine (TNF; TNFα) and glaucoma; however, the exact role of TNF in glaucoma progression remains unclear. Total inhibition of TNF against its receptors can cause side effects, although this is not the case when using selective inhibitors. In addition, TNF exerts its antithetic roles via stimulation of two receptors, TNF receptor I (TNFR1) and TNF receptor II (TNFR2). The pro-inflammatory responses and proapoptotic signaling pathways predominantly mediated through TNFR1, while neuroprotective and anti-apoptotic signals induced by TNFR2. In this review, we attempt to discuss the involvement of TNF receptors (TNFRs) and their signaling pathway in ocular tissues with focus on RGC and glial cells in glaucoma. This review also outlines the potential application TNFRs agonist and/or antagonists as neuroprotective strategy from a therapeutic standpoint. Taken together, a better understanding of the function of TNFRs may lead to the development of a treatment for glaucoma.

Brain-Derived Neurotrophic Factor-Mediated Neuroprotection in Glaucoma: A Review of Current State of the Art.

Retinal ganglion cells (RGCs) are neurons of the visual system that are responsible for transmitting signals from the retina to the brain via the optic nerve. Glaucoma is an optic neuropathy characterized by apoptotic loss of RGCs and degeneration of optic nerve fibers. Risk factors such as elevated intraocular pressure and vascular dysregulation trigger the injury that culminates in RGC apoptosis. In the event of injury, the survival of RGCs is facilitated by neurotrophic factors (NTFs), the most widely studied of which is brain-derived neurotrophic factor (BDNF). Its production is regulated locally in the retina, but transport of BDNF retrogradely from the brain to retina is also crucial. Not only that the interruption of this retrograde transport has been detected in the early stages of glaucoma, but significantly low levels of BDNF have also been detected in the sera and ocular fluids of glaucoma patients, supporting the notion that neurotrophic deprivation is a likely mechanism of glaucomatous optic neuropathy. Moreover, exogenous NTF including BDNF administration was shown reduce neuronal loss in animal models of various neurodegenerative diseases, indicating the possibility that exogenous BDNF may be a treatment option in glaucoma. Current literature provides an extensive insight not only into the sources, transport, and target sites of BDNF but also the intracellular signaling pathways, other pathways that influence BDNF signaling and a wide range of its functions. In this review, the authors discuss the neuroprotective role of BDNF in promoting the survival of RGCs and its possible application as a therapeutic tool to meet the challenges in glaucoma management. We also highlight the possibility of using BDNF as a biomarker in neurodegenerative disease such as glaucoma. Further we discuss the challenges and future strategies to explore the utility of BDNF in the management of glaucoma.

Applications of Alginate-Based Nanomaterials in Enhancing the Therapeutic Effects of Bee Products.

Since the ancient times, bee products (i.e., honey, propolis, pollen, bee venom, bee bread, and royal jelly) have been considered as natural remedies with therapeutic effects against a number of diseases. The therapeutic pleiotropy of bee products is due to their diverse composition and chemical properties, which is independent on the bee species. This has encouraged researchers to extensively study the therapeutic potentials of these products, especially honey. On the other hand, amid the unprecedented growth in nanotechnology research and applications, nanomaterials with various characteristics have been utilized to improve the therapeutic efficiency of these products. Towards keeping the bee products as natural and non-toxic therapeutics, the green synthesis of nanocarriers loaded with these products or their extracts has received a special attention. Alginate is a naturally produced biopolymer derived from brown algae, the desirable properties of which include biodegradability, biocompatibility, non-toxicity and non-immunogenicity. This review presents an overview of alginates, including their properties, nanoformulations, and pharmaceutical applications, placing a particular emphasis on their applications for the enhancement of the therapeutic effects of bee products. Despite the paucity of studies on fabrication of alginate-based nanomaterials loaded with bee products or their extracts, recent advances in the area of utilizing alginate-based nanomaterials and other types of materials to enhance the therapeutic potentials of bee products are summarized in this work. As the most widespread and well-studied bee products, honey and propolis have garnered a special interest; combining them with alginate-based nanomaterials has led to promising findings, especially for wound healing and skin tissue engineering. Furthermore, future directions are proposed and discussed to encourage researchers to develop alginate-based stingless bee product nanomedicines, and to help in selecting suitable methods for devising nanoformulations based on multi-criteria decision making models. Also, the commercialization prospects of nanocomposites based on alginates and bee products are discussed. In conclusion, preserving original characteristics of the bee products is a critical challenge in developing nano-carrier systems. Alginate-based nanomaterials are well suited for this task because they can be fabricated without the use of harsh conditions, such as shear force and freeze-drying, which are often used for other nano-carriers. Further, conjunction of alginates with natural polymers such as honey does not only combine the medicinal properties of alginates and honey, but it could also enhance the mechanical properties and cell adhesion capacity of alginates.

The role of TNFR2+ Tregs in COVID-19: An overview and a potential therapeutic strategy.

COVID-19 is a multi-faceted disease ranging from asymptomatic to severely ill condition that primarily affects the lungs and could advance to other organs as well. It's causing factor, SARS-CoV-2 is recognized to develop robust cell-mediated immunity that responsible to either control or exaggerate the infection. As an important cell subset that control immune responses and are significantly dysregulated in COVID-19, Tregs is proposed to be considered for COVID-19 management. Among its hallmark, TNFR2 is recently recognized to play important role in the function and survival of Tregs. This review gathers available TNFR2 agonists to directly target Tregs as a potential approach to overcome immune dysregulation that affect the severity in COVID-19. Furthermore, this review performs a rigid body docking of TNF-TNFR2 interaction and such interaction with TNFR2 agonist to predict the optimal targeting approach.

Magnesium acetyltaurate prevents retinal damage and visual impairment in rats through suppression of NMDA-induced upregulation of NF-κB, p53 and AP-1 (c-Jun/c-Fos).

Magnesium acetyltaurate (MgAT) has been shown to have a protective effect against N-methyl-D-aspartate (NMDA)-induced retinal cell apoptosis. The current study investigated the involvement of nuclear factor kappa-B (NF-κB), p53 and AP-1 family members (c-Jun/c-Fos) in neuroprotection by MgAT against NMDA-induced retinal damage. In this study, Sprague-Dawley rats were randomized to undergo intravitreal injection of vehicle, NMDA or MgAT as pre-treatment to NMDA. Seven days after injections, retinal ganglion cells survival was detected using retrograde labelling with fluorogold and BRN3A immunostaining. Functional outcome of retinal damage was assessed using electroretinography, and the mechanisms underlying antiapoptotic effect of MgAT were investigated through assessment of retinal gene expression of NF-κB, p53 and AP-1 family members (c-Jun/c-Fos) using reverse transcription-polymerase chain reaction. Retinal phospho-NF-κB, phospho-p53 and AP-1 levels were evaluated using western blot assay. Rat visual functions were evaluated using visual object recognition tests. Both retrograde labelling and BRN3A immunostaining revealed a significant increase in the number of retinal ganglion cells in rats receiving intravitreal injection of MgAT compared with the rats receiving intravitreal injection of NMDA. Electroretinography indicated that pre-treatment with MgAT partially preserved the functional activity of NMDA-exposed retinas. MgAT abolished NMDA-induced increase of retinal phospho-NF-κB, phospho-p53 and AP-1 expression and suppressed NMDA-induced transcriptional activity of NF-κB, p53 and AP-1 family members (c-Jun/c-Fos). Visual object recognition tests showed that MgAT reduced difficulties in recognizing the visual cues (i.e. objects with different shapes) after NMDA exposure, suggesting that visual functions of rats were relatively preserved by pre-treatment with MgAT. In conclusion, pre-treatment with MgAT prevents NMDA induced retinal injury by inhibiting NMDA-induced neuronal apoptosis via downregulation of transcriptional activity of NF-κB, p53 and AP-1-mediated c-Jun/c-Fos. The experiments were approved by the Animal Ethics Committee of Universiti Teknologi MARA (UiTM), Malaysia, UiTM CARE No 118/2015 on December 4, 2015 and UiTM CARE No 220/7/2017 on December 8, 2017 and Ethics Committee of Belgorod State National Research University, Russia, No 02/20 on January 10, 2020.

Dose-dependent effects of NMDA on retinal and optic nerve morphology in rats.

AIM: To investigate dose-dependent effects of N-methyl-D-aspartate (NMDA) on retinal and optic nerve morphology in rats. METHODS: Sprague Dawley rats, 180-250 g in weight were divided into four groups. Groups 1, 2, 3 and 4 were intravitreally administered with vehicle and NMDA at the doses 80, 160 and 320 nmol respectively. Seven days after injection, rats were euthanized, and their eyes were taken for optic nerve toluidine blue and retinal hematoxylin and eosin stainings. The TUNEL assay was done for detecting apoptotic cells. RESULTS: All groups treated with NMDA showed significantly reduced ganglion cell layer (GCL) thickness within inner retina, as compared to control group. Group NMDA 160 nmol showed a significantly greater GCL thickness than the group NMDA 320 nmol. Administration of NMDA also resulted in a dose-dependent decrease in the number of nuclei both per 100 µm GCL length and per 100 µm2 of GCL. Intravitreal NMDA injection caused dose-dependent damage to the optic nerve. The degeneration of nerve fibres with increased clearing of cytoplasm was observed more prominently as the NMDA dose increased. In accordance with the results of retinal morphometry analysis and optic nerve grading, TUNEL staining demonstrated NMDA-induced excitotoxic retinal injury in a dose-dependent manner. CONCLUSION: Our results demonstrate dose-dependent effects of NMDA on retinal and optic nerve morphology in rats that may be attributed to differences in the severity of excitotoxicity and oxidative stress. Our results also suggest that care should be taken while making dose selections experimentally so that the choice might best uphold study objectives.

Antiapoptotic effect of taurine against NMDA-induced retinal excitotoxicity in rats.

OBJECTIVE: N-methyl-D-aspartate (NMDA) excitotoxicity has been proposed to mediate apoptosis of retinal ganglion cells (RGCs) in glaucoma. Taurine (TAU) has been shown to have neuroprotective properties, thus we examined anti-apoptotic effect of TAU against retinal damage after NMDA exposure. METHODOLOGY: Sprague-Dawley rats were divided into 5 groups of 33 each. Group 1 was administered intravitreally with PBS and group 2 was similarly injected with NMDA (160 nmol). Groups 3, 4 and 5 were injected with TAU (320 nmol) 24 hours before (pre-treatment), in combination (co-treatment) and 24 hours after (post-treatment) NMDA exposure respectively. Seven days after injection, rats were sacrificed; eyes were enucleated, fixed and processed for morphometric analysis, TUNEL and caspase-3 staining. Optic nerve morphology assessment was done using toluidine blue staining. The estimation of BDNF, pro/anti-apoptotic factors (Bax/Bcl-2) and caspase-3 activity in retina was done using ELISA technique. RESULTS: Severe degenerative changes were observed in retinae after intravitreal NMDA exposure. The retinal morphology in the TAU pre-treated group appeared more similar to the control retinae and demonstrated a higher number of nuclei than the NMDA group both per 100 µm length (by 1.5-fold, p < 0.001) and per 100 µm2 area (by 1.41-fold, p < 0.05) of the GCL. After NMDA exposure, visible axonal swelling was observed in optic nerve sections. In comparison with the changes observed in the NMDA treated group, the TAU treated group showed fewer prominent changes; axonal swelling was less frequent and less marked. Additionally, no marked glial cell changes were observed in the TAU-pretreated group. All TAU treated groups, particularly the pre-treated group, showed a significant decrease in the NMDA-induced optic nerve damage, with a 50% reduction (p < 0.001) in the mean grading compared to NMDA group. For the same, there was 25% decrease in co- and post-treatment groups, as compared with the NMDA group. Pre-treatment with TAU abolished apoptotic response to NMDA as indicated by decrease in the number of TUNEL- and caspase-3-positive cells. TAU pre-treatment also increased the Bcl-2 level (by 2.80-fold, p < 0.001) and decreased the level of Bax (by 34%, p < 0.01), and activity of caspase-3 (by 36%, p < 0.001) compared to NMDA group. IN CONCLUSION: our study revealed that pre-treatment with TAU prevents NMDA-induced retinal cell apoptosis more effectively than co- and post-treatment with TAU.

Neuroprotective Effect of Magnesium Acetyltaurate Against NMDA-Induced Excitotoxicity in Rat Retina.

Glutamate excitotoxicity plays a major role in the loss of retinal ganglion cells (RGCs) in glaucoma. The toxic effects of glutamate on RGCs are mediated by the overstimulation of N-methyl-D-aspartate (NMDA) receptors. Accordingly, NMDA receptor antagonists have been suggested to inhibit excitotoxicity in RGCs and delay the progression and visual loss in glaucoma patients. The purpose of the present study was to examine the potential neuroprotective effect of Mg acetyltaurate (MgAT) on RGC death induced by NMDA. MgAT was proposed mainly due to the combination of magnesium (Mg) and taurine which may provide neuroprotection by dual mechanisms of action, i.e., inhibition of NMDA receptors and antioxidant effects. Rats were divided into 5 groups and were given intravitreal injections. Group 1 (PBS group) was injected with vehicle; group 2 (NMDA group) was injected with NMDA while groups 3 (pre-), 4 (co-), and 5 (post-) treatments were injected with MgAT, 24 h before, in combination or 24 h after NMDA injection respectively. NMDA and MgAT were injected in PBS at doses 160 and 320 nmol, respectively. Seven days after intravitreal injection, the histological changes in the retina were evaluated using hematoxylin & eosin (H&E) staining. Optic nerves were dissected and stained in Toluidine blue for grading on morphological neurodegenerative changes. The extent of apoptosis in retinal tissue was assessed by TUNEL assay and caspase-3 immunohistochemistry staining. The estimation of neurotrophic factor, oxidative stress, pro/anti-apoptotic factors and caspase-3 activity in retina was done using enzyme-linked immunosorbent assay (ELISA) technique. The retinal morphometry showed reduced thickness of ganglion cell layer (GCL) and reduction in the number of retinal cells in GCL in NMDA group compared to the MgAT-treated groups. TUNEL and caspase-3 staining showed increased number of apoptotic cells in inner retina. The results were further corroborated by the estimation of neurotrophic factor, oxidative stress, pro/anti-apoptotic factors, and caspase-3 activity in retina. In conclusion, current study revealed that intravitreal MgAT prevents retinal and optic nerve damage induced by NMDA. Overall, our data demonstrated that the pretreatment with MgAT was more effective than co- and posttreatment. This protective effect of MgAT against NMDA-induced retinal cell apoptosis could be attributed to the reduction of retinal oxidative stress and activation of BDNF-related neuroprotective mechanisms.

Protective effect of magnesium acetyltaurate against NMDA-induced retinal damage involves restoration of minerals and trace elements homeostasis.

Glutamate-mediated excitotoxicity involving N-methyl-d-aspartate (NMDA) receptors has been recognized as a final common outcome in pathological conditions involving death of retinal ganglion cells (RGCs). Overstimulation of NMDA receptors results in influx of calcium (Ca) and sodium (Na) ions and efflux of potassium (K). NMDA receptors are blocked by magnesium (Mg). Such changes due to NMDA overstimulation are also associated with not only the altered levels of minerals but also that of trace elements and redox status. Both the decreased and elevated levels of trace elements such as iron (Fe), zinc (Zn), copper (Cu) affect NMDA receptor excitability and redox status. Manganese (Mn), and selenium (Se) are also part of antioxidant defense mechanisms in retina. Additionally endogenous substances such as taurine also affect NMDA receptor activity and retinal redox status. Therefore, the aim of this study was to evaluate the effect of Mg acetyltaurate (MgAT) on the retinal mineral and trace element concentration, oxidative stress, retinal morphology and retinal cell apoptosis in rats after-NMDA exposure. One group of Sprague Dawley rats received intravitreal injection of vehicle while 4 other groups similarly received NMDA (160nmolL-1). Among the NMDA injected groups, 3 groups also received MgAT (320nmolL-1) as pre-treatment, co-treatment or post-treatment. Seven days after intravitreal injection, rats were sacrificed, eyes were enucleated and retinae were isolated for estimation of mineral (Ca, Na, K, Mg) and trace element (Mn, Cu, Fe, Se, Zn) concentration using Inductively Coupled Plasma (DRC ICP-MS) techniques (NexION 300D), retinal oxidative stress using Elisa, retinal morphology using H&E staining and retinal cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Intravitreal NMDA injection resulted in increased concentration of Ca (4.6 times, p<0.0001), Mg (1.5 times, p<0.01), Na (3 times, p<0.0001) and K (2.3 times, p<0.0001) compared to vehicle injected group. This was accompanied with significant increase of Ca/Mg and Na/K ratios, 3 and 1.27 times respectively, compared to control group. The trace elements such as Cu, Fe and Zn also showed a significant increase amounting to 3.3 (p<0.001), 2.3 (p<0.0001) and 3 (p<0.0001) times respectively compared to control group. Se was increased by 60% (p<0.005). Pre-treatment with MgAT abolished effect of NMDA on minerals and trace elements more effectively than co- and post-treatment. Similar observations were made for retinal oxidative stress, retinal morphology and retinal cell apoptosis. In conclusion, current study demonstrated the protective effect of MgAT against NMDA-induced oxidative stress and retinal cell apoptosis. This effect of MgAT was associated with restoration of retinal concentrations of minerals and trace elements. Further studies are warranted to explore the precise molecular targets of MgAT. Nevertheless, MgAT seems a potential candidate in the management of diseases involving NMDA-induced excitotoxicity.