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Tuberculosis (T.B.) remains a prominent global cause of health challenges and death, exacerbated by drug-resistant strains such as multidrug-resistant tuberculosis MDR-TB and extensively drug-resistant tuberculosis XDR-TB. For an effective disease management strategy, it is crucial to understand the dynamics of T.B. infection and the impacts of treatment. In the present article, we employ AI-based machine learning techniques to investigate the immunity impact of medications. SEIPR epidemiological model is incorporated with MDR-TB for compartments susceptible to disease, exposed to risk, infected ones, preventive or resistant to initial treatment, and recovered or healed population. These masses' natural trends, effects, and interactions are formulated and described in the present study. Computations and stability analysis are conducted upon endemic and disease-free equilibria in the present model for their global scenario. Both numerical and AI-based nonlinear autoregressive exogenous NARX analyses are presented with incorporating immediate treatment and delay in treatment. This study shows that the active patients and MDR-TB, both strains, exist because of the absence of permanent immunity to T.B. Furthermore, patients who have recovered from tuberculosis may become susceptible again by losing their immunity and contributing to transmission again. This article aims to identify patterns and predictors of treatment success. The findings from this research can contribute to developing more effective tuberculosis interventions.
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This study evaluated the impact of differential sowing windows and improved weed management strategies on weed dynamics, productivity, and economic viability of direct drum seeded rice (Oryza sativa L.) in the temperate agro-ecosystem of Kashmir. A two-year field experiment was conducted utilizing a split-plot design with two sowing dates (May 10 and June 3) as main plots and six weed management practices as sub-plots. The earlier sowing date (May 10) resulted in significantly enhanced leaf area index, crop growth rate, relative growth rate, net assimilation rate, and grain and straw yields compared to the later sowing (June 3). Among weed management treatments, four mechanized conoweedings (equivalent to weed-free conditions) and sequential application of bensulfuron methyl + pretilachlor (60 and 600 g a.i. ha-1) as pre-emergence followed by 2,4-D (0.75 kg a.i. ha-1) as post-emergence demonstrated superior efficacy in weed suppression and augmentation of crop growth parameters and yield attributes. These treatments also exhibited the lowest weed index and highest benefit-cost ratio. The May 10 sowing, coupled with efficacious weed control measures, significantly reduced weed density and biomass while concomitantly improving nutrient uptake and economic returns. The results indicate that adopting a May 10 sowing date for direct seeded rice, in conjunction with either four conoweedings or the aforementioned sequential herbicide application, can optimize agronomic productivity and economic profitability under the temperate conditions of Kashmir. The study aided in choosing the best sowing window and efficient weed management strategy for attaining higher productivity and profitability of direct seeded rice in temperate conditions.
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Oryza , Malezas , Control de Malezas , Oryza/crecimiento & desarrollo , Control de Malezas/métodos , Malezas/crecimiento & desarrollo , Herbicidas/farmacología , Agricultura/métodos , Agricultura/economía , Productos Agrícolas/crecimiento & desarrollo , Compuestos de Fenilurea/farmacología , Producción de Cultivos/métodos , Producción de Cultivos/economía , Acetanilidas , Compuestos de SulfonilureaRESUMEN
BACKGROUND: Intracerebral hemorrhage (ICH) is a severe type of stroke with high mortality. Persistent hyperglycemia following ICH is linked to deteriorated neurological functions and death. However, the exacerbating effect of hyperglycemia on ICH injury at the molecular level is still unclear. Therefore, this study explores the impact of diabetes on ICH injury using a non-obese diabetic (NOD) mouse model of type I diabetes mellitus. METHODS: NOD and non-diabetic (non-obese resistant) mice subjected to ICH by intrastriatal injection of collagenase were sacrificed three days following the ICH. Brains were collected for hematoma volume measurement and immunohistochemistry. Neurobehavioral assays were conducted 24 h before ICH and then repeated at 24, 48 and 72 h following ICH. RESULTS: NOD mice showed increased hematoma volume and impairment in neurological function, as revealed by rotarod and grip strength analyses. Immunohistochemical staining showed reduced glial cell activation, as indicated by decreased GFAP and Iba1 staining. Furthermore, the expression of oxidative/nitrosative stress markers represented by 3-nitrotyrosine and inducible nitric oxide synthase was reduced in the diabetic group. CONCLUSIONS: Overall, our findings support the notion that hyperglycemia exacerbates ICH injury and worsens neurological function and that the mechanism of injury varies depending on the type of diabetes model used.
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Apple, a vital fruit crop worldwide and a major crop grown in northern parts of India, acts as a backbone for the survival and livelihood of the farming community. However, it is prone to severe damage from insect pests and diseases. In the past few years, due to erratic weather patterns, there has been an alarmingly increased infestation of different insect pests, both invasive and non-invasive, resulting in substantial economic losses to this industry. One similar case was seen in the Himalayan region of India, where the apple crop in Karewas was heavily damaged by some invasive fruit borer, feeding on pulp and making galleries to reach the seed locules, thereby destroying the seed material. To ascertain the true identity of this pest, a study based on morpho-molecular characterization of this pest was carried out in the Faculty of Agriculture, Wadura, SKUAST Kashmir, India, during the years 2021 and 2022. The invasive fruit samples were collected from apple orchards at different locations (experimental sites) in North India by installing delta sticky traps @ 5 traps/ha for moth collection. The fruit-boring larvae and pupa were also collected and reared in confined chambers of the laboratory with controlled temperature and humidity. All the laboratory investigations were conducted at the Division of Entomology, FoA, Wadura, SKUAST Kashmir. During the investigation, it was confirmed that the invasive borer is a codling moth (Cydia pomonella L.), a member of the family Tortricidae, order Lepidoptera, which was earlier having quarantine importance in India, as it was only present in the Ladakh region of India. From the phylogenetic analysis of sample sequences, the species of codling moth present at all experimental sites was more identical to the codling moth sequence from Leh (the northernmost arid region), India. Further, the study of life cycle and voltinism revealed that codling moth completes three generations per year in Kashmir, with a single cycle lasting up to 2.5 months. However, the timing of various generations varies, depending on prevailing weather conditions at specific locations and times. The number of generations completed by codling moth in Kashmir conditions during apple growing season was three full and a half overwintering generations. The study of the life cycle of this important pest was necessary to know the weak link for its effective management and to prevent the economic loss in apple fruit.
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Malus , Mariposas Nocturnas , Animales , Malus/parasitología , Mariposas Nocturnas/fisiología , Mariposas Nocturnas/crecimiento & desarrollo , India , Frutas/parasitología , Larva/fisiología , Especies IntroducidasRESUMEN
Hyperchloremia and hypernatremia are associated with higher mortality in ischemic stroke, but it remains unclear whether their influence directly contributes to ischemic injury. We investigated the impact of 0.9% sodium chloride (154 mM NaCl), 0.9% sodium acetate (167 mM CH3COONa), and their different combinations (3:1, 2:1, and 1:1) on microglial (HMC-3) and neuronal (differentiated SH-SY5Y) survival during oxygen-glucose deprivation/reperfusion (OGD/R). Further, we assessed the effect of hyperchloremia and hypernatremia-treated and OGD/R-induced HMC-3-conditioned media on differentiated SH-SY5Y cells under OGD/R conditions. We performed cell viability, cell toxicity, and nitric oxide (NO) release assays and studied the alteration in expression of caspase-1 and caspase-3 in different cell lines when exposed to hyperchloremia and hypernatremia. Cell survival was decreased in 0.9% NaCl, 0.9% CH3COONa, combinations of HMC-3 and differentiated SH-SY5Y, and differentiated SH-SY5Y cells challenged with HMC-3-conditioned media under normal and OGD/R conditions. Under OGD/R conditions, differentiated SH-SY5Y cells were less likely to survive exposure to 0.9% NaCl. Expression of caspase-1 and caspase-3 in HMC-3 and differentiated SH-SY5Y cells was altered when exposed to 0.9% NaCl, 0.9% CH3COONa, and their combinations. A total of 0.9% NaCl and 0.9% CH3COONa and their combinations decreased the NO production in HMC-3 cells under normal and OGD/R conditions. Both hypernatremia and hyperchloremia reduced the survival of HMC-3 and differentiated SH-SY5Y cells under OGD/R conditions. Based on the OGD/R in vitro model that mimics human ischemic stroke conditions, it possibly provides a link for the increased death associated with hyperchloremia or hypernatremia in stroke patients.
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Neuroinflammation after intracerebral hemorrhage (ICH) is a crucial factor that determines the extent of the injury. Cofilin is a cytoskeleton-associated protein that drives neuroinflammation and microglia activation. A novel cofilin inhibitor (CI) synthesized and developed in our lab has turned out to be a potential therapeutic agent for targeting cofilin-mediated neuroinflammation in an in vitro model of ICH and traumatic brain injury. The current study aims to examine the therapeutic potential of CI in a mouse collagenase model of ICH and examine the neurobehavioral outcomes and its mechanism of action. Male mice were subjected to intrastriatal collagenase injection to induce ICH, and sham mice received needle insertion. Various concentrations (25, 50, and 100 mg/kg) of CI were administered to different cohorts of the animals as a single intravenous injection 3 h following ICH and intraperitoneally every 12 h for 3 days. The animals were tested for neurobehavioral parameters for up to 7 days and sacrificed to collect brains for hematoma volume measurement, Western blotting, and immunohistochemistry. Blood was collected for cofilin, TNF-α, and IL-1ß assessments. The results indicated that 50 mg/kg CI improved neurological outcomes, reversed post-stroke cognitive impairment, accelerated hematoma resolution, mitigated cofilin rods/aggregates, and reduced microglial and astrocyte activation in mice with ICH. Microglia morphological analysis demonstrated that CI restored the homeostasis ramification pattern of microglia in mice treated with CI. CI suppressed endoplasmic reticulum stress-related neuroinflammation by inhibiting inflammasomes and cell death signaling pathways. We also showed that CI prevented synaptic loss by reviving the pre- and post-synaptic markers. Our results unveil a novel therapeutic approach to treating ICH and open a window for using CI in clinical practice.
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This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer's, Parkinson's, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington's) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin's involvement is underscored by its impact on pathological hallmarks like Aß plaques and α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson's disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin's association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington's disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer's, Parkinson's, and schizophrenia exhibit 14-3-3 proteins in cofilin dysregulation as a shared pathological mechanism. In the case of stroke, cofilin takes center stage, mediating neurotoxicity and neuronal cell death. Notably, there is a potential overlap in the pathologies and involvement of cofilin in various diseases. In this context, referencing cofilin dysfunction could provide valuable insights into the common pathologies associated with the aforementioned conditions. Moreover, this review explores promising therapeutic interventions, including cofilin inhibitors and gene therapy, demonstrating efficacy in preclinical models. Challenges in inhibitor development, brain delivery, tissue/cell specificity, and long-term safety are acknowledged, emphasizing the need for precision drug therapy. The call to action involves collaborative research, biomarker identification, and advancing translational efforts. Cofilin emerges as a pivotal player, offering potential as a therapeutic target. However, unraveling its complexities requires concerted multidisciplinary efforts for nuanced and effective interventions across the intricate landscape of neurodegenerative diseases and stroke, presenting a hopeful avenue for improved patient care.
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Factores Despolimerizantes de la Actina , Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Enfermedad de Parkinson , Accidente Cerebrovascular , Humanos , alfa-Sinucleína , Accidente Cerebrovascular/metabolismoRESUMEN
Flavonoids are a large subgroup of polyphenols known to be sourced from over 6000 natural products, including fruits, vegetables, bark, and herbs. Due to their antioxidant properties, flavonoids have been implicated as a therapy source for many diseases and conditions, including inflammation, vasculitis, venous insufficiency, and hemorrhoids. Currently, some flavonoids are being researched for their antioxidant ability concerning neuroprotection. These flavonoids can penetrate the blood-brain barrier and, depending on the specific flavonoid, retain adequate bioavailability in certain brain regions. Further data suggest that flavonoids could have a strong anti-inflammatory effect in the brain, which not only could be a robust therapeutic source for known neuroinflammatory diseases such as Alzheimer's Disease or Parkinson's Disease but also could be a therapeutic source for ischemic or hemorrhagic conditions such as a stroke. While flavonoid toxicity exists, they are relatively safe and non-invasive drugs from natural origins. As such, exploring the known mechanisms and therapies may highlight and establish flavonoid therapy as a viable source of therapy for stroke patients. As stated, many flavonoids are already being isolated, purified, and implemented in both in vitro and in vivo experiments. As these flavonoids proceed to clinical trials, it will be important to understand how they function as a therapy, primarily as antioxidants, and by other secondary mechanisms. This review aims to elucidate those mechanisms and explore the neuroprotective role of flavonoids.
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Apple cankers are extremely destructive diseases threatening the global apple industry through direct and indirect losses. The population structure of the pathogens is of paramount significance for the development of efficient management strategies. Therefore, phenotypic, pathogenic, and genetic diversity of Diplodia seriata causing black rot canker of apple was investigated in this study. All the isolates were included for investigating the in vitro mycelial growth, conidial dimensions, and pathogenic variability on two-year-old potted apple seedlings. The ISSR approach was used to investigate the molecular diversity of D. seriata. Mycelial growth rates were found to vary significantly amongst the isolates; however, there were no major variations seen between the different geographical groupings of isolates. Pathogenicity tests revealed variations in the size of cankers among the isolates indicating the presence of virulence variability. The isolates were segregated into three virulence groups based on canker length. The Bayesian analyses of ISSR data divided the isolates into two genetic clusters. The genetic clustering of the isolates revealed no relationship with geographical origin of the isolates. Furthermore, no direct relationship of genetic clustering was observed with morphological or pathogenic variability. The ISSR primers revealed very high level of variability in D. seriata; however, no distinct populations of the pathogen existed which is an indication of high level of gene flow between the diverse geographical populations. According to our knowledge, this is the first thorough investigation on the diversity of D. seriata associated with apple black rot canker in India.
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Malus , Platelmintos , Animales , Teorema de Bayes , India , Variación GenéticaRESUMEN
Astrocytes are increasingly recognised as partaking in complex homeostatic mechanisms critical for regulating neuronal plasticity following central nervous system (CNS) insults. Ischaemic stroke and traumatic brain injury are associated with high rates of disability and mortality. Depending on the context and type of injury, reactive astrocytes respond with diverse morphological, proliferative and functional changes collectively known as astrogliosis, which results in both pathogenic and protective effects. There is a large body of research on the negative consequences of astrogliosis following brain injuries. There is also growing interest in how astrogliosis might in some contexts be protective and help to limit the spread of the injury. However, little is known about how astrocytes contribute to the chronic functional recovery phase following traumatic and ischaemic brain insults. In this review, we explore the protective functions of astrocytes in various aspects of secondary brain injury such as oedema, inflammation and blood-brain barrier dysfunction. We also discuss the current knowledge on astrocyte contribution to tissue regeneration, including angiogenesis, neurogenesis, synaptogenesis, dendrogenesis and axogenesis. Finally, we discuss diverse astrocyte-related factors that, if selectively targeted, could form the basis of astrocyte-targeted therapeutic strategies to better address currently untreatable CNS disorders.
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Traumatic brain injury (TBI) is a major healthcare problem and a common cause of mortality and morbidity. Clinical and preclinical research suggests sex-related differences in short- and long-term outcomes following TBI; however, males have been the main focus of TBI research. Females show a protective response against TBI. Female animals in preclinical studies and women in clinical trials have shown comparatively better outcomes against mild, moderate, or severe TBI. This reflects a favorable protective nature of the females compared to the males, primarily attributed to various protective mechanisms that provide better prognosis and recovery in the females after TBI. Understanding the sex difference in the TBI pathophysiology and the underlying mechanisms remains an elusive goal. In this review, we provide insights into various mechanisms related to the anatomical, physiological, hormonal, enzymatic, inflammatory, oxidative, genetic, or mitochondrial basis that support the protective nature of females compared to males. Furthermore, we sought to outline the evidence of multiple biomarkers that are highly potential in the investigation of TBI's prognosis, pathophysiology, and treatment and which can serve as objective measures and novel targets for individualized therapeutic interventions in TBI treatment. Implementations from this review are important for the understanding of the effect of sex on TBI outcomes and possible mechanisms behind the favorable response in females. It also emphasizes the critical need to include females as a biological variable and in sufficient numbers in future TBI studies.
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Insulin, a well-known hormone, has been implicated as a regulator of blood glucose levels for almost a century now. Over the past few decades, the non-glycemic actions of insulin i.e. neuronal growth and proliferation have been extensively studied. In 2005, Dr. Suzanne de La Monte and her team reported that insulin might be involved in the pathogenesis of Alzheimer's Disease (AD) and thus coined a term "Type-3 diabetes" This hypothesis was supported by several subsequent studies. The nuclear factor erythroid 2- related factor 2 (Nrf2) triggers a cascade of events under the regulation of distinct mechanisms including protein stability, phosphorylation and nuclear cytoplasmic shuttling, finally leading to the protection against oxidative damage. The Nrf2 pathway has been investigated extensively in relevance to neurodegenerative disorders, particularly AD. Many studies have indicated a strong correlation between insulin and Nrf2 signalling pathways both in the periphery and the brainbut merely few of them have focused on elucidating their inter-connective role in AD. The present review emphasizes key molecular pathways that correlate the role of insulin with Nrf2 during AD. The review has also identified key unexplored areas that could be investigated in future to further establish the insulin and Nrf2 influence in AD.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Insulina/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Transducción de Señal/fisiologíaRESUMEN
A major endoplasmic reticulum (ER) chaperone, binding of Immunoglobulin heavy chain protein (BIP) facilitates the assembly of newly synthesized proteins in the ER. Microglia vigorously respond to brain injuries and eliminate the damaged neuronal and apoptotic cells through phagocytosis in the central nervous system. However, the mechanism of BIP-mediated microglial function is not clear in hyperglycemia. We explored the molecular mechanism of BIP in microglial function during hyperglycemic conditions. Hyperglycemia was induced in mice by two consecutive intraperitoneal injections of streptozotocin (STZ 100/kg) and confirmed by measuring the blood glucose from day 2 to day 14. After 14 days of experimental hyperglycemia, mice were sacrificed and brains were collected for ER chaperone expression. In-vitro hyperglycemia was induced by exposing HMC3 cells to 25 mM glucose for 5 days and proteins involved in ER stress, apoptosis, and autophagy were analyzed. In hyperglycemic conditions, BIP protein expression was dramatically reduced in HMC3 cells, which led to increased apoptosis through the activation of CHOP and mitochondrial pro-apoptotic proteins (Bax, Bad, and cleaved caspase-3). The flow cytometry results indicate hyperglycemia-induced apoptosis and reactive oxygen species (ROS) production. Interestingly, the BIP inducer X restored the apoptosis in HMC3 cells by derepressing BIP expression and inhibiting ER stress. These results suggest that the ER chaperone BIP is required for the microglial function and protects from apoptosis in hyperglycemia. A better understanding of BIP's molecular mechanism and role in microglial function may contribute to developing novel therapies for microglia dysfunction-associated neurodegenerative diseases.
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Hiperglucemia , Microglía , Animales , Ratones , Apoptosis , Proteínas Portadoras/metabolismo , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Proteínas de Choque Térmico/metabolismo , Hiperglucemia/metabolismo , Microglía/metabolismo , Chaperonas Moleculares/metabolismo , HumanosRESUMEN
Apple cultivation is one of the most significant means of subsistence in the Kashmir region of the northwestern Himalayas. It is considered as the backbone of the region's economy. Apple cultivation in the region is dominated by a late maturing cultivar "Red Delicious" which usually on maturity causes glut in the market. In order to bring new cultivars in the cultivation, and to expand the maturity season, it is necessary to evaluate the new cultivars on fruit physico-chemical attributes which ultimately decide the market rates before recommending to farmers for cultivars adoption. Therefore, the current study was carried out to evaluate thirteen apple cultivars on physico-chemical attributes over two years, 2017 and 2018 under agro-climatic conditions of Kashmir region The results revealed that cultivars differed significantly in terms of physico-chemical properties. Cultivars with the highest and lowest values for initial fruit set, fruit drop, final fruit retention, and fruit firmness in 2017 did not follow the same trend in 2018. During 2017 and 2018, cultivar Mollie's Delicious possessed the highest fruit length (72.39 mm and 81.45 mm), fruit diameter (81.18 mm and 84.14 mm), and fruit weight (205.85 g and 247.16 g), whereas cultivar Baleman's Cider had the lowest values (50.76 mm and 52.83 mm, 60.10 mm and 62.08 mm, and 71.46 g and 86.94 g), respectively. The harvesting dates were quite spread out during both years of study. Cultivar Mollie's Delicious was harvested the earliest in both years, on August 5th, 2017 and August 8th, 2018. Cultivar Fuji Zehn Aztec was the last cultivar harvested in 2017 on October 2 and in 2018 on October 5. The maximum number of seeds per fruit was noticed in the cultivar Mollie's Delicious (8.34 and 8.71) during both 2017 and 2018, respectively. Cultivar Starkrimson had the fewest seeds per fruit in 2017 (7.11) and 2018 (7.42). Cultivar Baleman's Cider had the highest acidity in 2017 (0.63%) and 2018 (0.52%). In both 2017 (0.25%) and 2018 (0.23%), the Adam's Pearmain cultivar was the least acidic. Cultivar Allington Pippin (16.13 °Brix) and Red Gold (16.73 °Brix) had the highest TSS in 2017 and 2018, respectively, whereas Vance Delicious (12.30 °Brix) and Top Red (10.78 °Brix) had the lowest TSS in 2017 and 2018, respectively. The cultivars Mollie's Delicious and Red Gold had the highest total sugars (11.33 and 11.40%) in 2017 and 2018, respectively. Cultivar Baleman's Cider had the lowest total sugars (9.82%) in 2017 while Top Red (9.78%) in 2018. The cultivar Vance Delicious had the highest ratio of leaves to fruits in 2017 (55.44) and for Shalimar Apple-2 in 2018 (49.65). In 2017, cultivars Fuji Zehn Aztec (29.26) and Silver Spur (24.51), had the fewest leaves per fruit. The highest leaf chlorophyll content was recorded in cultivar Shireen (3.50 and 3.57 mg g-1 fresh weight) during the years 2017 and 2018, respectively. Cultivar Baleman's Cider had the lowest leaf chlorophyll content (2.15 mg g-1 fresh weight) during 2017, while cultivar Allington Pippin (2.09 mg g-1 fresh weight) had the lowest leaf chlorophyll content in 2018. The cultivars Fuji Zehn Aztec, with a yield efficiency of 0.78 kg/cm2 and Silver Spur with a yield efficiency of 1.14 kg/cm2 were the most yield efficient during the years 2017 and 2018, respectively. Cultivar Shalimar Apple-2 was least performing with yield efficiencies of 0.05 and 0.07 kg/cm2 during 2017 and 2018, respectively.The findings suggest that cultivar Mollie's Delicious commercially matures first and has the highest fruit length, diameter, and weight; hence, it can be a good option for cultivation so as to fetch the maximum price in the market when other cultivars are still maturing. Shalimar Apple-2 is precluded for cultivation due to least yield efficiency, whereas cultivars Fuji Zehn Aztec and Silver Spur are recommended to farmers for their higher yield efficiency.
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Intracerebral hemorrhage (ICH) is a significant health concern associated with high mortality. Cofilin plays a crucial role in stress conditions, but its signaling following ICH in a longitudinal study is yet to be ascertained. In the present study, we examined the cofilin expression in human ICH autopsy brains. Then, the spatiotemporal cofilin signaling, microglia activation, and neurobehavioral outcomes were investigated in a mouse model of ICH. Human autopsy brain sections from ICH patients showed increased intracellular cofilin localization within microglia in the perihematomal area, possibly associated with microglial activation and morphological changes. Various cohorts of mice were subjected to intrastriatal collagenase injection and sacrificed at time points of 1, 3, 7, 14, 21, and 28 days. Mice suffered from severe neurobehavioral deficits after ICH, lasting for 7 days, followed by a gradual improvement. Mice suffered post-stroke cognitive impairment (PSCI) both acutely and in the chronic phase. Hematoma volume increased from day 1 to 3, whereas ventricle size increased from day 21 to 28. Cofilin protein expression increased in the ipsilateral striatum on days 1 and 3 and then decreased from days 7 to 28. An increase in activated microglia was observed around the hematoma on days 1 to 7, followed by a gradual reduction up to day 28. Around the hematoma, activated microglia showed morphological changes from ramified to amoeboid. mRNA levels of inflammatory [tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), and interleukin-6 (IL-6) and anti-inflammatory markers [interleukin-10 (IL-10), transforming growth factor-ß TGF-ß, and arginase I (Arg1)] increased during the acute phase and decreased in the chronic phase. Blood cofilin levels increased on day 3 and matched the increase in chemokine levels. slingshot protein phosphatase 1 (SSH1) protein, which activates cofilin, was increased from day 1 to 7. These results suggest that microglial activation might be the sequel of cofilin overactivation following ICH, leading to widespread neuroinflammation and consequent PSCI.
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Lesiones Encefálicas , Accidente Cerebrovascular , Humanos , Ratones , Animales , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Factores Despolimerizantes de la Actina/metabolismo , Estudios Longitudinales , Hemorragia Cerebral/patología , Hematoma/patología , Lesiones Encefálicas/patología , Accidente Cerebrovascular/metabolismoRESUMEN
Microglial activation and failure of the antioxidant defense mechanisms are major hallmarks in different brain injuries, particularly traumatic brain injury (TBI). Cofilin is a cytoskeleton-associated protein involved in actin binding and severing. In our previous studies, we identified the putative role of cofilin in mediating microglial activation and apoptosis in ischemic and hemorrhagic conditions. Others have highlighted the involvement of cofilin in ROS production and the resultant neuronal death; however, more studies are needed to delineate the role of cofilin in oxidative stress conditions. The present study aims to investigate the cellular and molecular effects of cofilin in TBI using both in vitro and in vivo models as well as the first-in-class small-molecule cofilin inhibitor (CI). An in vitro H2O2-induced oxidative stress model was used in two different types of cells, human neuroblastoma (SH-SY5Y) and microglia (HMC3), along with an in vivo controlled cortical impact model of TBI. Our results show that treatment with H2O2 increases the expression of cofilin and slingshot-1 (SSH-1), an upstream regulator of cofilin, in microglial cells, which was significantly reduced in the CI-treated group. Cofilin inhibition significantly attenuated H2O2-induced microglial activation by reducing the release of proinflammatory mediators. Furthermore, we demonstrate that CI protects against H2O2-induced ROS accumulation and neuronal cytotoxicity, activates the AKT signaling pathway by increasing its phosphorylation, and modulates mitochondrial-related apoptogenic factors. The expression of NF-E2-related factor 2 (Nrf2) and its associated antioxidant enzymes were also increased in CI-treated SY-SY5Y. In the mice model of TBI, CI significantly activated the Nrf2 and reduced the expression of oxidative/nitrosative stress markers at the protein and gene levels. Together, our data suggest that cofilin inhibition provides a neuroprotective effect in in vitro and in vivo TBI mice models by inhibiting oxidative stress and inflammatory responses, the pivotal mechanisms involved in TBI-induced brain damage.
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Globally around 24 million elderly population are dealing with dementia, and this pathological characteristic is commonly seen in people suffering from Alzheimer's disease (AD). Despite having multiple treatment options that can mitigate AD symptoms, there is an imperative call to advance our understanding of the disease pathogenesis to unfold disease-modifying treatments/therapies. To explore the driving mechanisms of AD development, we stretch out further to study time-dependant changes after Okadaic acid (OKA)-induced AD-like conditions in zebrafish. We evaluated the pharmacodynamics of OKA at two-time points, i.e., after 4-days and 10-days exposure to zebrafish. T-Maze was utilized to observe the learning and cognitive behaviour, and inflammatory gene expressions such as 5-Lox, Gfap, Actin, APP, and Mapt were performed in zebrafish brains. To scoop everything out from the brain tissue, protein profiling was performed using LCMS/MS. Both time course OKA-induced AD models have shown significant memory impairment, as evident from T-Maze. Gene expression studies of both groups have reported an overexpression of 5-Lox, GFAP, Actin, APP, and OKA 10D group has shown remarkable upregulation of Mapt in zebrafish brains. In the case of protein expression, the heatmap suggested an important role of some common proteins identified in both groups, which can be explored further to investigate their mechanism in OKA-induced AD pathology. Presently, the preclinical models available to understand AD-like conditions are not completely understood. Hence, utilizing OKA in the zebrafish model can be of great importance in understanding the pathology of AD progression and as a screening tool for drug discovery.
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Enfermedad de Alzheimer , Anciano , Animales , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Pez Cebra/metabolismo , Proteómica , Actinas/metabolismo , Encéfalo/metabolismo , Ácido Ocadaico/efectos adversos , Ácido Ocadaico/metabolismo , Genómica , Modelos Animales de EnfermedadRESUMEN
Coronavirus disease 2019 (COVID-19) has affected a broad demographics, eliciting a more significant effect on specific groups such as males, African Americans, and Hispanic minorities. Treatment of COVID-19 often requires antiviral drugs or monoclonal antibodies. However, immunotherapies such as mesenchymal stem cells and mesenchymal stem cells-derived exosomal vesicles should be evaluated as treatment options for COVID-19. Mesenchymal stem cell therapy offers regenerative, anti-inflammatory, and immunomodulatory properties that can speed up the recovery from COVID-19. Mesenchymal stem cell therapy can also benefit COVID-19 patients who suffer from strokes, as COVID-19 increases the risk of strokes due to increased cytokines and clotting factors. Most stroke cases that occur in COVID-19 patients are ischemic strokes. Therefore, with the help of mesenchymal stem cell therapy and mesenchymal stem cells-derived exosomes, COVID-19-induced stroke patients might benefit from dual-ended treatment. The objective of this review was to discuss COVID-19 and stroke incidence and the available treatment options.
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A novel small molecule cofilin inhibitor (SZ-3) has recently become the focus of investigation for targeting neuroinflammation in different neurodegenerative diseases. In the present study, the metabolic stability, blood-brain barrier (BBB) penetration, and tissue concentration of SZ-3 were evaluated to support our future studies. In silico drug metabolism prediction was investigated using the StarDrop WhichP450 module. LC-MS/MS method was developed and validated to quantify the SZ-3 for in-vitro and in-vivo studies. The in-vitro metabolic stability was performed using human liver microsomes (HLMs), and the in-vivo pharmacokinetics were investigated in mice after a single intraperitoneal (IP) injection or oral (P.O.) administration, followed by a collection of blood and brain samples at different time points. The dose-proportionality was also evaluated after a single IP injection of three ascending doses (5, 10, and 25 mg/kg). In-vitro results showed that SZ-3 has a moderate intrinsic clearance (Clint) value of 17.42 ml/min/mg with a half-life (t1/2) value of 39.77 mins, indicative of good bioavailability. In vivo study revealed that SZ-3 was rapidly absorbed, entered the brain, and yielded a good concentration of the unbound drug after IP and oral administration. However, the higher maximum concentration (Cmax) values of IP and P.O. (2244 ng/ml and 1069 ng/g, respectively) revealed that the IP administration led to higher blood and brain concentrations than the P.O. Furthermore, Cmax and area under the curve (AUC) of SZ-3 increased in a dose-proportional manner between the three ascending doses. These results will guide us in optimizing the dosing regimen for future SZ-3 pharmacological studies targeting neuroinflammation.
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Enfermedades Neuroinflamatorias , Espectrometría de Masas en Tándem , Animales , Humanos , Ratones , Administración Oral , Antiinflamatorios/farmacología , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Factores Despolimerizantes de la Actina/antagonistas & inhibidoresRESUMEN
Stroke, a neurological disease, is one of the leading causes of death worldwide, resulting in long-term disability in most survivors. Annual stroke costs in the United States alone were estimated at $46 billion recently. Stroke pathophysiology is complex, involving multiple causal factors, among which atherosclerosis, thrombus, and embolus are prevalent. The molecular mechanisms involved in the pathophysiology are essential to understanding targeted drug development. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress, and neuroinflammation. In addition, various modifiable and non-modifiable risk factors increase the chances of stroke manifolds. Once a patient encounters a stroke, complete restoration of motor ability and cognitive skills is often rare. Therefore, shaping therapeutic strategies is paramount for finding a viable therapeutic agent. Apart from tPA, an FDA-approved therapy that is applied in most stroke cases, many other therapeutic strategies have been met with limited success. Stroke therapies often involve a combination of multiple strategies to restore the patient's normal function. Certain drugs like Gamma-aminobutyric receptor agonists (GABA), Glutamate Receptor inhibitors, Sodium, and Calcium channel blockers, and fibrinogen-depleting agents have shown promise in stroke treatment. Recently, a drug, DM199, a recombinant (synthetic) form of a naturally occurring protein called human tissue kallikrein-1 (KLK1), has shown great potential in treating stroke with fewer side effects. Furthermore, DM199 has been found to overcome the limitations presented when using tPA and/or mechanical thrombectomy. Cell-based therapies like Neural Stem Cells, Hematopoietic stem cells (HSCs), and Human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) are also being explored as a treatment of choice for stroke. These therapeutic agents come with merits and demerits, but continuous research and efforts are being made to develop the best therapeutic strategies to minimize the damage post-stroke and restore complete neurological function in stroke patients.