bluuebunny/crossref_metadata_2025_split huggingface dataset:
Krebs Cycle Rewired: Driver of Atherosclerosis Progression?
Authors: Liang Yamin , Chen Yanmei , Li Lu , Zhang Shulei , Xiao Jinyan , Wei Dangheng 
Published: August 2021

:The tricarboxylic acid (TCA) cycle is the center of energy metabolism in eukaryotic cells and is dynamically adjusted according to the energy needs of cells. Macrophages are activated by inflammatory stimuli, and then two breakpoints in TCA cycle lead to the accumulation of intermediates. Atherosclerosis is a chronic inflammatory process. Here, the "non-metabolic" signaling functions of TCA cycle intermediates in the macrophage under inflammatory stimulation and the role of intermediates in the progression of atherosclerosis are discussed.
Computational Prediction of Binding Affinity for CDK2-ligand Complexes.
A Protein Target for Cancer Drug Discovery
Authors: Veit-Acosta Martina , de Azevedo Junior Walter Filgueira 
Published: August 2021

Background:
CDK2 participates in the control of eukaryotic cell-cycle progression. Due to
the great interest in CDK2 for drug development and the relative easiness in crystallizing this enzyme,
we have over 400 structural studies focused on this protein target. This structural data is the basis for
the development of computational models to estimate CDK2-ligand binding affinity.

Objective:
This work focuses on the recent developments in the application of supervised machine
learning modeling to develop scoring functions to predict the binding affinity of CDK2.

Method:
We employed the structures available at the protein data bank and the ligand information accessed
from the BindingDB, Binding MOAD, and PDBbind to evaluate the predictive performance of
machine learning techniques combined with physical modeling used to calculate binding affinity. We
compared this hybrid methodology with classical scoring functions available in docking programs.

Results:
Our comparative analysis of previously published models indicated that a model created using
a combination of a mass-spring system and cross-validated Elastic Net to predict the binding affinity of
CDK2-inhibitor complexes outperformed classical scoring functions available in AutoDock4 and AutoDock
Vina.

Conclusion:
All studies reviewed here suggest that targeted machine learning models are superior to
classical scoring functions to calculate binding affinities. Specifically for CDK2, we see that the combination
of physical modeling with supervised machine learning techniques exhibits improved predictive
performance to calculate the protein-ligand binding affinity. These results find theoretical support
in the application of the concept of scoring function space.
A Comparative Insight on the Newly Emerging Rifamycins: Rifametane, Rifalazil, TNP-2092 and TNP-2198
Authors: Nazli Adila , He David L. , Xu Huacheng , Wang Zhi-Peng , He Yun 
Published: August 2021

Abstract:Rifamycins are considered a milestone for tuberculosis (TB) treatment because of their proficient sterilizing ability. Currently, available TB treatments are complicated and need a long duration, which ultimately leads to failure of patient compliance. Some new rifamycin derivatives, i.e., rifametane, TNP-2092 (rifamycin-quinolizinonehybrid), and TNP-2198 (rifamycin-nitromidazole hybrid) are under clinical trials, which are attempting to overcome the problems associated with TB treatment. The undertaken review is intended to compare the pharmacokinetics, pharmacodynamics and safety profiles of these rifamycins, including rifalazil, another derivative terminated in phase II trials, and already approved rifamycins. The emerging resistance of microbes is an imperative consideration associated with antibiotics. Resistance development potential of microbial strains against rifamycins and an overview of chemistry, as well as structure-activity relationship (SAR) of rifamycins, are briefly described. Moreover, issues associated with rifamycins are discussed as well. We expect that newly emerging rifamycins shall appear as potential tools for TB treatment in the near future.
Structure and Functions of T-cell Immunoglobulin-domain and Mucin- domain Protein 3 in Cancer
Authors: Lu Xinjie 
Published: August 2021

Background:T-cell immunoglobulin (Ig)-domain and mucin-domain (TIM) proteins represent a family of receptors expressed on T-cells that play essential cellular immunity roles. The TIM proteins span across the membrane belonging to type I transmembrane proteins. The N terminus contains an Ig-like V-type domain and a Ser/Thr-rich mucin stalk as a co-inhibitory receptor. The C-terminal tail oriented toward the cytosol predominantly mediates intracellular signaling.Methods:This review discusses the structural features and functions of TIM-3, specifically on its role in mediating immune responses in different cell types and the rationale for TIM-3-targeted cancer immunotherapy.Results:TIM-3 has gained significant importance to be a potential biomarker in cancer immunotherapy. It has been shown that blockade with checkpoint inhibitors promotes anti-tumor immunity and inhibits tumor growth in several preclinical tumor models.Conclusion:TIM-3 is an immune regulating molecule expressed on several cell types, including IFNγ-producing T-cells, FoxP3+ Treg cells, and innate immune cells. The roles of TIM-3 in immunosuppression support its merit as a target for cancer immunotherapy.
Pentacyclic Triterpenoids as Antibiofilm Agents against Methicillinresistant
and Biofilm-forming Staphylococcus aureus (MRSA)
Authors: Chung Pooi Yin Katrina , Gan Ming Yi , Chin Beek Yoke 
Published: August 2021

Background:
Methicillin-resistant Staphylococcus aureus (MRSA) has been constantly evolv-ing and developing resistance against conventional antibiotics. One of the key features of MRSA that enables it to develop resistance to antibiotics and host immune system is its ability to form biofilm in indwelling medical devices. In previous studies, the antimicrobial activity and mechanisms of action of three known pentacyclic triterpenoids α-amyrin, betulinic acid and betulinaldehyde against planktonic cells of MRSA were determined and elucidated.

Objective:
This study was carried out to evaluate the ability of the three compounds to significantly reduce the biomass of pre-formed biofilms of MRSA and metabolic activity of the bacterial cells in the biofilm.

Methods:
The anti-biofilm activity of α-amyrin, betulinic acid and betulinaldehyde, individually and in combination with oxacillin or vancomycin, against reference strain of MRSA in pre-formed biofilm were evaluated using the crystal violet and resazurin assays.

Results:
α-amyrin and betulinic acid significantly reduced the biomass of pre-formed biofilms of MRSA as individual compounds and in combination with oxacillin or vancomycin. Although betulinaldehyde individually increased the biomass, selected combinations with oxacillin and vancomycin were able to reduce the biomass. All three compounds did not show cytotoxic properties on normal mammalian cells.

Conclusion:
The three pentacyclic triterpenoids could significantly reduce pre-formed biofilm of MRSA with no cytotoxic effects on normal mammalian cells. These findings demonstrated that pentacyclic triterpenoids have the potential to be developed further as antibiofilm agents against MRSA cells in bio-films, to combat infections caused by multidrug-resistant and biofilm-forming S. aureus.
The Role of Bacterial Proteases in Microbe and Host-microbe Interactions
Authors: Hammers Daniel , Carothers Katelyn , Lee Shaun 
Published: August 2021

Background:
Secreted proteases are an important class of factors used by bacterial to
modulate their extracellular environment through the cleavage of peptides and proteins. These proteases
can range from broad, general proteolytic activity to high degrees of substrate specificity.
They are often involved in interactions between bacteria and other species, even across kingdoms,
allowing bacteria to survive and compete within their niche. As a result, many bacterial proteases
are of clinical importance. The immune system is a common target for these enzymes, and bacteria
have evolved ways to use these proteases to alter immune responses for their benefit. In addition to
the wide variety of human proteins that can be targeted by bacterial proteases, bacteria also use these
secreted factors to disrupt competing microbes, ranging from outright antimicrobial activity to
disrupting processes like biofilm formation.

Objective:
In this review, we address how bacterial proteases modulate host mechanisms of protection
from infection and injury, including immune factors and cell barriers. We also discuss the contributions
of bacterial proteases to microbe-microbe interactions, including antimicrobial and anti-
biofilm dynamics.

Conclusion:
Bacterial secreted proteases represent an incredibly diverse group of factors that bacteria
use to shape and thrive in their microenvironment. Due to the range of activities and targets of
these proteases, some have been noted for having potential as therapeutics. The vast array of bacterial
proteases and their targets remains an expanding field of research, and this field has many important
implications for human health.
The Role of Stem Cells in the Therapy of Stroke
Authors: Brzecka Anna , Ejma Maria , Madetko Natalia , Alster Piotr , Budrewicz Sławomir , Koszewicz Magdalena , Misiuk-Hojło Marta , Tomilova Irina K. , Somasundaram Siva G. , Kirkland Cecil E. 
Published: August 2021

Background:
Stroke is a major challenge in neurology due to its multifactorial genesis and
irreversible consequences. Processes of endogenous post-stroke neurogenesis, although
insufficient, may indicate possible direction of future therapy. Multiple research considers
stem-cell-based approaches in order to maximize neuroregeneration and minimize post-stroke
deficits.

Objective:
Aim of this study is to review current literature considering post-stroke stem-cell-
based therapy and possibilities of inducing neuroregeneration after brain vascular damage.

Methods:
Papers included in this article were obtained from PubMed and MEDLINE
databases. The following medical subject headings (MeSH) were used: “stem cell therapy”,
“post-stroke neurogenesis”, “stem-cells stroke”, “stroke neurogenesis”, “stroke stem cells”,
“stroke”, “cell therapy”, “neuroregeneration”, “neurogenesis”, “stem-cell human”, “cell therapy
in human”. Ultimate inclusion was made after manual review of the obtained reference list.

Results:
Attempts of stimulating neuroregeneration after stroke found in current literature
include supporting endogenous neurogenesis, different routes of exogenous stem cells
supplying and extracellular vesicles used as a method of particle transport.

Conclusion:
Although further research in this field is required, post stroke brain recovery
supported by exogenous stem cells seems to be promising future therapy revolutionizing
modern neurology.
Phytochemicals Targeting Oxidative Stress, Interconnected Neuroinflammatory,
and Neuroapoptotic Pathways Following Radiation
Authors: Fakhri Sajad , Piri Sana , Moradi Seyed Zachariah , Khan Haroon 
Published: August 2021

:
The radiation for therapeutic purposes has shown positive effects in different contexts;
however, it can increase the risk of many age-related and neurodegenerative diseases such as Alzheimer’s
disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and Parkinson’s
disease (PD). These different outcomes highlight a dose-response phenomenon called
hormesis. Prevailing studies indicate that high doses of radiation could play several destructive roles
in triggering oxidative stress, neuroapoptosis, and neuroinflammation in neurodegeneration. However,
there is a lack of effective treatments in combating radiation-induced neurodegeneration, and
the present drugs suffer from some drawbacks, including side effects and drug resistance. Among
natural entities, polyphenols are suggested as multi-target agents affecting the dysregulated pathogenic
mechanisms in neurodegenerative disease. This review discusses the destructive effects of radiation
on the induction of neurodegenerative diseases by dysregulating oxidative stress, apoptosis,
and inflammation. We also describe the promising effects of polyphenols and other candidate phytochemicals
in preventing and treating radiation-induced neurodegenerative disorders, aiming to
find novel/potential therapeutic compounds against such disorders.
Stress-Reducing Psychological Interventions as Adjuvant Therapies for
Diabetic Chronic Wounds
Authors: Carvalho Eugénia , Pombeiro Isadora , Moura João , Pereira M. Graça 
Published: August 2021

Background:
Diabetic foot ulcers (DFUs) are a major complication of diabetes mellitus
and a leading cause of lower limb amputation. Interventions to reduce psychological stress may
have the potential to improve self-care and greatly reduce the morbidity and mortality associated
with DFU. This review is focused on the consequences of psychological stress in wound healing
and reflects on the effects of currently used psychological stress-reducing interventions in patients
with DFU, proposing new applications for currently used stress-reduction interventions.

Results:
Stress is a natural and fundamental survival mechanism that becomes harmful when chronic.
DFU is associated with high levels of anxiety and chronic psychological stress. Chronic stressinduced
cortisol and adrenaline release impair wound healing, independently of the stressor. Psychological
stress-reducing interventions, such as relaxation with guided imagery, biofeedback-assisted
relaxation, mindfulness-based strategies, and hypnosis, can lead to a reduction in perceived
stress and improve wound healing by reducing wound inflammation and pain while improving
glycemic control. All stress reduction interventions also lead to pain relief and improved patient’s
quality of life.

Conclusion:
Psychological stress-reducing interventions are promising adjuvant therapies for
DFU. Their clinical application can improve self-care by tackling patient’s expectations, anxieties,
and fears. They can also help patients manage stress and pain while reducing wound inflammation
and improving wound healing.
Synthesis of 4-styrylpyrazoles and Evaluation of their Inhibitory Effects on
Cyclin-dependent Kinases
Authors: Kryštof Vladimír , Cankař Petr , Toman Daniel , Jorda Radek , Ajani Haresh 
Published: August 2021

Background:
Cycle-regulating and transcriptional cyclin-dependent kinases (CDKs) are
attractive targets in cancer drug development. Several CDK inhibitors have already been obtained or
are close to regulatory approval for clinical applications.

Objective:
Phenylazopyrazole CAN508 has been described as the first selective CDK9 inhibitor with
an IC50 of 350 nM. Since the azo-moiety is not a suitable functionality for drugs due to pharmacological
reasons, the preparation of carbo-analogues of CAN508 with similar biological activities is desirable.
The present work is focused on the synthesis of carbo-analogues similar to CAN508 and their
CDK inhibition activity.

Methods:
Herein, the synthesis of 21 novel carbo analogues of CAN508 and their intermediates is
reported. Subsequently, target compounds 8a - 8u were evaluated for protein kinase inhibition
(CDK2/cyclin E, CDK4/cyclin D, CDK9/cyclin T) and antiproliferative activities in cell lines (K562,
MCF-7, MV4-11). Moreover, the binding mode of derivative 8s in the active site of CDK9
was modelled.

Results:
Compounds 8a - 8u were obtained from key intermediate 7, which was prepared by linear
synthesis involving Vilsmeier-Haack, Knoevenagel, Hunsdiecker, and Suzuki-Miyaura reactions.
Styrylpyrazoles 8t and 8u were the most potent CDK9 inhibitors with IC50 values of approximately 1
μM. Molecular modelling suggested binding in the active site of CDK9. The flow cytometric analysis
of MV4-11 cells treated with the most active styrylpyrazoles showed a significant G1-arrest.

Conclusion:
The prepared styrylpyrazoles showed inhibition activity towards CDKs and can provide
a novel chemotype of kinase inhibitors.
Novel Pathways and Mechanisms of Nicotine-Induced Oral Carcinogenesis
Authors: Radhakrishnan Raghu A. , Sharma Mohit , Shetty Smitha S. 
Published: August 2021

Background:
Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked
Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine-
derived Nitrosamines (NDNs).

Methods:
A review of the literature was conducted with a tailored search strategy to unravel the
novel pathways and mechanisms of nicotine-induced oral carcinogenesis.

Results:
Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine
facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release.
Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance,
and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers
Ras/Raf-1/MEK1/ERK cascade, promoting anti-apoptosis and pro-proliferative effects. Furthermore,
the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear
localization of p-EGFR.

Conclusion:
Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes
cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects
of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of
any carcinogenicity.
Direct Modulation of the Gut Microbiota as a Therapeutic Approach for
Alzheimer’s Disease
Authors: Wang Yi , Dykes Gary A. 
Published: August 2021

:
Alzheimer’s disease is a neurodegenerative disease characterized by a progressive decline
in memory and cognitive functions. It is a multifactorial disease involving a wide range of
pathological factors that are not fully understood. As supported by a growing amount of evidence
in recent years, gut microbiota plays an important role in the pathogenesis of Alzheimer’s disease
through the brain-gut-microbiota axis. This suggests that direct modulation of the gut microbiota
can be a potential therapeutic target for Alzheimer’s disease. This review summarizes recent research
findings on the modulation of the gut microbiota by probiotic therapies and faecal microbiota
transplantation for controlling the pathologies of Alzheimer’s disease. Current limitations and future
research directions of this field are also discussed.
Medicinal Herbs and Nutritional Supplements for Dementia Therapy:
Potential Targets and Clinical Evidence
Authors: Dorman Guido , Flores Ignacio , Gutiérrez Carlos , Castaño Ramiro Fernández , Aldecoa Mayra , Kim Leandro 
Published: August 2021

:
Spices and herbs have been used for medicinal purposes for centuries. Also, in the last
decades, the use of different nutritional supplements has been implemented to treat all kinds of diseases,
including those that present an alteration in cognitive functioning. Dementia is a clinical syndrome
in which a person's mental and cognitive capacities gradually decline. As the disease progresses,
the person’s autonomy diminishes. As there is not an effective treatment to prevent progressive
deterioration in many of these pathologies, nutritional interventions have been, and still
are, one of the most widely explored therapeutic possibilities. In this review, we have discussed a
great number of potentially interesting plants, nutritional derivatives, and probiotics for the treatment
of dementia around the world. Their action mechanisms generally involve neuroprotective effects
via anti-inflammatory, antioxidant, anti-apoptotic, b-amyloid, and tau anti-aggregate actions;
brain blood flow improvement, and effects on synaptic cholinergic and dopaminergic neurotransmission,
which may optimize cognitive performance in patients with cognitive impairment. As for
their efficacy in patients with cognitive impairment and/or dementias, evidence is still scarce
andthe outcomes are controversial. We consider that many of these substances have promising therapeutic
properties. Therefore, the scientific community has to continue with a complete research focused
on both identifying possible action mechanisms and carrying out clinical trials, preferably
randomized, double-blind ones, with a greater number of patients, a long-term follow-up, dose standardization,
and the use of current diagnostic criteria.
Antihyperlipidemic and Hepatoprotective Properties of Vitamin B6 Supplementation in Rats with High-Fat Diet-Induced Hyperlipidemia
Authors: Zhang Qian , Zhang Da-long , Zhou Xiao-li , Li Qian , He Ning , Zhang Jing , Gu Qing , Qian Zhi-Yong 
Published: August 2021

Background:
The incidence and mortality of hyperlipidemia are increasing year by
year, showing a younger trend. At present, the treatment of hyperlipidemia is mainly dependent on
western medicine, but its side effects on liver and kidney function are common in clinics. Therefore,
it is necessary to study the treatment of hyperlipidemia by augmenting effective dietary nutrition
supplements. Vitamin B6 (VitB6), as an essential cofactor for enzymes, participates in lipid
metabolism. The effects of VitB6 on hyperlipidemia, however, have not been reported until now.

Aim:
The present study was to investigate the influence of VitB6 on hepatic lipid metabolism in hyperlipidaemia
rats induced by a High-Fat Diet (HFD).

Methods:
Male Sprague-Dawley rats were kept on HFD for two weeks to establish the hyperlipidemia
model. The rats in low-dosage and high-dosage groups were received 2.00 and 3.00 mg/kg/-
day of VitB6 for eight weeks, respectively.

Results:
The results showed that both doses of VitB6 reduced HFD-induced hepatic Low-Density
Lipoprotein Cholesterol (LDL-C); decreased blood cholesterol (TC), triglycerides, LDL-C, atherogenic
index (AI), Atherogenic Index of Plasma (AIP), apolipoprotein B (ApoB) and ApoB/apolipoprotein
A-1(ApoA1) ratio; increased liver High-Density Lipoprotein Cholesterol (HDL-C) and
serum ApoA1; reduced hepatic steatosis and triglyceride accumulation, lowered fat storage, and recovered
heart/body and brain/body ratio to a normal level. In addition, VitB6 supplementation
markedly decreased HMGR level, increased the mRNA abundance of LDLR and CYP7A1, and
protein expression of SIRT1, following the downregulation of SREBP-1 and PPARγ protein expression
in the liver of hyperlipidemia rats.

Conclusion:
In summary, oral VitB6 supplementation can ameliorate HFD-induced hepatic lipid
accumulation and dyslipidemia in SD rats by inhibiting fatty acid and cholesterol synthesis, promoting
fatty acid decomposition and cholesterol transport.