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"Hu, Hui"
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Roles and inhibitors of FAK in cancer: current advances and future directions
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that exhibits high expression in various tumors and is associated with a poor prognosis. FAK activation promotes tumor growth, invasion, metastasis, and angiogenesis via both kinase-dependent and kinase-independent pathways. Moreover, FAK is crucial for sustaining the tumor microenvironment. The inhibition of FAK impedes tumorigenesis, metastasis, and drug resistance in cancer. Therefore, developing targeted inhibitors against FAK presents a promising therapeutic strategy. To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. Moreover, many novel FAK inhibitors are currently in preclinical studies to advance targeted therapy for tumors with aberrantly activated FAK. The benefits of FAK degraders, especially in terms of their scaffold function, are increasingly evident, holding promising potential for future clinical exploration and breakthroughs. This review aims to clarify FAK’s role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies.
Journal Article
Finite-momentum Cooper pairing in proximitized altermagnets
Finite-momentum Cooper pairing is an unconventional form of superconductivity that is widely believed to require finite magnetization. Altermagnetism is an emerging magnetic phase with highly anisotropic spin-splitting of specific symmetries, but zero net magnetization. Here, we study Cooper pairing in metallic altermagnets connected to conventional
s
-wave superconductors. Remarkably, we find that the Cooper pairs induced in the altermagnets acquire a finite center-of-mass momentum, despite the zero net magnetization in the system. This anomalous Cooper-pair momentum strongly depends on the propagation direction and exhibits unusual symmetric patterns. Furthermore, it yields several unique features: (i) highly orientation-dependent oscillations in the order parameter, (ii) controllable 0-
π
transitions in the Josephson supercurrent, (iii) large-oblique-angle Cooper-pair transfer trajectories in junctions parallel with the direction where spin splitting vanishes, and (iv) distinct Fraunhofer patterns in junctions oriented along different directions. Finally, we discuss the implementation of our predictions in candidate materials such as RuO
2
and KRu
4
O
8
.
An altermagnet has highly anisotropic spin splitting but zero net magnetization. Here, S.-B. Zhang et al. theoretically study the behavior of
s
-wave superconductor/altermagnet hybrid structures, finding that Cooper pairs in the proximitized altermagnet have an anisotropic non-zero momentum.
Journal Article
A comprehensive analysis of weak transition form factors for doubly heavy baryons in the light front approach
The transition form factors for doubly heavy baryons into a spin-1/2 or spin-3/2 ground-state baryon induced by both the charged current and the flavor changing neutral current are systematically studied within the light-front quark model. In the transition the two spectator quarks have two spin configurations and both are considered in this calculation. We use an updated vertex functions, and inspired by the flavor SU(3) symmetry, we also provide a new approach to derive the flavor-spin factors. With the obtained transition form factors, we perform a phenomenological study of the corresponding semi-leptonic decays of doubly heavy baryons induced by the
c
→
d
/
s
ℓ
+
ν
,
b
→
c
/
u
ℓ
-
ν
¯
and
b
→
d
/
s
ℓ
+
ℓ
-
. Results for partial decay widths, branching ratios and the polarization ratios
Γ
L
/
Γ
T
s are given. We find that most branching ratios for the semi-leptonic decays induced by the
c
→
d
,
s
transitions are at the order of
10
-
3
∼
10
-
2
, which might be useful for the search of other doubly-heavy baryons. Uncertainties in form factors, the flavor SU(3) symmetry and sources of symmetry breaking effects are discussed. We find that the SU(3) symmetry breaking effects could be sizable in charmed baryon decays while in the bottomed case, the SU(3) symmetry breaking effects are less significant. Our results can be examined at the experimental facilities in the future.
Journal Article
Proto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy
Increased lipogenesis has been linked to an increased cancer risk and poor prognosis; however, the underlying mechanisms remain obscure. Here we show that phosphatidic acid phosphatase (PAP) lipin-1, which generates diglyceride precursors necessary for the synthesis of glycerolipids, interacts with and is a direct substrate of the Src proto-oncogenic tyrosine kinase. Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. Alteration of the three tyrosine residues to phenylalanine (3YF-lipin-1) disables lipin-1 from mediating Src-enhanced glycerolipid synthesis, cell proliferation and xenograft growth. Re-expression of 3YF-lipin-1 in PyVT;
Lpin1
−/−
mice fails to promote progression and metastasis of mammary tumours. Human breast tumours exhibit increased p-Tyr-lipin-1 levels compared to the adjacent tissues. Importantly, statistical analyses show that levels of p-Tyr-lipin-1 correlate with tumour sizes, lymph node metastasis, time to recurrence and survival of the patients. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic Src, providing a mechanistic link between obesity-associated mitogenic signaling and breast cancer malignancy.
Altered lipid metabolism has been associated with tumour malignancy, but underlying mechanisms are not clear. Here the authors show that proto-oncogene Src interacts and phosphorylates metabolic enzyme phosphatidic acid phosphatase LPIN1 (lipin-1) to promote growth and metastasis in breast cancer.
Journal Article
Photoelectrochemical asymmetric catalysis enables site- and enantioselective cyanation of benzylic C–H bonds
The enantioselective functionalization of ubiquitous C(
sp
3
)–H bonds is ideally suited for the construction of three-dimensional chiral structures. However, organic molecules often contain multiple C(
sp
3
)–H bonds with a similar energy and steric environment, rendering the simultaneous control of site-, chemo- and stereoselectivity extremely challenging. Here we show the merger of molecular photoelectrochemistry with asymmetric catalysis for the highly site- and enantioselective cyanation of benzylic C(
sp
3
)–H bonds. This example of photoelectrochemical asymmetric catalysis requires no chemical oxidant and exhibits an exceptional level of site selectivity and functional group tolerance, enabling not only the efficient conversion of feedstock chemicals but also the late-stage functionalization of complex bioactive molecules and natural products, including ones with multiple benzylic sites.
Asymmetric synthetic photoelectrochemical transformations are underdeveloped. Now, the combination of a photocatalyst, a chiral copper catalyst and an electrode allows the enantioselective cyanation of benzylic C–H bonds without a chemical oxidant.
Journal Article
2D vanadium carbide MXenzyme to alleviate ROS-mediated inflammatory and neurodegenerative diseases
Reactive oxygen species (ROS) are generated and consumed in living organism for normal metabolism. Paradoxically, the overproduction and/or mismanagement of ROS have been involved in pathogenesis and progression of various human diseases. Here, we reported a two-dimensional (2D) vanadium carbide (V
2
C) MXene nanoenzyme (MXenzyme) that can mimic up to six naturally-occurring enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione peroxidase (GPx), thiol peroxidase (TPx) and haloperoxidase (HPO). Based on these enzyme-mimicking properties, the constructed 2D V
2
C MXenzyme not only possesses high biocompatibility but also exhibits robust in vitro cytoprotection against oxidative stress. Importantly, 2D V
2
C MXenzyme rebuilds the redox homeostasis without perturbing the endogenous antioxidant status and relieves ROS-induced damage with benign in vivo therapeutic effects, as demonstrated in both inflammation and neurodegeneration animal models. These findings open an avenue to enable the use of MXenzyme as a remedial nanoplatform to treat ROS-mediated inflammatory and neurodegenerative diseases.
Materials with enzymatic-like activities are of interest for a wide range of applications. Here, the authors report on 2D vanadium carbide MXene nanozymes capable of mimicking multiple enzymes and demonstrate application to treat reactive oxygen species-mediated inflammatory and neurodegenerative diseases.
Journal Article
Study on relationship between elderly sarcopenia and inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10
Background and objectives
The pathophysiological mechanism of sarcopenia in the elderly has not yet been fully understood. Here, we aim to explore the relationship between sarcopenia and the inflammatory cytokine interleukin-6 (IL-6), and the anti-inflammatory cytokine interleukin-10 (IL-10) in an elderly population.
Methods
Our study comprised 118 males and 46 females aged between 61 and 90 who had received a general medical examination in Tianjin First Central Hospital. Subjects were divided into a sarcopenia group and a non-sarcopenia group, defined according to the criteria of the Asian Working Group for Sarcopenia (AWGS). We compared body composition, handgrip strength (HS), gait speed (GS), biochemical indexes, levels of IL-6 and IL-10, living habits, and disease status between these groups.
Results
Non-sarcopenia subjects undertook more regular physical exercise than sarcopenia patients. Sarcopenia subjects had higher nutrition risk but lower body mass index (BMI), serum albumin (ALB), triglyceride (TG), and creatinine (Cr) levels compared to non-sarcopenia subjects. Sarcopenia subjects were older and had higher visceral fat tissue (VFA) than non-sarcopenia subjects (
P
< 0.05), along with higher IL-6 and IL-10 levels. Furthermore, IL-6/IL-10 ratios were higher in subjects with sarcopenia (
P
< 0.05). Age, BMI, levels of physical activity, nutritional risk, VFA, IL-6, IL-10, IL-6/IL-10 ratio were independently associated with the presence of sarcopenia in univariate regression analyses. Following adjustment for confounding factors, the presence of sarcopenia was positively correlated with IL-6, IL-10, IL-6/IL-10 ratio and inversely correlated with BMI. Age is associated with increased presence of sarcopenia.
Conclusions
The levels of inflammation cytokine IL-6, anti-inflammatory IL-10 and IL-6/IL-10 ratio were increased in elderly sarcopenia subjects. Sarcopenia was associated with increased levels of inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10, and IL-6/IL-10 ratios.
Journal Article
A study on relationship between elderly sarcopenia and inflammatory factors IL-6 and TNF-α
Background
This report aims to study the relationship between sarcopenia of elderly in community and inflammatory factors IL-6 and TNF-α.
Methods
A total of 441 elders who undertook physical examinations were included into this study. The age of these subjects were >60, in which 235 subjects were male and 206 subjects were female. According to the diagnostic standards of sarcopenia set by EWGSOP and AWGS, these subjects were divided into two groups: sarcopenia, and non-sarcopenia groups. The living habits, disease status, biochemical indexes, and levels of IL-6 and TNF-α of these subjects were investigated.
Results
The morbidity rate of sarcopenia was 17.02% in male subjects and 18.9% in female subjects. In elderly subjects >80 years old, morbidity rate was 25.3% in male subjects and 35.1% in female subjects. The history of smoking in patients with sarcopenia was long, and their regular exercise history was short (
P
< 0.01). Furthermore, differences in handgrip strength (HG), fat-free mass (FFM), bone mineral content (BMC), plasma albumin (ALB) and serum creatinine (Cr), and body fat content (FAT) in patients between the sarcopenia and non-sarcopenia groups were statistically significant (
P
< 0.05). Moreover, differences in IL-6 and TNF-α levels between these two groups were statistically significant (
P
< 0.05). In addition, BMI was positively correlated to TNF-α levels, and ALB was negatively correlated to IL-6; while BMI and VFA were positively correlated to TNF-α levels, and SMM, HDL-C, Hb, HG were negatively correlated to IL-6 level (
P
< 0.05). Multiple linear regression analysis suggested plasma ALB and BMI were the independent risk factors of TNF-α, while VFA was the independent risk factor of IL-6.
Conclusions
The onset of sarcopenia was associated with poor exercise habits, disease history, and nutritional status. The emergence of sarcopenia was accompanied by increased levels of inflammation factors TNF-α and IL-6. Plasma albumin, BMI, and VFA were inflammatory factor predictors of TNF and IL-6.
Journal Article