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1.
Int Immunopharmacol ; 113(Pt B): 109421, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36403520

RESUMO

Diabetes Mellitus is accompanied by chronic hyperglycemia, inflammation, and related molecular processes, which leads to diabetic neuropathy. In this work, we tested Thiadiazine-thione (TDT) synthetic derivatives TDT1 and TDT2 against streptozotocin (STZ)-induced diabetic neuropathy. Sprague Dawley's rats, SH-SY5Y neuronal and BV2 microglial cells were employed in this work, followed by behavioral, biochemical, and morphological studies utilizing RT-qPCR, ELISA, Immunoblotting, immunohistochemistry, Immunofluorescence, and in silico analyses. TDT1 and TDT2 abolished STZ-induced allodynia and hyperalgesia. Next, we examined IRS1/PI3K/AKT signaling to assess TDT1 and TDT2's impact on diabetic neuropathy. STZ downregulated IRS1, PI3K, AKT mRNA and protein expression in rat spinal cord and SH-SY5Y neuronal cells. TDT1 and TDT2 improved IRS1, PI3k, and AKT mRNA and protein expression. STZ elevated GSK3ß mRNA and protein expression in vivo and in vitro, whereas TDT1 and TDT2 mitigated it. STZ increased the expression of inflammatory mediators such as p-NF-κB, TNF-α, and COX-2 in rat spinal cord lysates. TDT1 and TDT2 co-treatment with STZ decreased inflammatory cytokine expression by ameliorating astrocytosis (revealed by increased GFAP) and microgliosis (indicated by increased Iba1). TDT1 and TDT2 reduced STZ-induced JNK, Iba1, and COX-2 upregulation in BV2 microglial cells validating our in vivo findings. In silico molecular docking and MD simulations analyses suggested that TDT1 and TDT2 have IRS binding affinity, however, both compounds had an identical binding affinity, but distinct interaction pattern with IRS protein residues. Overall, these findings demonstrate that TDT derivatives mitigated STZ-induced neuropathy through modulating the insulin and inflammatory signaling pathways.


Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Neuroblastoma , Tiadiazinas , Humanos , Ratos , Animais , Insulina , Estreptozocina , Ratos Sprague-Dawley , Tionas , Neuropatias Diabéticas/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Ciclo-Oxigenase 2 , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-akt , RNA Mensageiro
2.
J Biomol Struct Dyn ; : 1-12, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36331082

RESUMO

Monkeypox virus is an infectious agent that causes fever, Pneumonitis encephalitis, rash, lymphadenopathy and bacterial infection. The current outbreak of monkeypox has reawakened the global health concern. In the current situation of increasing viral infection, no vaccine or drug is available for monkeypox. Thus, there is an urgent need for viable vaccine development to prevent viral transmission by boosting human immunity. Herein, using immunoinformatics approaches, a multi-epitope vaccine was constructed for the Monkeypox virus. In this connection, B-Cell and T-cell epitopes were identified and joined with the help of adjutants and linkers. The vaccine construct was selected based on promising vaccine candidates and immunogenic potential. Further epitopes were selected based on antigenicity score, non-allergenicity and good immunological properties. Molecular docking reveals strong interactions between TLR-9 and the predicted vaccine construct. Finally, molecular dynamics simulations were performed to evaluate the stability and compactness of the constructed vaccine. The MD simulation results demonstrated the significant stability of the polypeptide vaccine construct. The predicted vaccine represented good stability, expression, immunostimulatory capabilities and significant solubility. Design vaccine was verified as efficient in different computer-based immune response investigations. Additionally, the constructed vaccine also represents a good population coverage in computer base analysis.Communicated by Ramaswamy H. Sarma.

3.
BMC Pharmacol Toxicol ; 23(1): 86, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36443818

RESUMO

BACKGROUND: Allopurinol (ALP), a xanthine oxidase inhibitor, is a first line drug for the treatment of gout and hyperuricemia. Being the member of BCS class II drugs, ALP has solubility problem, which affects its bioavailability. Also, ALP has shorter half-life and showed GI related problems. In present study, ALP was encapsulated in nanostructured lipid carriers (NLCs) to ensure enhanced bioavailability, improved efficacy and safety in vivo. METHODOLOGY: ALP-loaded NLCs were fabricated by micro-emulsion technique. The prepared NLCs were optimized via design expert in term of particle size, zeta potential and entrapment efficiency. FTIR, PXRD and TEM analysis were carried out to check chemical interaction, polymorphic form and surface morphology of the optimized formulation. ALP-loaded NLCs were then loaded into HPMC based poloxamer-407 gel and were characterized. In vitro and ex vivo analysis were carried out via dialysis membrane method and franz diffusion cell, respectively. Uric acid was used for induction of gout and the anti-gout activity of ALP-loaded NLCs gel was performed and compared with ALP suspension. RESULTS: The optimized formulation had particles in nano-range (238.13 nm) with suitable zeta potential (-31.5 mV), poly-dispersity index (0.115) and entrapment of 87.24%. FTIR results confirmed absence of chemical interaction among formulation ingredients. XRD indicated amorphous nature of ALP-loaded NLCs, whereas TEM analysis confirmed spherical morphology of nanoparticles. The optimized formulation was successfully loaded in to gel and characterized accordingly. The in vitro release and drug release kinetics models showed sustained release of the drug from ALP-loaded NLCs gel. Furthermore, about 28 fold enhanced permeation was observed from ALP-loaded NLCs gel as compared to conventional gel. Skin irritation study disclosed safety of ALP-loaded NLCs gel for transdermal application. Furthermore, ALP-loaded NLCs gel showed significantly enhanced anti-gout activity in Sprague-Dawley rats after transdermal administration as compared to oral ALP suspension. CONCLUSION: ALP-loaded NLCs gel after transdermal administration sustained the drug release, avoid gastrointestinal side effects and enhance the anti-gout performance of ALP. It can be concluded, that NLCs have the potential to deliver drugs via transdermal route as indicated in case of allopurinol.


Assuntos
Alopurinol , Hiperuricemia , Ratos , Animais , Ratos Sprague-Dawley , Administração Cutânea , Lipídeos
4.
Life Sci ; 312: 121202, 2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36414090

RESUMO

AIMS: The current study explored the anti-nociceptive activity of magnolol in post-incisional inflammatory nociceptive pain. MAIN METHODS: Preliminary, the anti-inflammatory, antioxidant, and cytoprotective potential of magnolol were confirmed against hydrogen peroxide (H2O2)-induced PC12 cells. Next, an in-vivo model of planter incision surgery was established in BALB/c mice. Tramadol 50 mg/kg intraperitoneal (i.p.) and magnolol (0.1, 1, 10 mg/kg i.p. + 10 mg/kg intra planter) were administered after plantar incision surgery and behavior parameters were measured. KEY FINDINGS: The results indicate that magnolol significantly suppressed post-incision-induced mechanical allodynia, thermal hyperalgesia, and paw edema. Magnolol promisingly inhibited post-incision induces nitric oxide (NO), malondialdehyde (MDA), eosinophil peroxidase (EPO), and neutrophil infiltration. Magnolol strongly attenuated post-incision inducing the release of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and inhibited deoxyribonucleic acid (DNA) fragmentation. Magnolol markedly reverses post-incisional histopathological changes and biochemical composition of the incised paw. Magnolol markedly down-regulated post-incisional increase expression of transient receptor potential vanilloid 1 (TRPV1), purinergic (P2Y) nociceptors as well as toll-like receptor 4 (TLR4), nuclear factor kappa light chain enhancer of activated B cell (NF-κB), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) while upregulating the expression of inhibitor of nuclear kappa B alpha (IκB-α). SIGNIFICANCE: The present study strongly suggests that magnolol significantly suppressed post-incisional inflammatory nociceptive pain by targeting TRPV1/P2Y and TLR4/NF-κB signaling.

5.
Life Sci ; 311(Pt B): 121198, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36396112

RESUMO

AIMS: Herein, we investigate the potential of levosulpiride-loaded nanostructured lipid carriers (LEVO-NLCs) for effective brain delivery with anti-psychotic and antidepressant effects. MAIN METHODS: Micro-emulsion method was used to prepare LEVO-NLCs, followed by its optimization using Design Expert®, investigation of the particles properties and entrapment efficiency (%EE). Moreover, in-vitro release, in-vivo plasma and brain kinetic studies of LEVO-NLCs were executed. Anti-psychotic activity of LEVO-NLCs was accomplished in LPS-induced psychosis mice model. Additionally, expressions of neuro inflammatory mediators, neurodegeneration and neuro-inflammation in brain tissues was investigated. KEY FINDINGS: The optimized LEVO-NLCs were rounded shaped nanoparticles (157.2 nm) with suitable zeta potential (-29.6 mV), low PDI (0.395) and high EE (83.67 %). No chemical interactions were found, however, the crystalline drug was changed to amorphous. LEVO-NLCs displayed sustained drug release behavior when compared with drug suspension. Moreover, a meaningfully higher AUC (106,642.27 ± 876.44 ng.h/mL) and Cmax (38,534.72 ± 2344.10 ng/mL) of the LEVO-NLCs in brain was observed as compared to the AUC (15,684.33 ± 1005.49 ng.h/mL) and Cmax (7717.56 ± 871.23 ng/mL) of LEVO-Suspension. Similar profiles of both the formulations were perceived in plasma pharmacokinetic studies. Furthermore, LEVO-NLCs exhibited a meaningfully improved anti-psychotic activity in LPS-induced psychosis mice model with reduced immobility time and enhanced struggling time. Likewise, treatment with LEVO-NLCs showed reduced levels of neuro inflammatory markers (p-NF-κB and COX-2) in LPS-induced mice. Additionally, no neuro-degeneration and neuro-inflammation in brain tissues treated with LEVO-NLCs mice group was detected. SIGNIFICANCE: These results concluded that NLCs may effectively be used for the brain delivery of various active pharmaceutical agents with enhanced biopharmaceutical performance.


Assuntos
Antipsicóticos , Animais , Camundongos , Antipsicóticos/metabolismo , Portadores de Fármacos/química , Cinética , Lipopolissacarídeos/metabolismo , Tamanho da Partícula , Encéfalo/metabolismo , Antidepressivos/farmacologia , Antidepressivos/metabolismo , Inflamação/metabolismo
6.
Food Sci Anim Resour ; 42(6): 968-980, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36415574

RESUMO

Due to the bad aspects associated with the use of antibiotics, the pressure on poultry production prompted the efforts to find out suitable growth-promoting and disease-preventing alternatives. Although many cost-effective alternatives have been developed, currently, one of the most auspicious alternatives for poultry feed is spore-forming probiotics, which can exert more beneficial effects as compared to normal probiotics, because of their ability to withstand the harsh external and internal conditions which result in increased viability. Many studies have already used spore-forming probiotics to improve different parameters of poultry production. Our laboratory has recently isolated a spore-forming bacterial strain, which has the potential to be used as a probiotic. So, to provide a detailed understanding, the current review aimed to collect valuable references to describe the mechanism of action of spore-forming probiotics and their effect on all the key aspects of poultry production.

7.
Heliyon ; 8(10): e10893, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36247157

RESUMO

Environmental sustainability is essential in tourism literature, and sun-and-beach tourism (SBT) is one of the most popular subsections of the tourism field. The appropriate policies and strategies during the COVID-19 pandemic to revive SBT growth through the lens of the regulatory dimension (RED) and risk dimension (RID) of environmental sustainability are gaining timely ground to conduct this research. The current study examined the nexus between SBT, RED, and RID utilizing three novel indexes (i.e., weighted sun-and-beach tourism index, weighted regulatory dimension index, and weighted risk dimension index) by employing the principal component analysis within the framework of six stages of empirical estimation strategy. These three novel indexes combine the most commonly used SBT, RED, and RID indicators. This research tested the CSD and homogeneous, then employed the second generation CIPS-CADF panel unit root test, used an AMG estimator, and employed the panel Toda-Yamamoto (PTY) causality test. The findings revealed that the RED positively influences SBT while the RID mitigates SBT. Results also indicate bidirectional causality between SBT, RID, and RED. In other words, changes in RID and RED have predictive power for the SBT, which further highlights the role of SBT on the RID and RED. Therefore, concerned authorities can focus on environmental sustainability design initiatives and appropriate policy/strategy implications to boost SBT.

8.
R Soc Open Sci ; 9(10): 220428, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36249328

RESUMO

Topical delivery is preferable over systemic delivery for cutaneous leishmaniasis, because of its easy administration, reduced systemic adverse effects and low cost. Nitazoxanide (NTZ) has broad-spectrum activity against various parasites and has the potential to avoid drug resistance developed by enzymatic mutations. NTZ oral formulation is associated with severe dyspepsia and stomach pain. Herein, NTZ-transethosomes (NTZ-TES) were prepared and loaded into chitosan gel (NTZ-TEG) for topical delivery. NTZ-TES were prepared by the thin-film hydration method and optimized statistically via the Box-Behnken method. The optimized formulation indicated excellent particle size (176 nm), polydispersity index (0.093), zeta potential (-26.4 mV) and entrapment efficiency (86%). The transmission electron microscopy analysis showed spherical-sized particles and Fourier-transform infrared spectroscopy analysis indicated no interaction among the excipients. Similarly, NTZ-TEG showed optimal pH, desirable viscosity and good spreadability. NTZ-TES and NTZ-TEG showed prolonged release behaviour and higher skin penetration and deposition in the epidermal/dermal layer of skin in comparison with the NTZ-dispersion. Moreover, NTZ-TES showed higher percentage inhibition, lower half-maximal inhibitory concentration (IC50) against promastigotes and higher macrophage uptake. Additionally, skin irritation and histopathology studies indicated the safe and non-irritant behaviour of the NTZ-TEG. The obtained findings suggested the enhanced skin permeation and improved anti-leishmanial effect of NTZ when administered as NTZ-TEG.

9.
J Opt Soc Am A Opt Image Sci Vis ; 39(10): 1903-1912, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36215563

RESUMO

Lensless cameras are ultra-thin imaging systems that replace the lens with a thin passive optical mask and computation. Passive mask-based lensless cameras encode depth information in their measurements for a certain depth range. Early works have shown that this encoded depth can be used to perform 3D reconstruction of close-range scenes. However, these approaches for 3D reconstructions are typically optimization based and require strong hand-crafted priors and hundreds of iterations to reconstruct. Moreover, the reconstructions suffer from low resolution, noise, and artifacts. In this work, we propose FlatNet3D-a feed-forward deep network that can estimate both depth and intensity from a single lensless capture. FlatNet3D is an end-to-end trainable deep network that directly reconstructs depth and intensity from a lensless measurement using an efficient physics-based 3D mapping stage and a fully convolutional network. Our algorithm is fast and produces high-quality results, which we validate using both simulated and real scenes captured using PhlatCam.

10.
Cureus ; 14(9): e29356, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36284812

RESUMO

Guillain-Barré syndrome (GBS) is an autoimmune demyelinating disease that is usually triggered by an antecedent infection and is characterized by flaccid paralysis and hyporeflexia. Although a sporadic disease, a few cases of GBS have been reported in families, suggesting a genetic predisposition. Here, we present a case of simultaneous occurrence of GBS in three members of the same family, with two members having a preceding history of diarrhea. They were diagnosed via cerebrospinal fluid routine examination and nerve conduction study and responded to plasmapheresis. This suggests possible genetic susceptibility along with environmental triggers in the pathogenesis of GBS.

11.
Int J Biol Macromol ; 222(Pt A): 887-901, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36179868

RESUMO

The evolution and development of solid-matrix are considered a backbone for supporting and stabilizing of metal nanoparticles (NPs) and are the soul of the catalytic system. In the current study, the alginate-starch microsphere (Alg-St) was cross-linked using CaCl2 as a cross-linker. In addition, the Alg-St microsphere was blended with different percentages of activated carbon (AC). The microspheres adsorbed Cu+2 was reduced to zero-valent copper NPs through NaBH4 and used as a dip-catalyst. The supported Cu NPs cum NaBH4 system was used as dip-catalyst for the hydrogenation of 4-nitrophenol (4NP), 2-nitroanilline (2NA), and degradation of methylene blue (MB) and Congo red (CR) dyes. Among the different kinetics models, the experimental data were well-fitted in the zero-order kinetic model. Moreover pH, and recyclability were studied for 4NP, where the best activity was achieved at pH 7.0 for 4NP. No leaching was observed after 3rd cycle in the catalyst.


Assuntos
Corantes , Nanopartículas Metálicas , Carvão Vegetal , Microesferas , Hidrogenação , Alginatos , Amido , Catálise
12.
Artigo em Inglês | MEDLINE | ID: mdl-36121953

RESUMO

Deep Convolution Neural Networks (CNNs) can easily be fooled by subtle, imperceptible changes to the input images. To address this vulnerability, adversarial training creates perturbation patterns and includes them in the training set to robustify the model. In contrast to existing adversarial training methods that only use class-boundary information (e.g., using a cross-entropy loss), we propose to exploit additional information from the feature space to craft stronger adversaries that are in turn used to learn a robust model. Specifically, we use the style and content information of the target sample from another class, alongside its class-boundary information to create adversarial perturbations. We apply our proposed multi-task objective in a deeply supervised manner, extracting multi-scale feature knowledge to create maximally separating adversaries. Subsequently, we propose a max-margin adversarial training approach that minimizes the distance between source image and its adversary and maximizes the distance between the adversary and the target image. Our adversarial training approach demonstrates strong robustness compared to state-of-the-art defenses, generalizes well to naturally occurring corruptions and data distributional shifts, and retains the model's accuracy on clean examples.

13.
Int J Mol Sci ; 23(18)2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36142242

RESUMO

During the past two decades, the world has witnessed the emergence of various SARS-CoV-2 variants with distinct mutational profiles influencing the global health, economy, and clinical aspects of the COVID-19 pandemic. These variants or mutants have raised major concerns regarding the protection provided by neutralizing monoclonal antibodies and vaccination, rates of virus transmission, and/or the risk of reinfection. The newly emerged Omicron, a genetically distinct lineage of SARS-CoV-2, continues its spread in the face of rising vaccine-induced immunity while maintaining its replication fitness. Efforts have been made to improve the therapeutic interventions and the FDA has issued Emergency Use Authorization for a few monoclonal antibodies and drug treatments for COVID-19. However, the current situation of rapidly spreading Omicron and its lineages demands the need for effective therapeutic interventions to reduce the COVID-19 pandemic. Several experimental studies have indicated that the FDA-approved monoclonal antibodies are less effective than antiviral drugs against the Omicron variant. Thus, in this study, we aim to identify antiviral compounds against the Spike protein of Omicron, which binds to the human angiotensin-converting enzyme 2 (ACE2) receptor and facilitates virus invasion. Initially, docking-based virtual screening of the in-house database was performed to extract the potential hit compounds against the Spike protein. The obtained hits were optimized by DFT calculations to determine the electronic properties and molecular reactivity of the compounds. Further, MD simulation studies were carried out to evaluate the dynamics of protein-ligand interactions at an atomistic level in a time-dependent manner. Collectively, five compounds (AKS-01, AKS-02, AKS-03, AKS-04, and AKS-05) with diverse scaffolds were identified as potential hits against the Spike protein of Omicron. Our study paves the way for further in vitro and in vivo studies.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Anticorpos Monoclonais , Anticorpos Antivirais , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Quimioinformática , Humanos , Ligantes , Pandemias , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
14.
Artif Intell Med ; 131: 102349, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36100346

RESUMO

Cancer is a Toxic health concern worldwide, it happens when cellular modifications cause the irregular growth and division of human cells. Several traditional approaches such as therapies and wet laboratory-based methods have been applied to treat cancer cells. However, these methods are considered less effective due to their high cost and diverse side effects. According to recent advancements, peptide-based therapies have attracted the attention of scientists because of their high selectivity. Peptide therapy can efficiently treat the targeted cells, without affecting the normal cells. Due to the rapid increase of peptide sequences, an accurate prediction model has become a challenging task. Keeping the significance of anticancer peptides (ACPs) in cancer treatment, an intelligent and reliable prediction model is highly indispensable. In this paper, a FastText-based word embedding strategy has been employed to represent each peptide sample via a skip-gram model. After extracting the peptide embedding descriptors, the deep neural network (DNN) model was applied to accurately discriminate the ACPs. The optimized parameters of DNN achieved an accuracy of 96.94 %, 93.41 %, and 94.02 % using training, alternate, and independent samples, respectively. It was observed that our proposed cACP-DeepGram model outperformed and reported ~10 % highest prediction accuracy than existing predictors. It is suggested that the cACP-DeepGram model will be a reliable tool for scientists and might play a valuable role in academic research and drug discovery. The source code and the datasets are publicly available at https://github.com/shahidakbarcs/cACP-DeepGram.


Assuntos
Redes Neurais de Computação , Peptídeos , Sequência de Aminoácidos , Humanos , Software
15.
Biomedicines ; 10(8)2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-36009594

RESUMO

Over time, molecular biology and genomics techniques have been developed to speed up the early diagnosis and clinical management of cancer. These therapies are often most effective when administered to the subset of malignancies harboring the target identified by molecular testing. Important advances in applying molecular testing involve circulating-free DNA (cfDNA)- and cell-free RNA (cfRNA)-based liquid biopsies for the diagnosis, prognosis, prediction, and treatment of cancer. Both cfDNA and cfRNA are sensitive and specific biomarkers for cancer detection, which have been clinically proven through multiple randomized and prospective trials. These help in cancer management based on the noninvasive evaluation of size, quantity, and point mutations, as well as copy number alterations at the tumor site. Moreover, personalized detection of ctDNA helps in adjuvant therapeutics and predicts the chances of recurrence of cancer and resistance to cancer therapy. Despite the controversial diagnostic values of cfDNA and cfRNA, many clinical trials have been completed, and the Food and Drug Administration has approved many multigene assays to detect genetic alterations in the cfDNA of cancer patients. In this review, we underpin the recent advances in the physiological roles of cfDNA and cfRNA, as well as their roles in cancer detection by highlighting recent clinical trials and their roles as prognostic and predictive markers in cancer management.

16.
AAPS PharmSciTech ; 23(6): 226, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35970966

RESUMO

The prime objective of this study was to develop amphotericin B (AMB) and rifampicin (RIF) co-loaded transfersomal gel (AMB-RIF co-loaded TFG) for effective treatment of cutaneous leishmaniasis (CL). AMB-RIF co-loaded TF was prepared by the thin-film hydration method and was optimized based on particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (%EE), and deformability index. Similarly, AMB-RIF co-loaded TFG was characterized in terms of rheology, spread ability, and pH. In vitro, ex vivo, and in vivo assays were performed to evaluate AMB-RIF co-loaded TF as a potential treatment option for CL. The optimized formulation had vesicles in nanosize range (167 nm) with suitable PDI (0.106), zeta potential (- 19.05 mV), and excellent %EE of RIF (66%) and AMB (85%). Moreover, it had appropriate deformability index (0.952). Additionally, AMB-RIF co-loaded TFG demonstrated suitable rheological behavior for topical application. AMB-RIF co-loaded TF and AMB-RIF co-loaded TFG showed sustained release of the incorporated drugs as compared to AMB-RIF suspension. Furthermore, RIF permeation from AMB-RIF co-loaded TF and AMB-RIF co-loaded TFG was enhanced fivefold and threefold, whereas AMB permeation was enhanced by eightfold and 6.6-fold, respectively. The significantly different IC50, higher CC50, and FIC50 (p < 0.5) showed synergistic antileishmanial potential of AMB-RIF co-loaded TF. Likewise, reduced lesion size and parasitic burden in AMB-RIF co-loaded TF-treated mouse group further established the antileishmanial effect of the optimized formulation. Besides, AMB-RIF co-loaded TFG showed a better safety profile. This study concluded that TFG may be a suitable carrier for co-delivery of AMB-RIF when administered topically for the treatment of CL.


Assuntos
Antiprotozoários , Leishmaniose Cutânea , Nanopartículas , Anfotericina B , Animais , Leishmaniose Cutânea/tratamento farmacológico , Macrófagos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho da Partícula
17.
Pharmacol Res ; 183: 106392, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35940396

RESUMO

This study aimed to investigate the anti-neuropathic pain activity and its underlying molecular mechanism of Ajugarin-I (Aju-I) in a rat model of diabetic neuropathic pain. The rats were given a single injection of 60 mg/kg of streptozotocin (STZ) intraperitoneally (i.p.) to induce diabetic neuropathic pain. After two weeks, rats were given Aju-I (1 and 5 mg/kg/day) i.p. for four consecutive weeks. The results demonstrated that in diabetic rats, treatment with Aju-I decreased STZ-induced hyperglycemia. It reduced the pain hypersensitivity (mechanical, thermal, and cold nociception) caused by STZ. It effectively restored STZ-associated pathological changes in the pancreas. In the sciatic nerve and spinal cord, it attenuated STZ-associated histopathological alterations and DNA damage. It suppressed oxidative stress by increasing the expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2), thioredoxin (Trx), and heme oxygenase (HO-1), but decreasing the immunoreactivity of Kelch-like ECH-associated protein 1 (Keap1). Additionally, TRPV1 (transient receptor potential vanilloid 1) and TRPM8 (transient receptor potential melastatin 8) expression levels were considerably reduced by Aju-I treatment. It enhanced antioxidant levels and suppressed inflammatory cytokines production. Taken together, this research suggests that Aju-I treatment reduces pain behaviors in the STZ model of diabetic neuropathy via modulating Nrf2/Keap-1/HO-1 signaling and TRPV1/TRPM8 nociceptors.


Assuntos
Diabetes Mellitus Experimental , Neuropatias Diabéticas , Neuralgia , Canais de Cátion TRPM , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Nociceptores/metabolismo , Ratos , Estreptozocina/efeitos adversos , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-35816520

RESUMO

Adversarial training (AT) is an effective approach to making deep neural networks robust against adversarial attacks. Recently, different AT defenses are proposed that not only maintain a high clean accuracy but also show significant robustness against popular and well-studied adversarial attacks, such as projected gradient descent (PGD). High adversarial robustness can also arise if an attack fails to find adversarial gradient directions, a phenomenon known as "gradient masking." In this work, we analyze the effect of label smoothing on AT as one of the potential causes of gradient masking. We then develop a guided mechanism to avoid local minima during attack optimization, leading to a novel attack dubbed guided projected gradient attack (G-PGA). Our attack approach is based on a "match and deceive" loss that finds optimal adversarial directions through guidance from a surrogate model. Our modified attack does not require random restarts a large number of attack iterations or a search for optimal step size. Furthermore, our proposed G-PGA is generic, thus it can be combined with an ensemble attack strategy as we demonstrate in the case of auto-attack, leading to efficiency and convergence speed improvements. More than an effective attack, G-PGA can be used as a diagnostic tool to reveal elusive robustness due to gradient masking in adversarial defenses.

19.
J Infect Dev Ctries ; 16(6): 959-965, 2022 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-35797289

RESUMO

INTRODUCTION: India witnessed the catastrophic second wave of COVID-19 during the summer months of 2021. Many patients with non-resolution of symptoms admitted to dedicated COVID-19 treatment centers required prolonged inpatient care which led to the unavailability of beds for other COVID-19 patients. The objective of this study was to determine the duration of SARS-CoV-2 positivity in moderate and severe COVID-19 patients requiring long-term pulmonary care as well as to find out the association between different variables with the persistence of the virus. METHODOLOGY: A retrospective chart review of clinical and laboratory data of patients with moderate and severe COVID-19 between 1st April 2021 and 15th July 2021 admitted for more than 28 days and requiring long-term pulmonary care was carried out at National Cancer Institute, AIIMS, India. SARS-CoV-2 RNA was detected with real-time reverse transcriptase-polymerase chain reaction-based tests. Data from all consecutively included patients satisfying the selection criteria were presented temporally and analyzed by Fisher's exact test (p < 0.05). RESULTS: All 51 patients tested positive for SARS-CoV-2 RNA at the 5th week of initial laboratory confirmation of COVID-19. The majority of the patients (38; 74.5%) remained positive for viral RNA till the 6th week and the median duration of viral positivity was 45 days. The clinical presentation of SARI at admission was significantly higher among patients with viral persistence till the 6th week (p < 0.05). CONCLUSIONS: The median duration of the viral positivity was 45 days and SARI at admission was significantly associated with viral persistence till the 6th week.


Assuntos
COVID-19 , Pandemias , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Humanos , RNA Viral , Estudos Retrospectivos , SARS-CoV-2
20.
Molecules ; 27(13)2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35807562

RESUMO

Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic interactions. With TLR-4, rutin had the highest binding energy (-10.4 kcal/mol), poncirin had the highest binding energy (-9.4 kcal/mol) with NF-κB and JNK (-9.5 kcal/mol), respectively, and icariin had the highest binding affinity (-9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin's greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood-brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.


Assuntos
Receptor 4 Toll-Like , Fator de Transcrição AP-1 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , NF-kappa B/metabolismo , Rutina/farmacologia , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo
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