bluuebunny/crossref_metadata_2025_split huggingface dataset:
WTAP Mediated the N6-methyladenosine Modification of PDK4 to
Regulate the Malignant Behaviors of Colorectal Cancer Cells In Vitro
and In Vivo
Authors: Dai Xiaoyu , Chen Ke , Xie Yangyang 
Published: September 2022

Background:
The role of WT1-associated protein (WTAP) in mediating the
N6-methyladenosine (m6A) modification of pyruvate dehydrogenase kinase 4 (PDK4) in
colorectal cancer (CRC) has been previously reported

Objective:
This research manages to unveil the function and mechanism of WTAP mediating
the m6A modification in CRC

Methods:
Expressions of PDK4 and WTAP in CRC were assessed by bioinformatics analysis
and verified by Western blot. After the transfection with short hairpin RNAs (shRNAs)
for WTAP (shWTAP) and PDK4 (shPDK4) to manipulate the expressions of PDK4 and
WTAP, the viability, proliferation, migration, invasion, and levels of m6A, PDK4 and
WTAP in CRC cells were determined by cell counting kit-8 (CCK-8), colony formation,
transwell, Western blot, or M6A-RNA immunoprecipitation (MeRIP)-qPCR assays. M6A
binding sites in PDK4 were additionally predicted through bioinformatics analysis, and the
interaction of PDK4 and WTAP was confirmed using an RNA pull-down assay. Tumor volume
and weight in the constructed xenograft-tumor mouse model were recorded.

Results:
PDK4 expression was low, yet WTAP and m6A expressions were high in CRC
cells. WTAP bound with the m6A binding sites in PDK4. PDK4 silencing facilitated the
viability, proliferation, migration and invasion, inhibited the expression of PDK4 in CRC
cells, and accelerated the growth of xenografts in vivo. However, the depletion of WTAP4
exerted the opposite effects and further offset the impact of PDK4 silencing.

Conclusion:
WTAP mediates the m6A modification of PDK4 to regulate the malignant
behaviors of CRC cells in vitro and in vivo.
The Selective NLRP3-Inflammasome Inhibitor CY-09 Ameliorates
Kidney Injury in Diabetic Nephropathy by Inhibiting NLRP3-
inflammasome Activation
Authors: Yang Ming , Zhao Li 
Published: September 2022

Background:
Diabetic nephropathy (DN) is one of the most serious complications
of diabetes mellitus and the main cause of the end-stage renal disease (ESRD). Activation
of the NLRP3 inflammasome has been proven to play an important role in the development
of DN. Thus, specific and direct targets of NLRP3 inflammasome assembly
may have therapeutic potential. CY-09 is a new NLRP3 inflammasome specific inhibitor
that has been shown to protect against non-alcoholic fatty liver disease (NAFLD) by inhibiting
the activation of the NLRP3 inflammasome. However, its role in kidney disease,
especially DN, has not been reported.

Methods:
In this study, we used HE staining to assess renal pathological damage in each
group, and RT-PCR, immunofluorescence and WB were performed to detect the expression
changes in inflammatory and fibrosis proteins. The apoptosis level was detected by
TUNEL staining.

Results:
Here, we showed increased inflammation, oxidative stress, apoptosis and fibrosis
in db/db mice, while CY-09 exerted renoprotection by inhibiting NLRP3 inflammasome
activation. In vitro, CY-09 also inhibited NLRP3 and reduced caspase-1, IL-18, IL-1β and
apoptosis in a dose-dependent manner.

Conclusion:
CY-09 effectively protects the kidney from hyperglycemia induced damage
by inhibiting the NLRP3 inflammasome and may be a promising therapeutic strategy to
prevent the progression of DKD.
Multi-targeted HDAC Inhibitors as Anticancer Agents: Current
Status and Future Prospective
Authors: Patel Vijay K. , Shirbhate Ekta , Tiwari Priya , Kore Rakesh , Veerasamy Ravichandran , Mishra Achal , Rajak Harish 
Published: September 2022

Abstract:
Multi-targeted agents can interact with multiple targets sequentially, resulting
in synergistic and more effective therapies for several complicated disorders, including
cancer, even with relatively modest activity. Histone deacetylase (HDAC) inhibitors are
low molecular weight small compounds that increase the acetylation of histone and nonhistone
proteins, altering gene expression and thereby impacting angiogenesis, metastasis,
and apoptosis, among other processes. The HDAC inhibitors affect multiple cellular
pathways thus producing adverse issues, causing therapeutic resistance, and they have
poor pharmacokinetic properties. The designing of HDAC-based dual/multi-target inhibitor
is an important strategy to overcome adverse effects, drug resistance and increase the
effectiveness in controlling cancer. The selection of target combinations to design multitarget
HDAC inhibitor is generally accomplished on the basis of systematic highthroughput
screening (HTS), network pharmacology analysis methods. The identification
of the pharmacophore against individual targets is performed using rational or computation
methods. The identified pharmacophore can combine with merged, fused, or linked
with the cleavable or non-cleavable linker to retain the interaction with the original target
while being compatible with the other target. The objective of this review is to elucidate
the potential targets' design strategies, biological activity, and the recent development of
dual/multi-targeting HDAC inhibitors as potential anticancer agents. This review elucidates
the designing strategies of the potential target along with biological activity and the
recent development of dual/multi-targeting HDAC inhibitors as potential anticancer
agents. The development of HDAC-based dual/multi-target inhibitors is important for
overcoming side effects, drug resistance, and effective cancer control.
Innate Immune Response in Hypertension
Authors: De Sanctis Juan Bautista 
Published: September 2022

Abstract:
Even though an association between inflammation and hypertension has been known for many years,
it has not been simple to ascertain the role of several physiological responses involved. The innate immune
response plays a critical role in these physiological responses. Innate immune cells can be activated directly by
shear stress, activate the inflammasome and produce numerous cytokines and soluble mediators essential in
hypertension. NFkB activation is mainly involved in the activation of innate immune cells. Shear stress also
stimulates the expression of DAMP and PAMP receptors, enhancing pathogen and danger signals and magnifying
inflammation. The adaptative immune response is activated with the increased antigen presentation resulting
from the insults mentioned. Chronic inflammation may lead to autoimmunity. Peripheral hypoxia, a consequence
of hypertension, activates hypoxia-inducing factors 1-α and 1-β (HIF-1α, HIF-1β), which modulate
innate immune cells and promote inflammation. HIF-1α is involved in the upregulation of oxygen and nitrogen
radical production proteins. HIF-1β down-regulates antioxidant enzymes. However, the critical evidence of the
role of innate immune cells in hypertension came from the results of clinical trials involving therapies blocking
inflammatory cytokines and Toll-like receptor expression. Several lines of research have been conducted on this
complex disease. Pro-tolerogenic innate immune cells, myeloid suppressor cells, and M2 macrophages may
play a crucial role in promoting or resolving inflammation, cardiovascular diseases and hypertension, and
should be studied in detail.
Advancements in COVID-19 Testing: An In-depth Overview
Authors: Kumar Rajesh , Harilal Seetha , Al-Sehemi Abdullah G. , Pannipara Mehboobali , Mathew Githa Elizabeth , Mathew Bijo 
Published: September 2022

Abstract:
COVID-19 rapidly evolved as a pandemic, killing and hospitalising millions of people,
and creating unprecedented hurdles for communities and health care systems worldwide. The rapidly
evolving pandemic prompted the head of the World Health Organisation to deliver a critical message:
"test, test, test." The response from the diagnostic industry and researchers worldwide was
overwhelming, resulting in more than a thousand commercial tests being available worldwide. Several
sampling approaches and diagnostic techniques have been employed from the early stages of the
pandemic, such as SARS-CoV-2 detection by targeting the viral RNA or protein indirectly via antibody
testing, biochemical estimation, and various imaging techniques, and many are still in the various
stages of development and yet to be marketed. Accurate testing techniques and appropriate sampling
are the need of the hour to manage, diagnose and treat the pandemic, especially in the current
crisis where SARS-CoV-2 undergoes constant mutation, evolving into various strains, which are
pretty challenging. The article discusses various testing techniques as well as screening methods for
detection, treatment, and management of COVID-19 transmissions, such as NAAT, PCR, isothermal
detection including RT-LAMP, RPA, NASBA, RCA, SDA, NEAR, and TMA, CRISPR strategy,
nanotechnology approach, metagenomic profiling, point of care tests, virus neutralization test,
ELISA, biomarker estimation, utilization of imaging techniques such as CT, ultrasonography, brain
MRI in COVID-19 complications, and other novel strategies including microarray methods, microfluidic
methods and artificial intelligence with an emphasis on advancements in the testing strategies
for the diagnosis, management, and prevention of COVID-19.
A Recent Appraisal of Small-Organic Molecules as Anti-Alzheimer’s Agents
Authors: Gupta Mohan , Kumar Avinash , Ojha Madhwi , Khan Shabana Kausar , Nain Sumitra 
Published: September 2022

Background:
Alzheimer’s disease (AD) is an irreversible, progressive and very complex
brain disorder. There is still uncertainty about the etiology of AD; however, a few hallmarks like an
aggregation of tau proteins, amyloid-β plaques, oxidative stress, low level of choline in the brain etc.,
play significant roles.

Objective:
In the present work, we aim to evaluate the recent progress in the development of small
organic molecules containing heterocycles like thiazole, pyridines, dihydropyridines, piperidines, pyrrolidines,
pyrazoles, quinolines etc. as anti-Alzheimer’s agents.

Method:
Several databases, including SciFinder, ScienceDirect, Bentham Science, and PubMed,
were searched for relevant articles and reviewed for the present work.

Results:
Several research groups are actively working on these heterocycle-based compounds as potent
single-target inhibitors. Most of the analogues have been evaluated for their cholinesterase (acetylcholinesterase
and butyrylcholinesterase) inhibition potential. Several studies have also reported the
inhibitory potential of the analogues against MAO-A, MAO-B, and BACE-1 enzymes. However, instead
of targeting one enzyme or protein, more than one heterocycle ring is being joined to develop
MTDLs (multi-target-directed ligands). Donepezil has become the focal point of anti-AD drug discovery
projects. Several research groups have reported various donepezil-based analogues by replacing/
modifying its various ring systems like indanone, piperidine or the methylene linker.

Conclusion:
Small molecules with nitrogen-containing heterocycles have become the core of drug
discovery efforts for AD. With the increasing prominence of the MTDL approach, several new ligands
are being discovered as potent anti-AD agents.
The Involvement of Kynurenine Pathway in Neurodegenerative Diseases
Authors: Martins Lais B. , Silveira Ana L.M. , Teixeira Antonio L. 
Published: September 2022

Background:
A growing body of evidence has shown the involvement of the kynurenine
pathway (KP), the primary route of tryptophan (TRP) catabolism, in the pathophysiology of neuropsychiatric
disorders.

Objective:
The study aims to provide a comprehensive and critical overview of the clinical evidence
on the KP involvement in the pathophysiology of Alzheimer’s disease (AD) and Parkinson's disease
(PD), discussing therapeutic opportunities.

Methods:
We searched for studies investigating KP metabolites in human subjects with AD and/or PD.

Results:
Postmortem studies showed altered levels of KP metabolites in the brain of AD and PD patients
compared with controls. Cross-sectional studies have reported associations between peripheral
levels (serum or plasma) of KP metabolites and cognitive function in these patients, but the results are
not always concordant.

Conclusion:
Given the emerging evidence of the involvement of KP in the pathophysiology of neuropsychiatric/
neurodegenerative diseases and promising results from preclinical pharmacological studies,
a better understanding of the KP involvement in AD and PD is warranted. Future longitudinal
studies are needed to define the direction of the observed associations and specific therapeutic targets
within the KP.
Receptors for Advanced Glycation End Products (RAGE): Promising
Targets Aiming at the Treatment of Neurodegenerative Conditions
Authors: Koerich Suélyn , Parreira Gabriela Machado , de Almeida Douglas Lamounier , Vieira Rafael Pinto , de Oliveira Antônio Carlos Pinheiro 
Published: September 2022

Abstract:
Advanced glycation end products (AGEs) are compounds formed after the non-enzymatic
addition of reducing sugars to lipids, proteins, and nucleic acids. They are associated with the development
of various clinical complications observed in diabetes and cardiovascular diseases, such as retinopathy,
nephropathy, diabetic neuropathy, and others. In addition, compelling evidence indicates
that these molecules participate in the progression of neurodegenerative diseases, such as Alzheimer’s
disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Multiple cellular and molecular alterations
triggered by AGEs that could alter homeostasis have been identified. One of the main targets for
AGE signaling is the receptor for advanced glycation end-products (RAGE). Importantly, this receptor
is the target of not only AGEs, but also amyloid β peptides, HMGB1 (high-mobility group box-1),
members of the S100 protein family, and glycosaminoglycans. The activation of this receptor induces
intracellular signaling cascades that are involved in pathological processes and cell death. Therefore,
RAGE represents a key target for pharmacological interventions in neurodegenerative diseases. This
review will discuss the various effects of AGEs and RAGE activation in the pathophysiology of neurodegenerative
diseases, as well as the currently available pharmacological tools and promising drug
candidates.
Molecular Docking: Principles, Advances, and Its Applications in Drug
Discovery
Authors: Muhammed Muhammed Tilahun , Aki-Yalcin Esin 
Published: September 2022

Abstract:
Molecular docking is a structure-based computational method that generates the binding pose
and affinity between ligands and targets. There are many powerful docking programs. However, there is
no single program that is suitable for every system. Hence, an appropriate program is chosen based on
availability, need, and computer capacity. Molecular docking has clear steps that should be followed carefully
to get a good result.

:
Molecular docking has many applications at various stages in drug discovery. Although it has various
application areas, it is commonly applied in virtual screening and drug repurposing. As a result, it is playing
a substantial role in the endeavor to discover a potent drug against COVID-19. There are also approved
drugs in the pharmaceutical market that are developed through the use of molecular docking. As
the accessible data is increasing and the method is advancing with the contribution of the latest computational
developments, its use in drug discovery is also increasing.

:
Molecular docking has played a crucial role in making drug discovery faster, cheaper, and more effective.
More advances in docking algorithms, integration with other computational methods, and the introduction of
new approaches are expected. Thus, more applications that will make drug discovery easier are expected.
Recent Advances in Therapeutic Strategies against Hydatid Cysts using
Nanomaterials: A Systematic Review
Authors: Marzban Abdolrazagh , Cheraghipour Kourosh , Rouzbahani Arian Karimi , Fallahi Shirzad , Taherpour Farshad , Moradifard Farzaneh , Shakib Pegah , Lashgarian Hamed Esmaeil 
Published: September 2022

Background:
Hydatidosis is one of the most common zoonotic diseases affecting general
health due to the lack of effective treatment strategies. Hydatid cysts are commonly treated with benzimidazole
(BZ) derivatives. However, their management is fraught with complications.

Objective:
This systematic review discusses recent efforts toward developing benzimidazole-based antihydatid
nanodrugs.

Methods:
Data were retrieved using PRISMA guidelines from several databases, such as Scopus, Science
Direct, PubMed, Web of Science, Ovid, Google Scholar, and Cochrane. Relevant articles published in
English and Persian were retrieved in December 2021. Keywords related to the search process (combined
or singular) included echinococcosis, hydatidosis, hydatid cysts, cystic echinococcosis, protoscolicidal
effect, albendazole (ALB), mebendazole (MBZ), solid lipid nanoparticles (SLNs), in vitro and in vivo.

Results:
Twenty-three research articles were eligible for further analysis after considering the inclusion/
exclusion criteria. This study indicates that ALB is the most prevalent synthetic drug incorporated
into nanoparticles (n = 68.4%). Additionally, the study examined nanoparticles containing ALB sulfoxide
(n = 31.5%). A total of three studies (n = 25%) were conducted with SLNs and two (n = 16.6%) with lipid
nanocarriers (NLCs). BALB/c mice (58.3%) were used most frequently in vivo studies. Moreover, 50% of
the laboratory animals were treated orally, and 33% were treated intraperitoneally.

Conclusion:
As the main treatment option for hydatid, ALB has been studied more thoroughly than other
drugs when developing nano-based formulations. Nanomaterials like metal nanoparticles, nanopolymers,
SLNs, and nanocrystals are being investigated for antiparasitic drug development to enhance therapeutic
effectiveness and reduce side effects. The findings of this study lead to the hypothesis that nanoformulation
of antiparasitic drugs may open up new opportunities for developing and formulating effective antihypertensive
drugs.
Methods for Analysis of Fluorinated Quinolones in Mixtures with Nitroimidazole
Antibacterial Drugs
Authors: Peikova Lily , Balkanski Stefan , Georgieva Maya 
Published: September 2022

Background:
Mixtures of Fluorinated Quinolones and Nitroimidazole antibacterial
drugs take a significant place in the treatment of different inflammatory diseases. The necessity to
develop analytical techniques for quality control is inextricably related to the introduction of new
mixed dose forms into clinical practice.

Objective:
The objective of our study is to develop HPLC methods for the analysis of Fluorinated
Quinolones in combinations with Nitroimidazole antibiotics.

Methods:
We developed and described an HPLC method for the quantitative determination of
model mixtures composed of Metronidazole and Ofloxacin, Tinidazole, and Ciprofloxacin. HPLC
method has been developed for the quantitative determination of Metronidazole and Ciprofloxacin
in model tablets. The methods have been validated according to the requirements of European
Pharmacopoeia 7.0 and the ICH criteria in terms of: selectivity, linearity, repeatability, accuracy,
limit of detection, and limit of quantification.

Results:
The tests are highly efficient liquid chromatographic with and without the use of highly
specialized consumables (chiral chromatographic column) and are characterized by excellent reproducibility,
accuracy, high sensitivity, and selectivity.

Conclusion:
The methods would be useful and applicable in routine analytical practice, as well as
for regulatory institutions in the control of newly registered generic products.
Small-molecule Modulators Targeting SHP2 for Cancer Therapy
Authors: Chen Yihua , Mi Dazhao , Li Yuzhan 
Published: September 2022

Background:
SHP2 is a protein tyrosine phosphatase that is extensively involved in several signaling pathways related to cancer occurrence, and thus SHP2 has been proposed an attractive target for cancer treatment.

Methods:
After a brief introduction of SHP2, we provided a short overview of the structure, function and regulation mechanism of SHP2 in cancer occurrence. Then, this perspective focused on the current therapeutic strategies targeting SHP2, including SHP2 PTP inhibitors, SHP2 allosteric inhibitors and SHP2-targeting PROTACs, and discussed the benefits and defects of these strategies. Finally, the opportunities and challenges were presented.

Results:
SHP2 regulated RAS-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 signaling pathways involved in pathogenesis of cancer via conformations conversion. Current therapeutic strategies targeting SHP2, especially SHP2 allosteric inhibitors, hold significant potency and have broad application prospects for cancer therapy.

Conclusion:
In summary, SHP2 is a promising therapeutic target and strategies targeting SHP2 offer an alternative program for cancer patients.
Treatment Discontinuation Prediction in Patients With Diabetes Using a Ranking Model: Machine Learning Model Development
Authors: Kurasawa Hisashi , Waki Kayo , Chiba Akihiro , Seki Tomohisa , Hayashi Katsuyoshi , Fujino Akinori , Haga Tsuneyuki , Noguchi Takashi , Ohe Kazuhiko 
Published: September 2022

Background
Treatment discontinuation (TD) is one of the major prognostic issues in diabetes care, and several models have been proposed to predict a missed appointment that may lead to TD in patients with diabetes by using binary classification models for the early detection of TD and for providing intervention support for patients. However, as binary classification models output the probability of a missed appointment occurring within a predetermined period, they are limited in their ability to estimate the magnitude of TD risk in patients with inconsistent intervals between appointments, making it difficult to prioritize patients for whom intervention support should be provided.

Objective
This study aimed to develop a machine-learned prediction model that can output a TD risk score defined by the length of time until TD and prioritize patients for intervention according to their TD risk.

Methods
This model included patients with diagnostic codes indicative of diabetes at the University of Tokyo Hospital between September 3, 2012, and May 17, 2014. The model was internally validated with patients from the same hospital from May 18, 2014, to January 29, 2016. The data used in this study included 7551 patients who visited the hospital after January 1, 2004, and had diagnostic codes indicative of diabetes. In particular, data that were recorded in the electronic medical records between September 3, 2012, and January 29, 2016, were used. The main outcome was the TD of a patient, which was defined as missing a scheduled clinical appointment and having no hospital visits within 3 times the average number of days between the visits of the patient and within 60 days. The TD risk score was calculated by using the parameters derived from the machine-learned ranking model. The prediction capacity was evaluated by using test data with the C-index for the performance of ranking patients, area under the receiver operating characteristic curve, and area under the precision-recall curve for discrimination, in addition to a calibration plot.

Results
The means (95% confidence limits) of the C-index, area under the receiver operating characteristic curve, and area under the precision-recall curve for the TD risk score were 0.749 (0.655, 0.823), 0.758 (0.649, 0.857), and 0.713 (0.554, 0.841), respectively. The observed and predicted probabilities were correlated with the calibration plots.

Conclusions
A TD risk score was developed for patients with diabetes by combining a machine-learned method with electronic medical records. The score calculation can be integrated into medical records to identify patients at high risk of TD, which would be useful in supporting diabetes care and preventing TD.