bluuebunny/crossref_metadata_2025_split huggingface dataset:
SGLT-2 Inhibitors: The Next-generation Treatment for Type 2
Diabetes Mellitus
Authors: Lukic Nikola , Macvanin Mirjana T. , Gluvic Zoran , Rizzo Manfredi , Radak Djordje , Suri Jasjit S. , Isenovic Esma R. 
Published: October 2023

:
Type 2 diabetes mellitus (T2DM) has become a worldwide concern in recent
years, primarily in highly developed Western societies. T2DM causes systemic complications,
such as atherosclerotic heart disease, ischemic stroke, peripheral artery disease,
kidney failure, and diabetes-related maculopathy and retinopathy. The growing number
of T2DM patients and the treatment of long-term T2DM-related complications pressurize
and exhaust public healthcare systems. As a result, strategies for combating T2DM
and developing novel drugs are critical global public health requirements. Aside from
preventive measures, which are still the most effective way to prevent T2DM, novel and
highly effective therapies are emerging. In the spotlight of next-generation T2DM treatment,
sodium-glucose co-transporter 2 (SGLT-2) inhibitors are promoted as the most efficient
perspective therapy. SGLT-2 inhibitors (SGLT2i) include phlorizin derivatives,
such as canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. SGLT-2, along
with SGLT-1, is a member of the SGLT family of proteins that play a role in glucose absorption
via active transport mediated by Na+/K+ ATPase. SGLT-2 is only found in the
kidney, specifically the proximal tubule, and is responsible for more than 90% glucose
absorption. Inhibition of SGLT-2 reduces glucose absorption, and consequently increases
urinary glucose excretion, decreasing blood glucose levels. Thus, the inhibition of
SGLT-2 activity ultimately alleviates T2DM-related symptoms and prevents or delays
systemic T2DM-associated chronic complications. This review aimed to provide a more
detailed understanding of the effects of SGLT2i responsible for the acute improvement
in blood glucose regulation, a prerequisite for T2DM-associated cardiovascular complications
control.
Keywords: Type 2 diabetes mellitus, T2DM,
In Silico Screening and Molecular Dynamics Simulations against Tyrosine-protein Kinase Fyn Reveal Potential Novel Therapeutic Candidates for Bovine Papillomatosis
Authors: Barros Gerlane Salgueiro , Barreto Débora Machado , Cavalcanti Sandy Gabrielly Souza , Oliveira Tiago Branquinho , Rodrigues Ricardo Pereira , de Aragão Batista Marcus Vinicius 
Published: October 2023

Background:
Decreased beef productivity due to papillomatosis has led to
the development and identification of novel targets and molecules to treat the disease.
Protein kinases are promising targets for the design of numerous chemotherapy drugs.

Objective:
This study aimed to screen and design new inhibitors of bovine Fyn, a protein
kinase, using structure-based computational methods, such as molecular docking
and molecular dynamics simulation (MDS).

Methods:
To carry out the molecular docking analysis, five ligands obtained through
structural similarity between active compounds along with the cross-inhibition function
between the ChEMBL and Drugbank databases were used. Molecular modeling was performed,
and the generated models were validated using PROCHECK and Verify 3D.
Molecular docking was performed using Autodock Vina. The complexes formed between
Fyn and the three best ligands had their stability assessed by MDS. In these simulations,
the complexes were stabilized for 100 ns in relation to a pressure of 1 atm, with
an average temperature of 300 k and a potential energy of 1,145,336 kJ/m converged in
997 steps.

Results:
Docking analyses showed that all selected ligands had a high binding affinity
with Fyn and presented hydrogen bonds at important active sites. MDS results support
the docking results, as the ligand showed similar and stable interactions with amino
acids present at the binding site of the protein. In all simulations, sorafenib obtained the
best results of interaction with the bovine Fyn.

Conclusion:
The results highlight the identification of possible bovine Fyn inhibitors;
however, further studies are important to confirm these results experimentally.
LncRNA MEG3: Targeting the Molecular Mechanisms and Pathogenic causes of Metabolic Diseases
Authors: Luo Yiyang , Wang Hailin , Wang Lijun , Wu Wei , Zhao Jiale , Li Xueqing , Xiong Ruisi , Ding Xueliang , Yuan Ding , Yuan Chengfu 
Published: October 2023

Background:
Non-coding RNA is a type of RNA that does not encode proteins,
distributed among rRNA, tRNA, snRNA, snoRNA, microRNA and other RNAs
with identified functions, where the Long non-coding RNA (lncRNA) displays a nucleotide
length over 200. LncRNAs enable multiple biological processes in the human
body, including cancer cell invasion and metastasis, apoptosis, cell autophagy, inflammation,
etc. Recently, a growing body of studies has demonstrated the association of lncRNAs
with obesity and obesity-induced insulin resistance and NAFLD, where MEG3 is
related to glucose metabolism, such as insulin resistance. In addition, MEG3 has been
demonstrated in the pathological processes of various cancers, such as mediating inflammation,
cardiovascular disease, liver disease and other metabolic diseases.

Objective:
To explore the regulatory role of lncRNA MEG3 in metabolic diseases. It provides
new ideas for clinical treatment or experimental research.

Methods:
In this paper, in order to obtain enough data, we integrate and analyze the data
in the PubMed database.

Results:
LncRNA MEG3 can regulate many metabolic diseases, such as insulin resistance,
NAFLD, inflammation and so on.

Conclusion:
LncRNA MEG3 has a regulatory role in a variety of metabolic diseases,
which are currently difficult to be completely cured, and MEG3 is a potential target for
the treatment of these diseases. Here, we review the role of lncRNA MEG3 in mechanisms
of action and biological functions in human metabolic diseases.
Cathepsin D Attenuates the Proliferation of Vascular Smooth Muscle Cells
Induced by the AGE/RAGE Pathway by Suppressing the ERK Signal
Authors: Ye Ning , Miao Linlin , Wang Fengzhi , Wu Shaojun , Wu Boquan , Zhou Ying , Wang Chang , Sun Guozhe 
Published: October 2023

Background:
In this study, we aimed to clarify the role and mechanism by which Cathepsin D
(CTSD) mediates the advanced glycation end products (AGEs)-induced proliferation of vascular smooth muscle
cells (VSMCs).

Methods:
We conducted a Western blotting assay and co-immunoprecipitation assay to detect the expression
of target proteins and the interaction between different proteins. Cell Counting Kit-8 (CCK-8) assay and 5-
ethynyl-2’-deoxyuridine (EdU) were used to evaluate the proliferation.

Results:
AGEs significantly promoted phenotypic switching and proliferation of VSMCs in a concentration-dependent
manner. This effect of AGEs was accompanied by inhibition of CTSD. Both the proliferation of
VSMCs and inhibition of CTSD induced by AGEs could be attenuated by the specific inhibitor of the receptor
for advanced glycation end products (RAGE), FPS-ZM1. Overexpression of CTSD significantly alleviated these
effects of AGEs on VSMCs. The mechanism of CTSD action in VSMCs was also explored. Overexpression
of CTSD reduced the activation of p-ERK caused by AGEs. By contrast, the knockdown of CTSD, elicited
using a plasmid containing short hairpin RNA (shRNA) against CTSD, further increased the activation of
p-ERK compared to AGEs alone. Additionally, co-immunoprecipitation studies revealed an endogenous interaction
between CTSD, a protease, and p-ERK, its potential substrate.

Conclusion:
It has been demonstrated that CTSD downregulates the level of phosphorylated ERK by degrading
its target, and this interaction plays a critical role in the proliferation of VSMCs induced by the
AGE/RAGE axis. These results provide a novel insight into the prevention and treatment of vascular complications
in diabetes.
Raddeanin A Improves the Therapeutic Effect of Osimertinib in NSCLC by
Accelerating ROS/NLRP3-mediated Pyroptosis
Authors: Lin Liping , Wu Xuan , Jiang Yuanxue , Luo Xi , Cao Xiaolong 
Published: October 2023

Background:
Osimertinib (Osm) is the preferred treatment for non-small cell lung cancer (NSCLC)
patients with the epidermal growth factor receptor (EGFR) T790M mutation. Nevertheless, the resistance of
NSCLC cells to Osm will eventually develop, which remains the biggest obstacle to treating such diseases.
Raddeanin A (RA) exhibits a potent anti-tumor effect on various types of cancer cells. In this study, we aimed
to investigate whether RA suppresses NSCLC growth and increases the therapeutic effect of Osm.

Methods:
The effects of RA on inhibiting NSCLC cell viability and proliferation were tested using cell counting
kit 8 (CCK-8) and EdU assay. The roles of RA in improving the anti-tumor effect of Osm were tested with
CCK-8 and colony formation assays. The roles of RA in regulating reactive oxygen species (ROS)/NOD-, LRR-,
and pyrin domain-containing protein 3 (NLRP3)-mediated pyroptosis were assessed using quantitative real-
time PCR (qRT-PCR) and western blotting analysis.

Results:
RA treatment decreased A549 and H1975 cell viability in a dose- and time-dependent way. RA inhibited
NSCLC cell proliferation and tumor growth in vivo. Mechanistically, RA induced ROS overgeneration
and resulted in subsequent NLRP3-mediated pyroptosis. In particular, combination treatment with Osm and
RA reduced cell viability and clonogenic growth capacity more efficiently than Osm mono treatment in A549
and H1975 cells. Combination treatment also promoted NLRP3-mediated pyroptosis more efficiently than
Osm mono treatment.

Conclusion:
RA inhibited the NSCLC growth and increased the anti-tumor role of Osm in NSCLC by facilitating
ROS/NLRP3-mediated pyroptosis. These results suggested that combination therapy with RA and Osm
might be an effective strategy to treat Osm-resistant NSCLC.
Review of Analytical Methods for Evaluating Azithromycin in the Context of
Green Analytical Chemistry
Authors: Sinzervinch Aline , Lustosa Isadora Alves , Kogawa Ana Carolina 
Published: October 2023

Background:
Azithromycin (AZT) is an antimicrobial available in different pharmaceutical forms
and many people can have access to this medicine. Therefore, the existence of adequate and reliable analytical
methods for evaluating the quality of AZT and AZT-based products is essential.

Objective/Methods:
The purpose of this review is to discuss the analytical methods for evaluating AZT present
in the literature and official compendia in the context of Green Analytical Chemistry (GAC).

Results:
Among the methods found in the literature for evaluating AZT, the most used method is HPLC (62%)
followed by TLC (14%) and the microbiological method by agar diffusion (14%). Even pharmacopoeias recommend
the analysis of AZT by HPLC or agar diffusion. Acetonitrile and methanol account for 35% of the
most used solvents in the analyses, followed by buffer.

Conclusion:
AZT lacks analytical methods in the context of GAC. Both physical-chemical and microbiological
methods can contemplate the environmentally friendly way to analyze AZT and AZT-based products, depending
only on the chosen conditions. Ethanol, purified water, acetic acid instead of methanol, acetonitrile,
buffer, formic acid in the physical-chemical methods are excellent alternatives. However, in the microbiological
method, turbidimetry is a great option instead of agar diffusion.
Transcriptomic Analysis of THP-1 Cells Exposed by Monosodium Urate Reveals Key Genes Involved in Gout
Authors: Wang Guozhen , Liu Zijia , Zheng Yuchen , Sheng Chao , Hou Xiaonan , Yao Mengfei , Zong Qi , Tang Duo , Zhou Zhixiang , Zhang Tie , Yang Yishu 
Published: October 2023

Background:
Gout is a common inflammatory arthritis, which is mainly caused by
the deposition of monosodium urate (MSU) in tissues. Transcriptomics was used to explore the
pathogenesis and treatment of gout in our work.

Objective:
The objective of the study was to analyze and validate potential therapeutic targets
and biomarkers in THP-1 cells that were exposed to MSU.

Methods:
THP-1 cells were exposed to MSU. The inflammatory effect was characterized, and
RNA-Seq analysis was then carried out. The differential genes obtained by RNA-Seq were analyzed with gene expression omnibus (GEO) series 160170 (GSE160170) gout-related clinical
samples in the GEO database and gout-related genes in the GeneCards database. From the three
analysis approaches, the genes with significant differences were verified by the differential
genes’ transcription levels. The interaction relationship of long non-coding RNA (lncRNA) was
proposed by ceRNA network analysis.

Results:
MSU significantly promoted the release of IL-1β and IL-18 in THP-1 cells, which aggravated their inflammatory effect. Through RNA-Seq, 698 differential genes were obtained, including 606 differential mRNA and 92 differential `LncRNA. Cross-analysis of the RNA-Seq
differential genes, the GSE160170 differential genes, and the gout-related genes in GeneCards
revealed a total of 17 genes coexisting in the tripartite data. Furthermore, seven differential
genes—C-X-C motif chemokine ligand 8 (CXCL8), C-X-C motif chemokine ligand 2 (CXCL2),
tumor necrosis factor (TNF), C-C motif chemokine ligand 3 (CCL3), suppressor of cytokine
signaling 3 (SOCS3), oncostatin M (OSM), and MIR22 host gene (MIR22HG)—were verified
as key genes that analyzed the weight of genes in pathways, the enrichment of inflammationrelated pathways, and protein-protein interaction (PPI)nodes combined with the expression of
genes in RNA-Seq and GSE160170. It is suggested that MIR22HG may regulate OSM and
SOCS3 through microRNA 4271 (miR-4271), OSM, and SOCS3m; CCL3 through microRNA
149-3p (miR-149-3p); and CXCL2 through microRNA 4652-3p (miR-4652-3p).

Conclusion:
The potential of CXCL8, CXCL2, TNF, CCL3, SOCS3, and OSM as gout biomarkers and MIR22HG as a therapeutic target for gout are proposed, which provide new insights into the mechanisms of gout biomarkers and therapeutic methods.
Qingrexiaoji Recipe Regulates the Differentiation of M2 TAM via miR-29 in GC
Authors: Zhang Yiqiong , Chen Luting , Fei Yuchang , Chen Peifeng , Pan Lei 
Published: October 2023

Background:
Gastric cancer, one of the most familiar adenocarcinomas of the gastrointestinal
tract, ranks third in the world in cancer-related deaths. Traditional Chinese medicine
can suppress the growth of tumors, and the underlying mechanism may be associated with
the tumor microenvironment. Here, we investigated the anti-cancer effects of the Qingrexiaoji
recipe on gastric cancer and the underlying molecular mechanism.

Methods:
An in vivo nude mouse model was established, and the expression of CD206, CD80,
and M2 phenotype-related proteins (Arg-1, Fizz1) was obtained by flow cytometry and western
blotting. The expressions of the M2 phenotype-related cytokines were examined by ELISA.

Results:
Qingrexiaoji recipe inhibited gastric tumor growth and downregulated the expression
of CD206, IFN-γ, IL-13, IL-4, and TNF-α in vivo. Qingrexiaoji recipe deceased M2 phenotypic
polarization by upregulating microRNA (miR)-29a-3p level. Luciferase activity assays showed
that HDAC4 is a potential target of miR-29a-3p. In cells co-transfected with HDAC4 siRNA and
miR-29a-3p inhibitor and treated with IL-4 and Qingrexiaoji recipe, the miR-29a-3p inhibitorinduced
increase of M2 phenotypic polarization was reversed.

Conclusion:
In summary, these results suggested that the Qingrexiaoji recipe regulated M2
macrophage polarization by regulating miR-29a-3p/HDAC4, providing a different and innovative
treatment for gastric cancer.
The Treatment of Tubal Inflammatory Infertility using Yinjia Tablets
through EGFR/MEK/ERK Signaling Pathway based on Network
Pharmacology
Authors: Huang Yefang , He Zhelin , Zhou Hang , Wen Yi , Ji Xiaoli , Ding Weijun , Zhu Boyu , Zhang Yongqing , Tan Ying , Yang Kun , Wang Yan 
Published: October 2023

Background:
Salpingitis obstructive infertility (SOI) refers to infertility caused by abnormal
conditions such as tubal adhesion and blockage caused by acute and chronic salpingitis.
SOI has a serious impact on women's physical and mental health and family harmony, and it is a
clinical problem that needs to be solved urgently.

Objective:
The purpose of the present study was to explore the potential pharmacological mechanisms
of the Yinjia tablets (Yin Jia Pian, YJP) on tubal inflammation.

Methods:
Networks of YJP-associated targets and tubal inflammation-related genes were constructed
through the STRING database. Potential targets and pathway enrichment analysis related
to the therapeutic efficacy of YJP were identified using Cytoscape and Database for Annotation,
Visualization, and Integrated Discovery (metascape). E. coli was used to establish a rat model of
tubal inflammation and to validate the predictions of network pharmacology and the therapeutic
efficacy of YJP. H&E staining was used to observe the pathological changes in fallopian tubes.
TEM observation of the ultrastructure of the fallopian tubes. ELISA was used to detect the changes
of IL-6 and TNF-α in fallopian tubes. Immunohistochemistry was used to detect the expression of
ESR1. The changes of Bcl-2, ERK1/2, p-ERK1/2, MEK, p-MEK, EGFR, and p-EGFR were detected
by western blot.

Results:
Through database analysis, it was found that YJP shared 105 identical targets with the
disease. Network pharmacology analysis showed that IL-6, TNF, and EGFR belong to the top 5
core proteins associated with salpingitis, and EGFR/MEK/ERK may be the main pathway involved.
The E. coli-induced disease rat model of fallopian tube tissue showed damage, mitochondrial
disruption, and increased levels of the inflammatory factors IL-6 and TNF-α. Tubal inflammatory
infertility rats have increased expression of Bcl-2, p-ERK1/2, p-MEK, and p-EGFR, and
decreased expression of ESR1. In vivo, experiments showed that YJP improved damage of tissue,
inhibited shedding of tubal cilia, and suppressed the inflammatory response of the body. Furthermore,
YJP inhibited EGFR/MEK/ERK signaling, inhibited the apoptotic protein Bcl-2, and upregulated
ESR1.

Conclusion:
This study revealed that YJP Reducing tubal inflammation and promoting tissue repair
may be associated with inhibition of the EGFR/MEK/ERK signaling pathway.
TPD52 is a Potential Prognostic Biomarker and Correlated with Immune Infiltration: A Pan-cancer Analysis
Authors: Miao Lu , Jing Li , Chen Buze , Zeng Tian , Chen Youguo 
Published: October 2023

Background:
Some tumors have a poor prognosis regarding TPD52 (tumor
protein D52). This study aims to explore TPD52's role in the cancer process from a
pan-cancer perspective.

Methods:
A pan-cancer analysis was conducted to investigate how TPD52 may be
involved in cancer as well as its association with prognosis.

Results:
A variety of human cancers express TPD52 abnormally and correlate with
clinical stage. There was a significant association between low expression of TPD52
and poor survival in BRCA, KIRP, LAML, LIHC, UCEC, and UVM. TPD52 alterations
were most frequently amplified in pan-cancer. The co-occurrence of 10 genes
alterations was found in the TPD52 altered group. There was a significant association
between TPD52 expression and MSI in four cancer types and TMB in twelve cancer
types. There was a significant correlation between TPD52 expression and immunerelated
cell infiltration. A significant correlation was found between TPD52 expression
in many tumor types and 8 immune checkpoint genes. There were signaling pathways
involved in pan-cancer caused by TPD52, including endocytosis, Fc gamma Rmediated
phagocytosis, and so on. TPD52 may be involved in chemotherapy and
chemoresistance.

Conclusion:
The TPD52 gene may be important for human cancer treatment.
Stem Cell-Based or Cell-Free Gene Therapy in Chondrocyte
Regeneration: Synovial Fluid-Derived Mesenchymal Stem Cell
Exosomes
Authors: Uysal Onur , Erybeh Haya , Canbek Mediha , Ekenel Emilia Qomi , Gunes Sibel , Büyükköroğlu Gülay , Semerci Sevimli Tugba , Cemrek Fatih , Sariboyaci Ayla Eker 
Published: October 2023

Background:
Cartilage injuries are currently the most prevalent joint
disease. Previous studies have emphasized the use of stem cells as the effective
treatment for regenerating cartilage damage.

Objective:
In this study, considering the difficulties of the cellular therapy method, it
was hypothesized that human synovial fluid-derived mesenchymal stem cell (hSFMSC)
exosomes as a SC source could be used to treat these injuries as a safer and
cell-free therapeutic alternative procedure due to its direct relevance to cartilage
regeneration. Moreover, this study aimed to determine the miRNA and target genes
required for the formation of SC treatment combined with gene therapy in order to
reveal the mechanism of cartilage regeneration and increase its effectiveness.

Methods:
MSCs were characterized by flow cytometry, and immunocytochemical and
differentiation analyses were done. To characterize functionally isolated exosomes, in
vitro uptake analysis was performed. RT-qPCR was used to examine in terms of the
advantages of cellular and cell-free therapy, mature human chondroblasts derived by
differentiation from hSF-MSCs and human chondrocyte profiles were compared in
order to demonstrate the above profile of hSF-MSCs and exosomes isolated from
them, and the effectiveness of SC therapy in repairing cartilage damage.

Results:
According to our findings, the expression level of hsa-miR-155-5p was found
to be considerably higher in chondrocytes differentiated from human synovial fluid
MSCs than in mature human chondrocytes. These findings were also supported by the
TGF-signalling pathway and chondrogenesis marker genes.

Conclusion:
It was concluded that hSF-MSCs and exosomes can be used in the
treatment of cartilage damage, and hsa-miR-155-5p can be used as a target miRNA in
a new gene therapy approach because it increases the therapeutic effect on cartilage
damage.
Liquisolid Technique: A Novel Technique with Remarkable Applications
in Pharmaceutics
Authors: Singh Sahibpreet , Singh Jyoti , Arora Disha 
Published: October 2023

Abstract:
Recently, it has been observed that newly developed drugs are lipophilic and have low
aqueous solubility issues, which results in a lower dissolution rate and bioavailability of the drugs.
To overcome these issues, the liquisolid technique, an innovative and advanced approach, comes
into play. This technique involves the conversion of the drug into liquid form by dissolving it in
non-volatile solvent and then converting the liquid medication into dry, free-flowing, and compressible
form by the addition of carrier and coating material. It offers advantages like low cost of production,
easy method of preparation, and compactable with thermo labile and hygroscopic drugs. It
has been widely applied for BCS II drugs to enhance dissolution profile. Improving bioavailability,
providing sustained release, minimizing pH influence on drug dissolution, and improving drug photostability
are some of the other promising applications of this technology. This review article presents
an overview of the liquisolid technique and its applications in formulation development.
Iodoxybenzoic Acid (IBX) in Organic Synthesis: A Septennial Review
Authors: Varala Ravi , Seema Vittal , Alam Mohammed Mujahid , Dubasi Narsimhaswamy , Vummadi Rama Devi 
Published: October 2023

Abstract:
This study reviews the oxidative applications of 2-iodoxybenzoic acid (IBX) in organic
synthesis, focusing on C-H functionalization, hetero-hetero bond formations, ring cleavage reactions,
dehydrogenation, heterocyclic ring formations, and some miscellaneous reactions in a comprehensive
and critical way. It compiles the literature starting from mid-2015 to date.