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Evaluation and application analysis of animal models of PIPNP based on data mining

  • Jun Yu , Shengbo Jin , Haozhe Piao EMAIL logo and Mingzhu Li EMAIL logo
Published/Copyright: July 8, 2025
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Open Life Sciences
From the journal Open Life Sciences Volume 20 Issue 1

Abstract

The aim of this study is to systematically retrieve, synthesize, and assess methodologies employed in the development of paclitaxel-induced peripheral neuropathic pain (PIPNP) animal models, with the objective of optimizing protocols for model construction and evaluation. A structured search strategy was implemented using the terms “Paclitaxel-induced peripheral neuropathic pain” OR “Chemotherapy-induced peripheral neuropathic pain” AND “animal models” OR “rats” OR “mice” OR “experimental animals” across the China National Knowledge Infrastructure, Wanfang, and VIP databases. Identical search criteria were applied to the PubMed and Web of Science platforms. The literature search covered publications from database inception through December 31, 2024. A total of 128 articles were reviewed, including 18 in Chinese and 110 in English. All studies employed rodent models, including 16 strains and including both sexes, with ages ranging from 5 weeks to 10 months. In rats, 28 distinct modeling protocols were identified: 4 involving continuous paclitaxel injections, 23 employing alternate-day injections, and 1 using a single administration. For mice, 21 methods were recorded, comprising 6 continuous, 13 alternate-day, and 2 single-injection protocols. Upon successful model induction, six behavioral pain alterations were consistently documented, evaluated using 16 different assessment techniques. Current PIPNP models predominantly utilize 6- to 8-week-old male Sprague-Dawley (SD) rats, with paclitaxel administered at 2 mg/kg on either days 0, 2, 4, and 6 or days 1, 3, 5, and 7. Based on data mining and comparative evaluation of modeling approaches, the use of 6- to 8-week-old male SD rats or 8- to 10-week-old male C57BL/6J mice with paclitaxel administered at 2 mg/kg on days 1, 3, 5, and 7 is recommended for establishing PIPNP models. The translational alignment between PIPNP models and clinical phenotypes remains insufficient and requires further refinement.

Keywords: paclitaxel; peripheral neuropathic pain; animal models; data mining

1 Introduction

Malignant tumors remain the leading cause of death worldwide, significantly impeding efforts to enhance global life expectancy [1]. Data from the International Agency for Research on Cancer indicate that approximately 20 million new cancer cases were diagnosed globally in 2022, accompanied by 9.7 million cancer-related deaths, both figures inclusive of non-melanoma skin cancers. By 2050, the global cancer burden is projected to escalate to 35 million new cases annually [2]. This trajectory firmly establishes malignant tumors as the dominant global health threat [3]. Paclitaxel, a broad-spectrum chemotherapeutic primarily extracted from medicinal plants such as the yew and Taxus chinensis [4], continues to serve as a standard first-line treatment for multiple malignancies, including breast, lung, and ovarian cancers [5]. Despite its efficacy, paclitaxel therapy is frequently compromised by severe side effects, particularly paclitaxel-induced peripheral neuropathic pain (PIPNP), which affects up to 87% of recipients [6]. Characterized by persistent sensory disturbances – numbness, tingling, and pain in the extremities – PIPNP may also impair motor function, often persisting for extended periods and leading to significant treatment interruptions and deterioration in patients’ quality of life [7]. The pathogenesis of PIPNP remains poorly understood, hindering the development of effective preventive and therapeutic strategies. Current interventions for chronic PIPNP are limited, with duloxetine being the sole pharmacological agent conditionally endorsed by the American Society of Clinical Oncology guidelines, primarily for cases associated with platinum compounds rather than taxanes [8]. Despite growing interest in mitigating PIPNP, its underlying mechanisms and preventive measures continue to present substantial research challenges. Progress in this area relies on the establishment of a robust and reproducible animal model; however, agreement is lacking regarding optimal species selection, modeling protocols, and assessment methodologies. This study presents a comprehensive analysis of preclinical models to inform the development of a standardized framework, emphasizing critical variables including animal species, induction methods, pain-related behaviors, evaluation strategies, and relevant biomarkers.

2 Materials and methods

2.1 Data sources and search strategy

A comprehensive search was performed across China National Knowledge Infrastructure, Wanfang, and VIP databases (from inception to December 31, 2024) using the following terms: (“Paclitaxel-induced peripheral neuropathic pain” OR “Chemotherapy-induced peripheral neuropathic pain”) AND (“animal models” OR “mice” OR “rats” OR “experimental animals”). The same strategy was applied to PubMed and Web of Science for the same period. Only documented queries were retained, with detailed search terms presented in Table 1.

Table 1

List of main search formats

Serial number Search formats
1 Themes = “Paclitaxel-induced peripheral neuropathic pain” + “animal models”
2 Themes = “Paclitaxel-induced peripheral neuropathic pain” + “rats”
3 Themes = “Paclitaxel-induced peripheral neuropathic pain” + “mice”
4 Themes = “Paclitaxel-induced peripheral neuropathic pain” + “experimental animals”
5 Themes = “Chemotherapy-induced peripheral neuropathic pain” + “animal models”
6 Themes = “Chemotherapeutic alcohol-induced peripheral neuropathic pain” + “rats”
7 Themes = “Chemotherapy-induced peripheral neuropathic pain” + “mice”
8 Themes = “Chemotherapy-induced peripheral neuropathic pain” + “experimental animals”

2.2 Literature screening and selection criteria

A total of 467 records were initially retrieved. Following the removal of duplicates from both Chinese and English databases, the remaining entries underwent further screening to enhance literature quality. Conference abstracts, monographs, reviews, and records with incomplete data were excluded. Ultimately, 128 studies involving animal experiments on PIPNP were selected based on predefined inclusion criteria.

2.3 Statistical analysis

The experimental animal specifications adhered to the guidelines outlined in Experimental Animals and Animal Experimental Techniques. Data concerning animal selection (species, gender, and age), modeling approach, paclitaxel administration method, pain behavior during model induction, detection protocols, solvent choice for paclitaxel, safety profile, application contexts, and relevant experimental indicators were systematically recorded in Microsoft Excel 2021 to construct the PIPNP animal model database. Subsequent data processing – including summarization, cleaning, and analysis – was conducted using the same software. Due to missing information in some cases, the sum of individual data points in the statistical results may not add up to the total, and the final statistical results shall prevail.

3 Results

3.1 Experimental animal attributes

The 128 included documents contained 16 rodent species and strains, comprising two rat species – Sprague-Dawley (SD) and Wistar rats – with SD rats used more frequently (68 instances, 51.91%), and 14 mouse strains, including C57BL, C57BL/6, C57BL/NRj, C57BL/c, ICR, CD1, Swiss albino, ddY, CF-1, NMRI, s1-KO CD-1, and σ1R-KO CD-1. C57BL/6, C57BL/6J, and CD1 mice appeared most frequently (8 instances, 6.11%). Three studies lacked specific strain identification, referring only to rats or mice, while another three employed dual mouse strains for modeling. In total, rodent species were cited 128 times, as presented in Table 2. Male animals were predominantly used (96 instances, 75.00%), although eight studies omitted gender specification. Gender-related data are detailed in Table 3. Most subjects were aged 8–12 weeks (23 instances, 17.97%), followed by those aged 6–8 weeks (17 instances, 13.28%), and 7–9 weeks (5 instances, 3.91%). Eighteen studies indicated the use of adult mice without further age clarification, while 53 provided no age information. Age-related data are summarized in Table 4.

Table 2

PIPNP model – animal species and their usage frequency

Species Frequency (instances) Frequency/total (%) Refs.
SD rats 68 51.91 [9,10,11,12,13,14,15,16,17,18,19,20,21,22, 23,24,25,26,27,28,29,30,31,32,33,34, 35,36,37,38,39,40,41,42,43, 44,45,46,47,48,49,50,51,52,53,54,55,56,57,58, 59,60,61,62,63,64,65,66,67, 68,69,70,71,72,73,74,75,76]
Wistar rats 13 9.92 [77,78,79,80,81,82,83, 84,85,86,87,88,89]
C57BL mice 2 1.53 [90,91]
C57 BL/6 mice 8 6.11 [92,93,94, 95,96,97,98,99]
C57 BL/6J mice 8 6.11 [100,101, 102,103,104,105,106,107]
C57BL/6N mice 2 1.53 [108,109]
C57BL/NRj mice 1 0.76 [110]
C57BL/c mice 6 4.58 [111,112,113,114,115,116]
ICR mice 6 4.58 [26,117,118,119,120,121]
CD1 mice 8 6.11 [122,123,124,125,126,127,128,129]
Swiss albino 1 0.76 [130]
ddY mice 1 0.76 [131]
CF-1 mice 1 0.76 [132]
NMRI mice 1 0.76 [133]
s1-KO CD-1 mice 1 0.76 [88]
σ1R-KO CD-1 mice 1 0.76 [89]
Not mentioned 3 2.29 [134,135,136]
Total 131 100
Table 3

PIPNP model – animal gender and their usage frequency

Gender Frequency (instances) Frequency/total (%) Refs.
Both male and female 12 9.38 [20,30,36,85,97,104,107,109,110,121,127,128]
Female 12 9.38 [38,69,72,80,88,89,101,111,113,114,117,124]
Male 96 75.00 [9,10,11,12,13,14,15,16,17,18, 19,21,22,23,24,25,26,27,29,31,32,33,34,35,37,39,40,41, 42,43,44,45,46,47,48,49,50,51,52,53,54,55,56, 57,58,59,60,61,62,63,64,65,66,67,68, 69,70,71,73,74,75,76,77,78,79,81,82,84,86,87,91,92,93,95,96,98,100,102,103,105,106,108,112,115,117,118,119,120,122,123,126,129,130,131,132,134]
Not mentioned 8 6.25 [28,83,90,94,125,133,135,136]
Total 128 100
Table 4

PIPNP model – animal age and their usage frequency

Age Frequency (instances) Frequency/total (%) Refs.
10 months 1 0.78 [130]
3–4 months 2 1.56 [40,123]
12–14 weeks 2 1.56 [100,103]
10 weeks 2 1.56 [28,104]
8–12 weeks 23 17.97 [59,61,65,67,71,78,85,90,91,93,97, 99,107,108,110,111,113,114,115,116,120,121,129]
6–12 weeks 1 0.78 [109]
7–9 weeks 5 3.91 [9,51,87,95,122]
6–8 weeks 17 13.28 [17,23,25,33,44,58,73,81,86,92,94,96, 98,102,106,126,127]
5–8 weeks 1 0.78 [43]
5–6 weeks 3 2.34 [24,101,117]
Adult 18 14.06 [10,11,14,18,21,26,30,32,34, 35,39,45,53,57,76,82,84,132]
Not mentioned 53 41.41 [12,13,15,16,19,20,22,27,29,31, 36,37,38,41,42,46,47,48,49,50,52,54, 55,56,60,62,63,64,66,68,69,70,72,74,75,77,79,80,83,88, 89,105,112,118,119,124,125,128,131,133,134,135,136]
Total 128 100

3.2 Paclitaxel solvent

Of the 128 documents reviewed, 18 distinct methods for paclitaxel solvent preparation were identified. The most commonly reported combinations included Cremophor EL/ethanol (1:1) with 0.9% saline (38 instances, 29.69%) and 0.9% saline alone (24 instances, 18.75%). In 23 documents, the solvent preparation method was either omitted or not specified. A comprehensive summary is presented in Table 5.

Table 5

PIPNP model – paclitaxel solvent and their usage frequency

Paclitaxel solvent Frequency (instances) Frequency/total (%) Refs.
0.9% saline solution 24 18.75 [11,14,19,26,41,47,49,52,55,56, 60,62,65,67,69, 71,75,112,120,124,126,127,131]
Cremophor EL/ethanol (1:1) 13 10.16 [9,13,18,34,35,42,73,84,87,89,121,129,132]
Cremophor EL/ethanol (1:1) + 0.9% saline solution 38 29.69 [15,27,29,31,32,36,37,40,43,44,46, 50,51,58,64, 70,72,85,88,92,93,99,100,103,104,105, 108,109,110,111,113,114,115,116,117,122,135,136]
Cremophor EL/ethanol (1:1) + PBS solution 8 6.25 [81,91,94,96,98,102,106,128]
Cremophor EL/ethanol (1:1) + PBS solution + DMSO 1 0.78 [107]
5% DMSO + 40% PEG 300 + 5%Tween 80 + ddH2O 1 0.78 [123]
40% DMSO 2 1.56 [21,118]
10% DMSO 1 0.78 [39]
10% DMSO + 20%PEG300 + 10％Tween 80 + 0.9% saline solution 1 0.78 [53]
10％ DMSO + 40％PEG300 + 5%Tween 80 + 0.9% saline solution 1 0.78 [17]
4% DMSO + 4%Tween80 + 0.9% saline solution 1 0.78 [54]
2%DMSO + 0.9% saline solution 1 0.78 [78]
DMSO/Tween80 (1:1) + 0.9%saline solution 1 0.78 [16]
Cremophor EL 2 1.56 [63,76]
DMSO (concentration not mentioned) + 0.9% saline solution 6 4.69 [10,23,24,48,83,95]
PBS solution 1 0.78 [22]
99.9% HPLC-grade methanol + 0.9% saline solution 1 0.78 [82]
Cremophor EL + 10% saline solution 1 0.78 [125]
5% DMSO 1 0.78 [119]
Not mentioned 23 17.97 [12,20,25,28,30,33,38,45,57,59,61,66, 74,77,79, 80,86,90,97,101,130,133,134]
Total 128 100

3.3 Paclitaxel injection methods

Of the 128 studies reviewed, model induction was predominantly achieved via intraperitoneal injection, accounting for 127 instances (99.22%) in rats or mice. In contrast, intravenous administration was rarely applied, appearing in only a single instance (0.78%), as presented in Table 6.

Table 6

PIPNP model – paclitaxel injection methods and their usage frequency

Injection methods Frequency (instances) Frequency/total (%) Refs.
Intraperitoneal injection 127 99.22 [9,10,11,12,13,14,15,16,17,18,19,20,21,22, 23,24,25,26,27,28,29,30,31,32,33,34, 35,36,37,38,39,40,41,42,43,44,45,46, 47,48,49,50,51,52,53,54,55,56,57,58,59,60,61, 62,63,64,65,66,67,68,69,70,71,73,74, 75,76,77,78,79,80,81,82,83,84,85,86,87,88,89, 90,91,92,93,94,95,96,97,98,99,100,101,102,103,104, 105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128, 129,130,131,132,133,134,135,136]
Intravenous injection 1 0.78 [72]
Total 128 100

3.4 Modeling protocols

In patients with malignant tumors receiving paclitaxel chemotherapy, acute neuropathic symptoms typically emerge within 24–72 h following a single dose of 135 or 175 mg/m2 (equivalent to 3.6 and 4.7 mg/kg, respectively), in the absence of detectable changes in joint or musculoskeletal structures. These transient symptoms usually resolve within 1 week post-infusion. When paclitaxel is administered intravenously every 3 weeks over 3–24 h, with cumulative doses ranging from 1,400 to 1,500 mg/m2 (37.8–40.5 mg/kg), patients frequently exhibit chronic manifestations, including sensory deficits, paresthesia, or functional impairments impacting daily life. Consequently, current rat and mouse PIPNP models predominantly replicate chronic pain phenotypes, while validated models of the acute phase remain lacking [137,138]. Literature mining identified 28 rat model induction protocols, comprising 4 continuous dosing strategies, 23 alternating-day regimens, and 1 single-dose protocol. The most prevalent schedules involved 2 mg/kg injections on days 0, 2, 4, and 6 (17 instances, 20.48%) and on days 1, 3, 5, and 7 (24 instances, 28.92%), as summarized in Table 7. For mouse models, 21 distinct approaches were documented, including 6 continuous dosing regimens, 13 alternating-day protocols, and 2 single-dose methods. The most frequently reported included 2 mg/kg on days 1–5 (12 instances, 24.49%) and on days 0, 2, 4, and 6 (9 instances, 18.37%), with details outlined in Table 8. Among the 128 studies reviewed, 80 employed rat-based modeling strategies, 45 utilized mouse-based approaches (including 1 study applying both), and 3 incorporated both species for model development.

Table 7

PIPNP rat model – modeling protocols and their usage frequency

Modeling protocols Specific protocols Frequency (instances) Frequency/total (%) Refs.
Alternate-day injection protocols 2 mg/kg, injected once every other day, for a total of four injections 4 4.82 [28,36,51,134]
2 mg/kg, injected every 5 days, for a total of five injections 1 1.20 [84]
2 mg/kg, injected every 4 days for a total of four injections 1 1.20 [76]
3 mg/kg, injected once every other day, for a total of four injections 1 1.20 [70]
6 mg/kg, injected once a week for 4 weeks 1 1.20 [74]
16 mg/kg, injected once a week for 5 weeks 1 1.20 [75]
1 mg/kg, injected on days 1, 3, 5, and 7 3 3.61 [21,39,63]
1 mg/kg, injected on days 0, 2, 4, and 6 2 2.41 [41,83]
2.47 mg/kg, injected on days 1, 3, 5, and 7 3 3.61 [60,65,71]
2 mg/kg, injected on days 0, 2, 4, and 6 17 20.48 [11,15,16,17,19,20,22,23,30,42, 45,53,54,64,80,81,87]
2 mg/kg, injected on days 1, 3, 5, and 7 24 28.92 [13,14,18,24,26,29,31,32,34, 35,43,45,48,50,58,59,61,62, 66,67,68,78,79,136]
2 mg/kg, injected on days 1, 3, 5, 7, and 9 1 1.20 [10]
3, 6 mg/kg, injected on days 1, 2, 8, 9, 15, 16, 22, and 23 1 1.20 [9]
4 mg/kg, injected on days 0, 2, 4, and 6 1 1.20 [56]
4 mg/kg, injected on days 1, 3, 5, and 7 2 2.41 [12,38]
4 mg/kg, injected on days 1, 4, 8, and 11 1 1.20 [73]
4, 6 mg/kg, injected on days 1, 8, and 15 1 1.20 [57]
5 mg/kg, injected on days 0, 2, 4, and 6 1 1.20 [69]
5 mg/kg, injected on days 0, 7, 14, and 21 1 1.20 [27]
8 mg/kg, injected on days 1, 4, and 7 5 6.02 [40,47,49,52,55]
8 mg/kg, injected on days 0, 3, and 6 1 1.20 [85]
8 mg/kg, injected on days1, 3, 5, 7, and 9 1 1.20 [25]
9 mg/kg, injected on days 0, 2, 4, and 6 1 1.20 [77]
Continuous injection protocols 2 mg/kg, injection on days 1–4 1 1.20 [44]
2 mg/kg, injection on days 1–5 4 4.82 [33,86,88,89]
2 mg/kg, injection on days 0–6 1 1.20 [82]
3–7 mg/kg, injection on days 1–5 1 1.20 [72]
Single administration protocols 5, 10 mg/kg, injected once 1 1.20 [37]
Total 83 100
Table 8

PIPNP mouse model – modeling protocols and their usage frequency

Modeling protocols Specific protocol Frequency (instances) Frequency/total (%) Refs.
Alternate-day injection protocols 4 mg/kg, injected once every other day, for a total of four injections 1 2.04 [129]
4 mg/kg, injected once every other day, for a total of six injections 1 2.04 [93]
4 mg/kg, injected once every other day, for a total of eight injections 1 2.04 [122]
1 mg/kg, injected on days 0, 2, 4, and 6 1 2.04 [118]
1 mg/kg, injected on days 1, 3, 5, and 7 1 2.04 [117]
2 mg/kg, injected on days 0, 2, 4, and 6 9 18.37 [91,94,96,98,102,106,109,110,120]
2 mg/kg, injected on days 1, 3, 5, and 7 3 6.12 [26,99,112]
2 mg/kg, injected on days 1, 3, 5, and 8 1 2.04 [125]
2 mg/kg, injected on days 1, 4, 7, and 11 1 2.04 [107]
4 mg/kg, injected on days 0, 2, 4, and 6 3 6.12 [110,103,105]
4 mg/kg, injected on days 1, 3, 5, and 7 2 6.12 [104,121]
8 mg/kg, injected on days 1, 3, 5, and 7 2 4.08 [101,123]
20 mg/kg, injected on days 15, 17, 19, and 21 1 2.04 [92]
Continuous injection protocols 1 mg/kg, injection on days 1–4 1 2.04 [95]
1, 3, 6 mg/kg, injection on days 1–7 1 2.04 [90]
2 mg/kg, injection on days 1–5 12 24.49 [88,89,111,113,114,115,116,124,130,131,132,133]
4 mg/kg, injection on days 1–4 1 2.04 [128]
4 mg/kg, injection on days 1–5 2 4.08 [119,135]
4 mg/kg, injection on days 1–8 1 2.04 [108]
Single administration protocols 6 mg/kg, injected once 2 4.08 [97,109]
8 mg/kg, injected once 2 4.08 [126,127]
Total 49 100

3.5 Modeling safety

Of the 128 reviewed publications, 33 explicitly reported an absence of fatalities in both rats and mice. A single study documented two deaths during PIPNP model induction using a regimen of 16 mg/kg administered weekly over 5 weeks; one rat died following the initial dose, and another after the fourth injection [75]. The remaining 94 publications did not mention mortality outcomes. The specific data are summarized in Table 9.

Table 9

PIPNP model – modeling safety and their usage frequency

Safety Frequency (instances) Frequency/total (%) Refs.
Clearly document that no animal deaths occurred 33 25.78 [13,15,19,21,22,29,30,36,38,39,43,45,46, 51,53,58,61,62,64, 68,70,80, 87,91,96,98,100,103,110,112,117,120]
Clearly record the number of deaths 1 0.78 [75]
Deathless description 94 73.44 [9,10,11,12,14,16,17,18,20,23, 24,25,26,27,28,31,32,33,34, 35,37,40,41,42,44,47,48,49,50,42,54, 55,56,57, 59,60,63,65,66,67,69,71,72, 73,74,76,77,78,79,81,82,83,84,85,86, 88,89,90,92,93,94,95,97,101,102,104,105, 106,107,108,109,111,113,114,115,116,118,119, 121, 122,123,124,125,126,127,128,129,130,131,132,133,134,135,136]
Total 128 100

3.6 Pain-related behaviors in established model

PIPNP in clinical populations typically presents as numbness, tingling, pain, and sensory disturbances in the extremities. Comparable behavioral phenotypes have been observed in rodent models, mirroring the sensory abnormalities reported in humans. Based on established interspecies dose-conversion formulas and pharmacokinetic differences, a single paclitaxel dose of 1.0–32.0 mg/kg and cumulative exposure of 8.0–82.0 mg/kg in humans correspond to 1.3–12.9 mg/kg in rats. Similarly, human regimens involving single doses of 4.0–18.0 mg/kg and cumulative doses of 4.0–38.0 mg/kg translate to 0.33–3.1 mg/kg in mice. Within these dosage ranges, both rats and mice consistently exhibit characteristic behavioral alterations following paclitaxel administration, initially including pallor of distal limbs, elevated toe-licking frequency, and increased paw-lifting episodes. As nociceptive alterations progress, hallmark signs such as mechanical allodynia and thermal hypersensitivity emerge [139,140]. In the development of rodent PIPNP models, mechanical allodynia (111 instances, 48.47%) and thermal hyperalgesia (63 instances, 27.51%) represented the most frequently reported and widely adopted behavioral endpoints for model validation. A total of 229 pain-related behavioral responses were documented, with individual studies often reporting multiple endpoints. Refer to Table 10 for detailed quantitative data.

Table 10

PIPNP model – pain behaviors and their usage frequency

Pain-related behaviors Frequency (instances) Frequency/total (%) Refs.
+MA 111 48.47 [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23, 24,25,26,27,28,29,30,31,34,35,36,37,38,39,40, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55, 56,57,58,59,61,62,63,64,65,66,67,68,69,70,71, 73,74,75,76,77,78,79,80,85,87,88,89, 90,91,93,100,103,114,116,117,118,119,120,122,123,124,126, 129,130,131,132,133,134,135,136]
+MH 18 7.86 [31,32,34,35,42,46,60,75,76,81,84, 86,92,101,121,123,127,128]
+CA 27 11.79 [12,31,38,41,56,77,78,82,83,86,88,89,91,92,94, 96,98,100,102,103,106,112, 118,124,130,133,135]
+CH 5 2.18 [9,44,73,120,122]
+TA 5 2.18 [33,75,83,111,115]
+TH 63 27.51 [11,12,18,20,21,23,24,26,29,30,31, 33,37,38,39,43,45,47,48,52,56,57,58, 60,62,65,68,71,75,77,78,82,90,92,93, 97,99,101,104,108,109,111,112,113,114,115, 118, 119,120,122,123,124,126,127,129,130,132,133,134,135]
Total 229 100

Note: MA: Mechanical allodynia, MH: Mechanical hyperalgesia, CA: Cold allodynia, CH: Cold hyperalgesia, TA: Thermal allodynia, TH: Thermal hyperalgesia. Symbols: +, This behavior was assessed as pain-like following paclitaxel administration.

3.7 Assessment techniques for established model

Evaluation of model validity and drug efficacy relies on specific detection methods designed to quantify alterations in pain-related behaviors. Analysis of 128 publications identified 17 distinct validation techniques, cumulatively applied 238 times, as individual studies often incorporated multiple assessments. Among methods targeting mechanical allodynia and hyperalgesia, the Von Frey test emerged as the most prevalent, accounting for 103 instances (43.28%), followed by the Randall-Selitto paw pressure test with 12 instances (5.04%). Cold sensitivity was evaluated using four techniques, with the acetone test being the most frequently employed (26 instances, 26%). Assessment of thermal sensitivity involved five methodologies, with the plantar test – applying thermal stimuli to the hind paw – being the most widely adopted (41 instances, 16.82%). Comprehensive data are summarized in Table 11.

Table 11

PIPNP model – assessment techniques and their usage frequency

Pain-related behaviors Assessment techniques Frequency (instances) Frequency/total (%) Refs.
+MA, +MH Von Frey test 103 43.28 [9–21,23–27,29–32,34–60,63–66,69–71,73,78,81,84,85,88,90,91, 93,101,103, 104,106,109,111,112,117–124,126–129,131–136]
Plantar dynamic test 9 3.78 [22,28,67,89,92,110,113,114,116]
Mechanical claw pressure test 3 1.26 [61,87,105]
Randall-Selitto foot pressure test 12 5.04 [34,35,42,46,62,68,75, 76,79,80,101,123]
Pin prick test 2 0.84 [86,130]
Tail pinch test 1 0.42 [130]
Dynamic brush test 1 0.42 [31]
+CA, +CH Acetone test 26 10.92 [9,12,38,41,44,73,78,82,86,88,89,91,94, 96,98,100,102,103,106, 112,118,120,124,130,133,135]
Cold plate test 4 1.68 [56,111,122,125]
Cold water bath and tail withdrawal method 5 2.10 [12,38,82,83,92]
Cold water soaking test 1 0.42 [77]
+TA, +TH Hot plate test 21 8.82 [12,20,24,30,31,33,37,38,48,58, 78,90,101,111,115,127,132,133]
Thermal radiation rat rear foot method 40 16.81 [11,18,21,23,29, 31,39,43,45,47, 52,56,57,60,61,62,65,68,71,75,92,93, 97,99,101,104, 108,109,118,119,122, 124,126,129,130,134,135]
Thermal radiation rat tail method 4 1.68 [72,77,82,130]
Hot water bath and tail withdrawal method 5 2.10 [12,26,38,75,120]
Hot-tail test 1 0.42 [83]
Total 238 100

3.8 Applications of the PIPNP model

Among the 128 reviewed studies, 96 (75%) established PIPNP models in rats or mice primarily for pharmacodynamic evaluation and mechanistic investigations. Of these, 27 studies (21.09%) concentrated on pharmacodynamic assessments, while 4 (3.13%) explored the underlying pathogenesis of PIPNP using animal models. A single study (0.78%) focused on characterizing behavioral phenotypes associated with the condition. Comprehensive data are provided in Table 12.

Table 12

PIPNP model – applications and their usage frequency

Applications Frequency (instances) Frequency/total (%) Refs.
Pharmacodynamic evaluation + mechanistic investigations 96 75.00 [9,10,11,12,13,14,15,17,18,20,21,22,23,24,25, 26,28,29,30,31,32,34,35,36, 37,38,39,40,42,44,45,46,47,48,49,50, 52,53,54,55,56,58,59,60,61,62,63,64,65,66,67, 68,69,71,74,76,77,78,84,85,86,87,88,89,90,91, 92,95,97,98,99,100,101,102,104,106,108,109, 110,112,114,115,118,119,120,121,122,125,126,127,128,129,130,132,134,135]
Pharmacodynamic evaluation 27 21.09 [16,19,27,33,41,51,70,72,73,79,94, 96,103,105,107,111,113,116,117,123,124,131,133]
Underlying pathogenesis 4 3.13 [43,57,93,136]
Characterizing behavioral phenotypes 1 0.78 [75]
Total 128 100

3.9 Experimental indicators

Current rat and mouse models of PIPNP were predominantly employed for pharmacodynamic evaluation, mechanistic exploration, and investigations into disease pathogenesis. Literature mining indicated that, depending on specific research aims, commonly examined tissues included the spinal cord, sciatic nerve, nerve root, and serum. Analytical methods such as Western blotting (WB), immunohistochemistry, and ELISA were frequently applied to quantify protein and mRNA expression levels associated with PIPNP. These molecular indicators supported both the interpretation of drug mechanisms and the investigation of PIPNP pathophysiology. For example, McCormick B’s study [51] demonstrated that MitoVitE attenuated paclitaxel-induced oxidative stress and mitochondrial dysfunction while reducing mechanical hyperalgesia in a rat model, implicating oxidative and mitochondrial disturbances in the condition’s etiology. The validity of the animal model was thereby reinforced by paclitaxel’s capacity to replicate these pathological features. To elucidate the methodological basis for model establishment, key experimental indicators and their usage frequencies are extracted from 128 studies and summarized in Table 13.

Table 13

PIPNP model – experimental indicators and their usage frequency

Experimental indicators Specific indicator Frequency (instances) Frequency/total (%) Refs.
Expression of related proteins TPPV1 11 3.38 [24,26,30,31,35,44,48,98,106,109,114]
TPPV4 2 0.62 [44,48]
Nrf2 3 0.92 [54,101,120]
HIF-1α 4 1.23 [16,29,80,105]
HO-1 4 1.23 [16,54,101,120]
Iba1 17 5.23 [25,48,49,52,54,57,60,64,71,77,110,114,125,127,135,136]
CREB 2 0.62 [44,122]
GFAP 30 9.23 [22,29,32,37,40,42,45,47,48,49,50,52,53,54,55,57, 60,65,71,76,77, 84,110,115,121,125,126,132,135,136]
NLRP3 2 0.62 [66,101]
ERK1/2 4 1.23 [46,88,92,99]
P-ERK1/2 5 1.54 [32,46,88,92,99]
NF-κB 4 1.23 [57,71,92,127]
NF-κB P65 5 1.54 [22,40,46,78,90]
P-NF-κB 1 0.31 [127]
P-P38 3 0.92 [32,46,101]
MAPK 2 0.62 [46,101]
IB4 4 1.23 [44,47,50,127]
P-AKT 4 1.23 [18,55,85,101]
DNMT3a 3 0.92 [49,122,129]
CGRP 5 1.54 [12,44,50,126,127]
NeuN 5 1.54 [28,49,50,52,54]
NGF 1 0.31 [62]
NKCC1 1 0.31 [64]
GLT-1 4 1.23 [10,29,32,42]
TLR4 2 0.62 [22,95]
iNOS 1 0.31 [127]
PI3K 2 0.62 [55,101]
c-FOS 4 1.23 [28,108,110,127]
c-Jun 2 0.62 [90,122]
P-JNK 2 0.62 [32,90]
PGC-1α 1 0.31 [17]
RIP3 1 0.31 [15]
MAP2 2 0.62 [28,45]
CD68 4 1.23 [37,77,85,120]
CD11b 3 0.92 [84,114,132]
OX-42 3 0.92 [42,45,50]
PGC-1α 3 0.92 [17,18,39]
Expression of related mRNA OX-42 3 0.92 [42,45,50]
Nav1.7 2 0.62 [44,50]
K2p1.1 2 0.62 [56,128]
TNF-α 29 8.92 [12,15,21,22,23,37,40,42, 44,48,55,57,59,60,65,71,78,84,90, 92,95,97,99,104,120,123,134]
IL-1β 26 8.00 [12,14,15,18,21,22,23,29,37,38, 40,46,48,55,57,59,60,61,66,78, 79,92,95,120,123,134]
IL-6 15 4.62 [12,21,37,40,44,48,57,60,61,84, 92,99,104,123,134]
IL-4 4 1.23 [42,47,61,120]
IL-10 11 3.38 [18,23,42,46,47,57,61,84,99,120,121]
MDA 6 1.85 [18,38,39,66,79,130]
SOD 7 2.15 [18,21,39,42,66,86,114]
GSH 4 1.23 [38,79,86,130]
ROS 2 0.62 [66,120]
Acetylated histone H4 2 0.62 [40,52]
Acetylated histone H3 4 1.23 [52,56,122,129]
Mitochondrial membrane potential (MMP) 1 0.31 [49]
TRPV1 3 0.92 [44,98,114]
Iba1 1 0.31 [52]
NEuN 1 0.31 [28]
GFAP 2 0.62 [84,115]
c-FOS 2 0.62 [28,44]
TLR4 1 0.31 [57]
NF-κB p65 1 0.31 [57]
DNMT3a 1 0.31 [49]
c-Jun 1 0.31 [44]
Nav1.7 2 0.62 [44,50]
GLT-1 1 0.31 [115]
GLuA1 1 0.31 [115]
PGC-1α 1 0.31 [39]
Nrf2 1 0.31 [114]
CCL2 1 0.31 [84]
CD11b 1 0.31 [84]
KCNQ5 1 0.31 [136]
TNF-α 6 1.85 [12,21,38,84,123,134]
IL-1β 6 1.85 [12,38,44,120,123,134]
IL-6 6 1.85 [12,38,44,84,123,134]
IL-4 1 0.31 [120]
IL-10 3 0.92 [47,84,120]
Cytological examination Transmission electron microscopy (TEM) was employed to examine mitochondrial morphology 1 0.31 [89]
Ultrastructural alterations in the sciatic nerve were visualized using TEM 2 0.62 [67,68]
Toluidine blue staining was utilized to evaluate axonal degeneration 1 0.31 [74]
Plasma biochemical indexes NO (nitric oxide) 2 0.62 [38,39]
5-HT 1 0.31 [63]
Total 325 100

4 Evaluation and application analysis of the PIPNP animal model

The pathogenesis of PIPNP remains poorly understood. Current evidence indicates a multifactorial origin involving chemotherapy-induced mitochondrial impairment, oxidative stress, dysregulation of ion channel activity, neuroimmune dysfunction, dorsal root ganglion sensory neuron injury, and microvascular alterations [141]. This limited mechanistic insight continues to constrain the development of effective preventive and therapeutic interventions. Establishing a reproducible and reliable PIPNP animal model necessitates rigorous parameter optimization, including selection of animal strain, sex, developmental stage, paclitaxel dosage, modeling protocol, and outcome measures.

4.1 Evaluation and application analysis of animal species

The bibliometric analysis reveals that the rodent models are exclusively employed in current PIPNP model establishment, primarily due to their cost-effectiveness in husbandry, rapid reproductive cycle, and accelerated growth characteristics. Among rat models, SD rats predominate (68 instances, 51.91%), demonstrating enhanced pharmacological sensitivity compared to Wistar rats, which may potentiate intervention efficacy [142,143,144]. In mouse models, C57BL/6J and CD1 strains are frequently utilized (8 instances, 6.11%). However, CD1 mice as closed-colony stocks exhibit genetic heterogeneity and substantial phenotypic variability, potentially compromising experimental reproducibility [145]. In contrast, C57BL/6J – the inaugural mouse strain with fully sequenced genome – possesses a homogeneous genetic background that minimizes experimental variability [146]. Moreover, their immune system shares notable homology with humans, rendering this strain particularly suitable for mechanistic investigations into disease pathogenesis and pharmacological actions [147]. These comparative advantages strongly support the preferential selection of SD rats or C57BL/6J mice for optimized PIPNP model development.

4.2 Evaluation and application analysis of animal age

The 128 studies included 11 developmental stages, with animal ages ranging from 5 weeks to 10 months in both rats and mice. The most commonly selected age intervals were 6–8 weeks (17 instances, 13.28%) and 8–12 weeks (23 instances, 17.97%). Evidence suggests that early-life stressors, including maternal separation, may predispose young rats to depressive phenotypes in adulthood [148]. Accordingly, experimental modeling should utilize sexually mature adult rodents, with established maturation thresholds at 8–10 weeks for SD rats and 6–8 weeks for C57BL/6J mice, to avoid developmental variability associated with juvenile specimens.

4.3 Evaluation and application analysis of animal gender

Analysis of the literature revealed that male rodents were predominantly used for model induction, accounting for 96 sessions (75%). Although human studies have demonstrated greater experimental pain sensitivity in females across various modalities [149], no significant differences in the incidence or severity of PIPNP have been identified between sexes in preclinical models [150], indicating comparable pain responses during PIPNP progression. Nonetheless, numerous studies have shown that estrogen influences multiple signaling pathways within the nervous system. It alleviates neuropathic pain by suppressing microglial and astrocytic activation and downregulating pro-inflammatory cytokines such as IL-1β and IL-6 [151]. Additionally, estrogen enhances inhibitory neurotransmission via upregulation of NMDA receptor 1 and provides neuroprotection by mitigating oxidative neuronal damage [152,153]. Through its regulatory effects on neuroinflammation, neuronal excitability, and oxidative stress, estrogen exerts a multifactorial role in neuropathic pain modulation. Given these neuroregulatory functions, estrogen may confound the evaluation of paclitaxel-induced neurotoxicity when female rodents are employed in PIPNP models. Although direct sex-based comparative data in PIPNP modeling are limited, the established influence of estrogen on the peripheral nervous system supports the continued use of male rodents to minimize hormonal interference and improve model consistency.

4.4 Evaluation and application analysis of paclitaxel solvent

Literature mining identified Cremophor EL/ethanol (1:1) combined with 0.9% saline as the most frequently utilized solvent system for paclitaxel (38 instances, 29.69%), followed by direct dilution with 0.9% saline (24 instances, 18.75%). The choice of solvent largely depends on the formulation of paclitaxel. Owing to its poor aqueous solubility, conventional paclitaxel injections often require solubilizing excipients such as polyoxyethylene castor oil and ethanol. In preclinical models, alternative agents like DMSO and Tween 80 are also employed, though their inherent toxicity necessitates stringent control over concentration and dosing. Albumin-bound paclitaxel, formulated with human albumin as a carrier and stabilizer, exhibits high aqueous solubility and typically requires only dilution with 0.9% saline prior to administration [154,155,156]. Solvent selection should therefore align with the physicochemical properties of the paclitaxel formulation applied in each study.

4.5 Evaluation and application analysis of modeling protocols

Comprehensive analysis of the literature identified three primary paclitaxel-based modeling approaches: continuous injection, alternate-day injection, and single administration. All were validated as effective through various behavioral assessments. Among these, the 2 mg/kg dosing regimen administered on days 1, 3, 5, and 7 is recommended for both rats and mice, as it demonstrates superior alignment with clinical PIPNP symptomatology. This protocol most accurately replicates the characteristic phenotypes observed in PIPNP patients, who commonly present with distal limb numbness, tingling, and exaggerated responses to normally non-noxious stimuli. In rodent models, these clinical manifestations are paralleled by measurable reductions in mechanical pain thresholds and increased nociceptive sensitivity – key behavioral endpoints used to quantify symptom severity [157]. Data mining results indicate that 111 of 128 studies reported altered mechanical pain thresholds, with 25 of these employing the 2 mg/kg, days 1, 3, 5, and 7 protocol – the highest incidence among all dosing regimens. Similarly, among 63 studies documenting thermal hyperalgesia, 15 utilized this same schedule, again representing the highest proportion. Comprehensive data are provided in Table 14. These findings highlight a strong correlation between this dosing strategy and the induction of pain behaviors most representative of the PIPNP clinical symptomatology. This may be related to the prolonged half-life of paclitaxel in the body, as alternate-day injections can lead to repeated accumulation of the drug in the nervous system, preventing complete metabolism and resulting in prolonged exposure of nerves to toxic environments, thereby enhancing neuropathological responses [158,159,160]. Accordingly, we support its preferential adoption in preclinical modeling. From a pathological perspective, although the mechanisms underlying PIPNP remain unresolved, clinical trials have reported that certain patients undergoing paclitaxel chemotherapy exhibit not only neuropathic pain but also elevated serum IL-6 and IL-10 levels [161,162,163,164]. Data mining of 128 studies revealed that IL-6 levels were assessed in 16 cases, with 3 employing the 2 mg/kg dosing protocol on days 1, 3, 5, and 7 – representing the highest frequency among all regimens. Similarly, among the 11 studies measuring IL-10, this protocol appeared in 3 instances, again constituting a higher proportion. Comprehensive data are provided in Table 15. These patterns suggest a closer alignment between the 2 mg/kg, days 1, 3, 5, and 7 regimen and the inflammatory biomarkers observed in clinical PIPNP. Additionally, this protocol reflects the clinical pharmacological profile more accurately than single or continuous injections. The standard paclitaxel monotherapy regimen involves 175 mg/m2 administered intravenously over 3 h every 3 weeks [165]. The alternate-day dosing schedule better mirrors this clinical cadence. Furthermore, the 2 mg/kg dosage corresponds to the human equivalent dose derived from established interspecies conversion formulas, ensuring both translational relevance and safety in preclinical settings. Overall, the 2 mg/kg injection administered on days 1, 3, 5, and 7 establishes an animal model that better replicates the clinical and pathological attributes of PIPNP, offering a more representative platform for mechanistic investigation and therapeutic development.

Table 14

Modeling protocols for mechanical allodynia and thermal hyperalgesia: Frequency analysis

Pain-related behavior Modeling protocols Frequency (instances) Frequency/total (%) Refs.
+MA 2 mg/kg, injected once every other day, for a total of four injections 4 3.60 [28,36,51,134]
2 mg/kg, injected every 4 days for a total of four injections 1 0.90 [76]
3 mg/kg, injected once every other day, for a total of four injections 1 0.90 [70]
4 mg/kg, injected once every other day, for a total of four injections 1 0.90 [129]
4 mg/kg, injected once every other day, for a total of six injections 1 0.90 [122]
4 mg/kg, injected once every other day, for a total of eight injections 1 0.90 [93]
6 mg/kg, injected once a week for 4 weeks 1 0.90 [74]
16 mg/kg, injected once a week for 5 weeks 1 0.90 [72]
1 mg/kg, injected on days 1, 3, 5, and 7 4 3.60 [75]
1 mg/kg, injected on days 0, 2, 4, and 6 2 1.80 [41,118]
2 mg/kg, injected on days 0, 2, 4, and 6 24 21.62 [11,15,17,19,20,22,23,30,42,46, 53,54,64, 80,87,91,94,96,98,106,109,110,120]
2 mg/kg, injected on days 1, 3, 5, 7, and 9 1 0.90 [10]
2 mg/kg, injected on days 1, 3, 5, and 7 25 22.52 [13,14,18,24,26,29,31,34,35,43,45,48,50, 58,59,61,62,66,67,68,78,79,99,112,136]
2 mg/kg, injected on days 1, 4, 7, and 11 1 0.90 [107]
2.47 mg/kg, injected on days 1, 3, 5, and 7 2 1.80 [65,71]
3, 6 mg/kg, injected on days 1, 2, 8, 9, 15, 16, 22, and 23 1 0.90 [9]
4 mg/kg, injected on days 1, 4, 8, and 11 1 0.90 [73]
4 mg/kg, injected on days 0, 2, 4, and 6 4 3.60 [56,100,103,105]
4 mg/kg, injected on days 1, 3, 5, and 7 3 2.70 [12,38,104]
4, 6 mg/kg, injected on days 1, 8, and 15 1 0.90 [57]
5 mg/kg, injected on days 0, 2, 4, and 6 1 0.90 [69]
5 mg/kg, injected on days 0, 7, 14, and 21 1 0.90 [27]
8 mg/kg, injected on days 1, 4, and 7 5 4.50 [40,47,49,52,55]
8 mg/kg, injected on days 0, 3, and 6 1 0.90 [85]
8 mg/kg, injected on days 1, 3, 5, and 7 1 0.90 [125]
8 mg/kg, injected on days 1, 3, 5, 7, and 9 1 0.90 [25]
9 mg/kg, injected on days 0, 2, 4, and 6 1 0.90 [77]
1 mg/kg, injected on days 1–4 1 0.90 [95]
1, 3, 6 mg/kg, injected on days 1–7 1 0.90 [90]
2 mg/kg, injected on days 1–4 1 0.90 [44]
2 mg/kg, injected on days 1–5 11 9.91 [86,89,111,113,114, 116,124,130,131,132,133]
4 mg/kg, injected on days 1–5 1 0.90 [119,135]
4 mg/kg, injected on days 1–8 2 1.80 [108]
6 mg/kg, injected once 1 0.90 [109]
8 mg/kg, injected once 1 0.90 [126]
5, 10 mg/kg, injected once 1 0.90 [37]
Total 111 100
+TH 2 mg/kg, injected once every other day, for a total of four injections 1 1.59 [134]
3 mg/kg, injected once every other day, for a total of four injections 1 1.59 [70]
4 mg/kg, injected once every other day, for a total of four injections 1 1.59 [129]
4 mg/kg, injected once every other day, for a total of six injections 1 1.59 [122]
4 mg/kg, injected once every other day, for a total of eight injections 1 1.59 [93]
16 mg/kg, injected once a week for 5 weeks 1 1.59 [75]
1 mg/kg, injected on days 0, 2, 4, and 6 1 1.59 [118]
1 mg/kg, injected on days 1, 3, 5, and 7 2 3.17 [21,39]
2.47 mg/kg, injected on days 1, 3, 5, and 7 3 4.76 [60,65,71]
2 mg/kg, injected on days 0, 2, 4, and 6 6 9.52 [11,20,23,30,109,120]
2 mg/kg, injected on days 1, 3, 5, and 7 15 23.81 [18,24,26,29,31,43,45, 48,58,61,62,68, 78,99,112]
4 mg/kg, injected on days 0, 2, 4, and 6 1 1.59 [56]
4 mg/kg, injected on days 1, 3, 5, and 7 3 4.76 [12,38,104]
4, 6 mg/kg, injected on days 1, 8, and 15 1 1.59 [57]
5 mg/kg, injected on days 0, 2, 4, and 6 1 1.59 [69]
8 mg/kg, injected on days 1, 4, and 7 2 3.17 [47,52]
8 mg/kg, injected on days 1, 3, 5, and 7 2 3.17 [101,123]
9 mg/kg, injected on days 0, 2, 4, and 6 1 1.59 [77]
20 mg/kg, injected on days 15, 17, 19, and 21 1 1.59 [92]
1, 3, 6 mg/kg, injected on days 1–7 1 1.59 [90]
2 mg/kg, injected on days 0–6 1 1.59 [82]
2 mg/kg, injected on days 1–5 9 14.29 [33,111,113,114,115,124,130,132,133]
4 mg/kg, injected on days 1–5 1 1.59 [119,135]
4 mg/kg, injected on days 1–8 2 3.17 [108]
5, 10 mg/kg, injected once 1 1.59 [37]
6 mg/kg, injected once 1 1.59 [107]
8 mg/kg, injected once 2 3.17 [126,127]
Total 63 100
Table 15

Modeling protocols for IL-6 and IL-10 detection: Frequency analysis

Experimental indicators Modeling protocols Frequency (instances) Frequency/total (%) Refs.
IL6 2 mg/kg, injected once every other day, for a total of four injections 1 6.25 [134]
2 mg/kg, injected every 5 days, for a total of five injections 1 6.25 [84]
1 mg/kg, injected on days 1, 3, 5, and 7 1 6.25 [21]
2.47 mg/kg, injected on days 1, 3, 5, and 7 1 6.25 [60]
2 mg/kg, injected on days 1, 3, 5, and 7 3 18.75 [48,61,99]
4 mg/kg, injected on days 1, 3, 5, and 7 3 18.75 [12,38,104]
4, 6 mg/kg, injected on days 1, 8, and 15 1 6.25 [57]
8 mg/kg, injected on days 1, 3, 5, and 7 1 6.25 [123]
8 mg/kg, injected on days 1, 4, and 7 1 6.25 [40]
20 mg/kg, injected on days 15, 17, 19, and 21 1 6.25 [92]
2 mg/kg, injected on days 1–4 1 6.25 [44]
5, 10 mg/kg, injected once 1 6.25 [37]
Total 16 100
IL10 2 mg/kg, injected every 5 days, for a total of five injections 1 9.09 [84]
2 mg/kg, injected on days 0, 2, 4, and 6 4 36.36 [23,42,46,120]
2 mg/kg, injected on days 1, 3, 5, and 7 3 27.27 [18,61,99]
2 mg/kg, injected on days 1, 3, 5, and 7 1 9.09 [121]
4, 6 mg/kg, injected on days 1, 8, and 15 1 9.09 [57]
8 mg/kg, injected on days 1, 4, and 7 1 9.09 [47]
Total 11 100

4.6 Evaluation and application analysis of pain behavior and assessment techniques

Literature mining indicated that mechanical allodynia (111 instances, 48.47%) and thermal hyperalgesia (63 instances, 27.51%) were the most frequently evaluated behavioral endpoints for validating PIPNP animal models. Mechanical hypersensitivity is conventionally assessed by delivering incremental mechanical stimuli to determine the minimum force eliciting a withdrawal response. This approach provides a reliable method for pain quantification in non-verbal subjects, as it enables objective assessment and yields reproducible results. Furthermore, the presence of mechanical allodynia correlates with the severity and duration of neuropathic pain, serving as a predictor of patient prognosis and risk for chronic pain development [166,167]. The widespread adoption of the Von Frey filament test underscores its methodological robustness in detecting mechanical pain thresholds [168]. The Thermal Nociceptive Sensitivity Assay enables consistent evaluation of pain sensitivity in laboratory animals by applying controlled heat stimuli and determining the threshold temperature that elicits a nociceptive response. Similar to mechanical pain assessments, it is particularly appropriate for subjects incapable of self-reporting. In addition, thermal hyperalgesia demonstrates high sensitivity to alterations in pain perception thresholds, capable of detecting even subtle changes in nociceptive thresholds. This not only mirrors peripheral nociceptor sensitization but also provides insights into central nervous system pain modulation dynamics [169,170]. Among thermal-based methods, the hot plate test remains the benchmark for quantifying nociceptive sensitization in rodents, offering high reproducibility through standardized temperature settings and precise measurement of response latency. Compared to other methodologies such as tail flick, thermal radiation, or paw/incisor assays, the hot plate test inflicts minimal somatic trauma on animals while mitigating stress-related confounding variables. This ensures more reliable quantifications of pain sensitivity with enhanced experimental reproducibility and specificity [171,172,173]. Therefore, we propose the implementation of both hot plate and Von Frey testing to evaluate alterations in mechanical allodynia and thermal hyperalgesia during PIPNP animal model establishment, serving as critical criteria for validating model success.

4.7 Specific operation methods

4.7.1 Von Frey test

Animals were individually housed in chambers and permitted a 30 min acclimatization period. Commencing with a 2 g filament, a standardized series of Von Frey filaments (1, 1.4, 2, 4, 6, 8, 10, and 15 g) were applied perpendicularly to the plantar mid-region of the hind paw, exerting sufficient force to induce filament bending. A positive response was defined as either abrupt paw withdrawal or licking behavior upon filament stimulation. The minimum force (in grams) required to elicit a positive response was recorded as the paw withdrawal threshold. Given paclitaxel’s induction of bilateral allodynia, threshold values from both hind paws were averaged to yield a final measure [9,11].

4.7.2 Hot plate test

The subject was retrieved from its housing cage and positioned on the heated surface of the hot plate apparatus for a 10–15 min habituation period. During this phase, the plate remained at ambient temperature, and ambulatory activity was restricted to a cylindrical acrylic enclosure featuring a ventilated upper portion. Following environmental acclimatization, the hot plate was equilibrated to and sustained at 52.0°C ± 0.1°C. Thermal stimulation was initiated upon temperature stabilization, with response timing synchronized via a foot-operated switch integrated with the apparatus. Nociceptive behaviors, defined as hind paw elevation or directed licking, immediately terminated the trial, and corresponding latency measurements were documented. A safety cutoff of 30 s was enforced to mitigate thermal injury risk, in compliance with ethical guidelines for thermal nociception assays [12,20].

4.8 Analysis of experimental indicators

Paclitaxel has been shown to trigger neuroinflammation through the release of pro-inflammatory and chemotactic mediators, alongside the recruitment of non-resident macrophages into the spinal cord and dorsal root ganglia (DRG). This cascade promotes glial activation and accumulation, ultimately contributing to the development of neuropathic pain [174]. Literature mining highlights a higher frequency of reported expression for several proteins and mRNAs – namely, Iba1, GFAP, CD68, CD11b, CCL2, TNF-α, IL-1β, and IL-6 – compared to other molecular markers. Among them, TNF-α, IL-1β, and IL-6 are well-established pro-inflammatory cytokines implicated in neuropathic mechanisms [175]; CCL2, a chemokine with strong chemotactic activity, mediates a range of pro-inflammatory responses [176]; CD68 and CD11b are markers predominantly expressed by macrophages and mononuclear phagocytes; GFAP indicates astrocyte reactivity [177]; and Iba1 serves as a hallmark of microglial activation [178]. Inflammatory signaling pathways such as NF-κB, MAPK, and TLR4 are also frequently reported, suggesting a consistent mechanistic pattern across studies. Collectively, these observations support the association between successful PIPNP model establishment and paclitaxel-induced neuroimmune alterations. In parallel, accumulating evidence links chemotherapeutic agents to ion channel dysregulation in DRG neurons. Altered channel function leads to increased action potential amplitude and firing frequency, heightened neuronal excitability, and spontaneous ectopic discharges, all of which contribute to neuropathic pain pathogenesis [179]. Literature mining further identifies Nav1.7, a voltage-gated sodium channel primarily expressed in peripheral nociceptors, as a key modulator of nociceptive signal propagation [180]. These data converge on the conclusion that paclitaxel disrupts ion channel homeostasis, playing a significant role in model pathophysiology. Additionally, elevated reactive oxygen species (ROS) levels in DRG neurons have been implicated in the maintenance of hypersensitivity in paclitaxel-induced neuropathic pain states [181]. Furthermore, paclitaxel-induced mechanical hyperalgesia has been linked to spinal oxidative stress, which sustains central sensitization and contributes to nociceptive signaling. Excessive ROS production activates aberrant ion channel responses, leading to mitochondrial membrane depolarization, disruption of respiratory chain complexes, and release of pro-apoptotic proteins – cascading into mitochondrial dysfunction. This compromise in mitochondrial integrity disrupts intracellular signaling and interferes with physiological transmission pathways [182]. Literature mining identified MDA, SOD, ROS, GSH, and MMP as commonly employed biomarkers. Among them, MDA, SOD, ROS, and GSH serve as established indicators of oxidative stress, whereas MMP provides a quantitative measure of mitochondrial function. These data corroborate the mechanistic framework described above, indicating that the PIPNP model reflects paclitaxel-induced mitochondrial impairment and redox imbalance in DRG neurons. Moreover, chemotherapeutic agents have been reported to induce persistent NET accumulation, triggering microcirculatory impairment in peripheral tissues, including limbs, sciatic nerves, and DRGs, ultimately resulting in localized ischemia and hypoxia [141]. The frequent citation of HIF-1α across studies further supports its involvement in mediating cellular adaptation to hypoxic stress. Collectively, the literature-based analysis substantiates the role of paclitaxel-induced microvascular dysfunction as a core mechanism underlying PIPNP pathogenesis. Furthermore, research conducted by Li et al. identified TRPV1 as a key mediator in pain perception, with a prominent role in the progression of PIPNP [31]. Literature mining indicated consistent upregulation of TRPV1 at both the protein and mRNA levels, corroborating earlier mechanistic insights and linking paclitaxel administration to altered TRPV1 expression during model development. Beyond molecular profiling, TEM has been utilized to evaluate sensory neuron ultrastructure and detect cytological damage. This approach, highlighted in multiple studies, reinforces the association between paclitaxel exposure and structural neuronal injury, thereby supporting model validity. Collectively, the observed molecular and morphological alterations establish a mechanistic rationale for the effective construction of the PIPNP model.

In summary, analysis of data mining outcomes and comparative evaluation of modeling protocols supports the use of 6- to 8-week-old male SD rats or 8- to 10-week-old male C57BL/6J mice as the preferred model organisms. Induction of the PIPNP model is achieved through intraperitoneal administration of paclitaxel at 2 mg/kg on days 1, 3, 5, and 7, a regimen that elicits mitochondrial dysfunction, oxidative stress, ion channel imbalance, neuroimmune alterations, sensory neuron damage within the DRG, and microcirculatory impairment. Mechanical allodynia and thermal hyperalgesia can be quantitatively assessed using the Von Frey and hot plate tests, respectively, to validate model establishment. The detailed experimental protocol is presented in Figure 1.

Figure 1 Flowchart for the development of a PIPNP animal model based on data mining outcomes and modeling evaluation analysis.
Figure 1

Flowchart for the development of a PIPNP animal model based on data mining outcomes and modeling evaluation analysis.

5 Discussion

The pathogenesis of PIPNP remains unclear, and selecting an appropriate animal model has become essential for advancing research in this area. An optimized PIPNP model not only supports the elucidation of underlying mechanisms but also serves as a foundational platform for drug screening and target validation, thereby enhancing the transition from preclinical pharmacodynamic studies to clinical applications. Moreover, effective models contribute to the refinement of therapeutic strategies and the development of preventive interventions. Rat and mouse PIPNP models provide distinct advantages, including methodological simplicity, reliable detection metrics, and broad applicability. These features have positioned rodent models as indispensable tools for investigating PIPNP-related neurobiological processes and evaluating emerging therapeutic approaches with translational potential.

In experimental research, aligning the selection of animal models with both the study objective and the specific attributes of each model is fundamental for ensuring data validity. A chronological review of the literature indicates that early PIPNP modeling efforts remained largely exploratory, primarily demonstrating mechanical hypersensitivity as the predominant phenotype. With the advancement of hypotheses regarding PIPNP pathogenesis, models have progressively incorporated additional pain modalities, including thermal and cold hypersensitivity, along with broader behavioral alterations. Contemporary model construction now involves multi-system, multi-dimensional evaluation strategies, accompanied by a gradual expansion in the scope of assessment parameters. Attention has increasingly shifted from purely behavioral endpoints toward integrative analyses including serological, cytological, and molecular dimensions. Technologies such as proteomics, cytomics, and genomics have become more widely implemented, reflecting a progression in research focus from organ-level observations to cellular and molecular interrogation. This methodological evolution has strengthened the robustness and translational relevance of criteria used to evaluate model fidelity.

In summary, current research on PIPNP animal models remains in a phase of refinement, with the primary challenge being the alignment between experimental models and clinical phenotypes. Enhancing this translational relevance requires addressing several limitations identified through literature mining. First, the implementation of a dynamic dose-adjustment strategy is warranted. Clinically, PIPNP represents a dose-dependent neurotoxic response, where symptom severity escalates with cumulative exposure [160]. However, most existing studies adopt fixed-dose regimens – typically involving alternate-day or continuous paclitaxel administration – without incorporating the adaptive dosing strategies common in clinical practice. While such approaches simulate general treatment patterns, they fail to capture the clinical course of PIPNP onset and progression. Future models should therefore integrate dose modulation, including reductions or temporary cessation upon the emergence of marked neurotoxicity. Monitoring the reversibility of symptoms following dose adjustment would further clarify the extent to which the model reflects the clinical dose-response relationship, thereby enhancing its predictive validity. Enhancing the alignment between PIPNP animal models and clinical phenotypes requires methodological refinement. Second, extending the observation window and optimizing the intervals for pain behavior assessments are essential. Recent evidence indicates that approximately 30% of paclitaxel-treated patients continue to experience PIPNP symptoms years after chemotherapy completion [44]. Correspondingly, preclinical studies have shown that pronounced nociceptive hypersensitivity in animals emerges around week 3 [92], with thermal hyperalgesia persisting beyond 8 weeks and mechanical allodynia extending up to 12 weeks [183]. Despite this, most current PIPNP models, both domestically and internationally, limit the modeling period to 21 days and the observation window to 56 days [89], resulting in behavioral assessments conducted almost exclusively within the first 3 weeks. Such temporal constraints may hinder accurate modeling of the chronic nature of clinical PIPNP. To improve translational relevance, future protocols should extend monitoring durations and refine the timing of behavioral evaluations accordingly. Third, a shift toward multimodal assessment strategies is warranted. Current model validation primarily relies on passively elicited responses, such as altered mechanical thresholds and evoked nociceptive hypersensitivity. However, clinical PIPNP is often characterized by spontaneous pain and sensory disturbances, including numbness – features not adequately captured by existing paradigms. This mismatch suggests that sole dependence on reflexive behavioral endpoints limits the model’s capacity to replicate the full clinical spectrum. Incorporating complementary assessment tools capable of detecting spontaneous pain behaviors may enhance model fidelity and provide a more comprehensive representation of clinical symptomatology. The nerve conduction velocity assay evaluates motor axonal function by stimulating the sciatic nerve and recording evoked muscle action potentials [184], while neuromuscular ultrasound enables real-time visualization of nerve swelling and muscle denervation [185]. These techniques provide dynamic, objective assessments of nociceptive alterations in PIPNP animal models, addressing the limitations inherent to behavioral testing. Future studies would benefit from a multimodal assessment framework that integrates behavioral, electrophysiological, and neuroimaging approaches to enhance model validity and better approximate the complexity of clinical pain. Fourth, the development of a PIPNP animal model aligned with both disease presentation and syndrome differentiation is essential. Literature mining on PIPNP mechanisms in traditional chinese medicine (TCM) indicates that existing models lack clear correspondence with clinical diagnostic patterns such as qi deficiency, blood deficiency, cold congealment, and blood stasis. Future investigations should prioritize constructing models that incorporate TCM pathophysiological classifications alongside established Western biomedical indicators. This integrative approach would strengthen the translational relevance of preclinical models by improving alignment with clinically observed phenotypes. While the present study primarily sourced literature from English databases, strategic incorporation of findings from Chinese repositories has established a methodological foundation for international utilization of PIPNP animal models. However, to facilitate global adoption of the optimized PIPNP model proposed herein, subsequent investigations should (1) conduct comparative analyses with established international models (e.g., spared nerve injury, chronic constriction injury) to validate superior alignment with human chronic pain pathophysiology and (2) develop alternative validation protocols for resource-constrained research settings, particularly through identification of molecular biomarkers potentially substituting traditional behavioral pain assessments.

Addressing the four aforementioned challenges demands continued methodological refinement to develop a robust animal model of PIPNP that more precisely recapitulates the pathophysiological complexity and clinical heterogeneity observed in human patients. A model with greater translational relevance would provide a robust framework for elucidating disease mechanisms and guiding the development of frontline therapeutic strategies aimed at effective prevention and symptom control, thereby enhancing patient quality of life.

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Acknowledgments

The authors would like to express their gratitude to all members of Mingzhu Li and Haozhe Piao’s group for their support and help. This manuscript was supported by China National Natural Science Foundation (82104838), China Promotion Foundation Spark Program (XH-D001), and Liaoning Provincial Key Research and Development Program (2024JH2/102500062), which is gratefully acknowledged. Figure 1 was drawn using Figdraw.

  1. Funding information: This work was supported by China National Natural Science Foundation (82104838), China Promotion Foundation Spark Program (XH-D001), and Liaoning Provincial Key Research and Development Program (2024JH2/102500062).

  2. Author contributions: Jun Yu: conceptualization, writing – original draft, and writing – review and editing. Mingzhu Li and Haozhe Piao: conceptualization, writing – revision, project administration, and funding acquisition. Shengbo Jin: performed the literature search. All authors read and approved the final manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2025-02-06
Revised: 2025-04-13
Accepted: 2025-05-03
Published Online: 2025-07-08

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/biol-2025-1122
Keywords for this article
paclitaxel; peripheral neuropathic pain; animal models; data mining
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Mechanism of triptolide regulating proliferation and apoptosis of hepatoma cells by inhibiting JAK/STAT pathway
  3. Maslinic acid improves mitochondrial function and inhibits oxidative stress and autophagy in human gastric smooth muscle cells
  4. Comparative analysis of inflammatory biomarkers for the diagnosis of neonatal sepsis: IL-6, IL-8, SAA, CRP, and PCT
  5. Post-pandemic insights on COVID-19 and premature ovarian insufficiency
  6. Proteome differences of dental stem cells between permanent and deciduous teeth by data-independent acquisition proteomics
  7. Optimizing a modified cetyltrimethylammonium bromide protocol for fungal DNA extraction: Insights from multilocus gene amplification
  8. Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway
  9. Efficacy of alginate-coated gold nanoparticles against antibiotics-resistant Staphylococcus and Streptococcus pathogens of acne origins
  10. Battling COVID-19 leveraging nanobiotechnology: Gold and silver nanoparticle–B-escin conjugates as SARS-CoV-2 inhibitors
  11. Neurodegenerative diseases and neuroinflammation-induced apoptosis
  12. Impact of fracture fixation surgery on cognitive function and the gut microbiota in mice with a history of stroke
  13. COLEC10: A potential tumor suppressor and prognostic biomarker in hepatocellular carcinoma through modulation of EMT and PI3K-AKT pathways
  14. High-temperature requirement serine protease A2 inhibitor UCF-101 ameliorates damaged neurons in traumatic brain-injured rats by the AMPK/NF-κB pathway
  15. SIK1 inhibits IL-1β-stimulated cartilage apoptosis and inflammation in vitro through the CRTC2/CREB1 signaling
  16. Rutin–chitooligosaccharide complex: Comprehensive evaluation of its anti-inflammatory and analgesic properties in vitro and in vivo
  17. Knockdown of Aurora kinase B alleviates high glucose-triggered trophoblast cells damage and inflammation during gestational diabetes
  18. Calcium-sensing receptors promoted Homer1 expression and osteogenic differentiation in bone marrow mesenchymal stem cells
  19. ABI3BP can inhibit the proliferation, invasion, and epithelial–mesenchymal transition of non-small-cell lung cancer cells
  20. Changes in blood glucose and metabolism in hyperuricemia mice
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  22. IL-11 promotes Ang II-induced autophagy inhibition and mitochondrial dysfunction in atrial fibroblasts
  23. Short-chain fatty acid attenuates intestinal inflammation by regulation of gut microbial composition in antibiotic-associated diarrhea
  24. Application of metagenomic next-generation sequencing in the diagnosis of pathogens in patients with diabetes complicated by community-acquired pneumonia
  25. NAT10 promotes radiotherapy resistance in non-small cell lung cancer by regulating KPNB1-mediated PD-L1 nuclear translocation
  26. Phytol-mixed micelles alleviate dexamethasone-induced osteoporosis in zebrafish: Activation of the MMP3–OPN–MAPK pathway-mediating bone remodeling
  27. Association between TGF-β1 and β-catenin expression in the vaginal wall of patients with pelvic organ prolapse
  28. Primary pleomorphic liposarcoma involving bilateral ovaries: Case report and literature review
  29. Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study
  30. Sleep architecture in Alzheimer’s disease continuum: The deep sleep question
  31. Ephedra fragilis plant extract: A groundbreaking corrosion inhibitor for mild steel in acidic environments – electrochemical, EDX, DFT, and Monte Carlo studies
  32. Langerhans cell histiocytosis in an adult patient with upper jaw and pulmonary involvement: A case report
  33. Inhibition of mast cell activation by Jaranol-targeted Pirin ameliorates allergic responses in mouse allergic rhinitis
  34. Aeromonas veronii-induced septic arthritis of the hip in a child with acute lymphoblastic leukemia
  35. Clusterin activates the heat shock response via the PI3K/Akt pathway to protect cardiomyocytes from high-temperature-induced apoptosis
  36. Research progress on fecal microbiota transplantation in tumor prevention and treatment
  37. Low-pressure exposure influences the development of HAPE
  38. Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis
  39. AKAP12, mediated by transcription factor 21, inhibits cell proliferation, metastasis, and glycolysis in lung squamous cell carcinoma
  40. Association between PAX9 or MSX1 gene polymorphism and tooth agenesis risk: A meta-analysis
  41. A case of bloodstream infection caused by Neisseria gonorrhoeae
  42. Case of nasopharyngeal tuberculosis complicated with cervical lymph node and pulmonary tuberculosis
  43. p-Cymene inhibits pro-fibrotic and inflammatory mediators to prevent hepatic dysfunction
  44. GFPT2 promotes paclitaxel resistance in epithelial ovarian cancer cells via activating NF-κB signaling pathway
  45. Transfer RNA-derived fragment tRF-36 modulates varicose vein progression via human vascular smooth muscle cell Notch signaling
  46. RTA-408 attenuates the hepatic ischemia reperfusion injury in mice possibly by activating the Nrf2/HO-1 signaling pathway
  47. Decreased serum TIMP4 levels in patients with rheumatoid arthritis
  48. Sirt1 protects lupus nephritis by inhibiting the NLRP3 signaling pathway in human glomerular mesangial cells
  49. Sodium butyrate aids brain injury repair in neonatal rats
  50. Interaction of MTHFR polymorphism with PAX1 methylation in cervical cancer
  51. Convallatoxin inhibits proliferation and angiogenesis of glioma cells via regulating JAK/STAT3 pathway
  52. The effect of the PKR inhibitor, 2-aminopurine, on the replication of influenza A virus, and segment 8 mRNA splicing
  53. Effects of Ire1 gene on virulence and pathogenicity of Candida albicans
  54. Small cell lung cancer with small intestinal metastasis: Case report and literature review
  55. GRB14: A prognostic biomarker driving tumor progression in gastric cancer through the PI3K/AKT signaling pathway by interacting with COBLL1
  56. 15-Lipoxygenase-2 deficiency induces foam cell formation that can be restored by salidroside through the inhibition of arachidonic acid effects
  57. FTO alleviated the diabetic nephropathy progression by regulating the N6-methyladenosine levels of DACT1
  58. Clinical relevance of inflammatory markers in the evaluation of severity of ulcerative colitis: A retrospective study
  59. Zinc valproic acid complex promotes osteoblast differentiation and exhibits anti-osteoporotic potential
  60. Primary pulmonary synovial sarcoma in the bronchial cavity: A case report
  61. Metagenomic next-generation sequencing of alveolar lavage fluid improves the detection of pulmonary infection
  62. Uterine tumor resembling ovarian sex cord tumor with extensive rhabdoid differentiation: A case report
  63. Genomic analysis of a novel ST11(PR34365) Clostridioides difficile strain isolated from the human fecal of a CDI patient in Guizhou, China
  64. Effects of tiered cardiac rehabilitation on CRP, TNF-α, and physical endurance in older adults with coronary heart disease
  65. Changes in T-lymphocyte subpopulations in patients with colorectal cancer before and after acupoint catgut embedding acupuncture observation
  66. Modulating the tumor microenvironment: The role of traditional Chinese medicine in improving lung cancer treatment
  67. Alterations of metabolites related to microbiota–gut–brain axis in plasma of colon cancer, esophageal cancer, stomach cancer, and lung cancer patients
  68. Research on individualized drug sensitivity detection technology based on bio-3D printing technology for precision treatment of gastrointestinal stromal tumors
  69. CEBPB promotes ulcerative colitis-associated colorectal cancer by stimulating tumor growth and activating the NF-κB/STAT3 signaling pathway
  70. Oncolytic bacteria: A revolutionary approach to cancer therapy
  71. A de novo meningioma with rapid growth: A possible malignancy imposter?
  72. Diagnosis of secondary tuberculosis infection in an asymptomatic elderly with cancer using next-generation sequencing: Case report
  73. Hesperidin and its zinc(ii) complex enhance osteoblast differentiation and bone formation: In vitro and in vivo evaluations
  74. Research progress on the regulation of autophagy in cardiovascular diseases by chemokines
  75. Anti-arthritic, immunomodulatory, and inflammatory regulation by the benzimidazole derivative BMZ-AD: Insights from an FCA-induced rat model
  76. Immunoassay for pyruvate kinase M1/2 as an Alzheimer’s biomarker in CSF
  77. The role of HDAC11 in age-related hearing loss: Mechanisms and therapeutic implications
  78. Evaluation and application analysis of animal models of PIPNP based on data mining
  79. Therapeutic approaches for liver fibrosis/cirrhosis by targeting pyroptosis
  80. Fabrication of zinc oxide nanoparticles using Ruellia tuberosa leaf extract induces apoptosis through P53 and STAT3 signalling pathways in prostate cancer cells
  81. Haplo-hematopoietic stem cell transplantation and immunoradiotherapy for severe aplastic anemia complicated with nasopharyngeal carcinoma: A case report
  82. Modulation of the KEAP1-NRF2 pathway by Erianin: A novel approach to reduce psoriasiform inflammation and inflammatory signaling
  83. The expression of epidermal growth factor receptor 2 and its relationship with tumor-infiltrating lymphocytes and clinical pathological features in breast cancer patients
  84. Innovations in MALDI-TOF Mass Spectrometry: Bridging modern diagnostics and historical insights
  85. BAP1 complexes with YY1 and RBBP7 and its downstream targets in ccRCC cells
  86. Hypereosinophilic syndrome with elevated IgG4 and T-cell clonality: A report of two cases
  87. Electroacupuncture alleviates sciatic nerve injury in sciatica rats by regulating BDNF and NGF levels, myelin sheath degradation, and autophagy
  88. Polydatin prevents cholesterol gallstone formation by regulating cholesterol metabolism via PPAR-γ signaling
  89. RNF144A and RNF144B: Important molecules for health
  90. Analysis of the detection rate and related factors of thyroid nodules in the healthy population
  91. Artesunate inhibits hepatocellular carcinoma cell migration and invasion through OGA-mediated O-GlcNAcylation of ZEB1
  92. Endovascular management of post-pancreatectomy hemorrhage caused by a hepatic artery pseudoaneurysm: Case report and review of the literature
  93. Efficacy and safety of anti-PD-1/PD-L1 antibodies in patients with relapsed refractory diffuse large B-cell lymphoma: A meta-analysis
  94. SATB2 promotes humeral fracture healing in rats by activating the PI3K/AKT pathway
  95. Overexpression of the ferroptosis-related gene, NFS1, corresponds to gastric cancer growth and tumor immune infiltration
  96. Understanding risk factors and prognosis in diabetic foot ulcers
  97. Atractylenolide I alleviates the experimental allergic response in mice by suppressing TLR4/NF-kB/NLRP3 signalling
  98. FBXO31 inhibits the stemness characteristics of CD147 (+) melanoma stem cells
  99. Immune molecule diagnostics in colorectal cancer: CCL2 and CXCL11
  100. Inhibiting CXCR6 promotes senescence of activated hepatic stellate cells with limited proinflammatory SASP to attenuate hepatic fibrosis
  101. Cadmium toxicity, health risk and its remediation using low-cost biochar adsorbents
  102. Pulmonary cryptococcosis with headache as the first presentation: A case report
  103. Solitary pulmonary metastasis with cystic airspaces in colon cancer: A rare case report
  104. RUNX1 promotes denervation-induced muscle atrophy by activating the JUNB/NF-κB pathway and driving M1 macrophage polarization
  105. Morphometric analysis and immunobiological investigation of Indigofera oblongifolia on the infected lung with Plasmodium chabaudi
  106. The NuA4/TIP60 histone-modifying complex and Hr78 modulate the Lobe2 mutant eye phenotype
  107. Experimental study on salmon demineralized bone matrix loaded with recombinant human bone morphogenetic protein-2: In vitro and in vivo study
  108. A case of IgA nephropathy treated with a combination of telitacicept and half-dose glucocorticoids
  109. Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study
  110. Wound healing and signaling pathways
  111. Combination of immunotherapy and whole-brain radiotherapy on prognosis of patients with multiple brain metastases: A retrospective cohort study
  112. To explore the relationship between endometrial hyperemia and polycystic ovary syndrome
  113. Research progress on the impact of curcumin on immune responses in breast cancer
  114. Biogenic Cu/Ni nanotherapeutics from Descurainia sophia (L.) Webb ex Prantl seeds for the treatment of lung cancer
  115. Dapagliflozin attenuates atrial fibrosis via the HMGB1/RAGE pathway in atrial fibrillation rats
  116. Glycitein alleviates inflammation and apoptosis in keratinocytes via ROS-associated PI3K–Akt signalling pathway
  117. ADH5 inhibits proliferation but promotes EMT in non-small cell lung cancer cell through activating Smad2/Smad3
  118. Apoptotic efficacies of AgNPs formulated by Syzygium aromaticum leaf extract on 32D-FLT3-ITD human leukemia cell line with PI3K/AKT/mTOR signaling pathway
  119. Novel cuproptosis-related genes C1QBP and PFKP identified as prognostic and therapeutic targets in lung adenocarcinoma
  120. Bee venom promotes exosome secretion and alters miRNA cargo in T cells
  121. Treatment of pure red cell aplasia in a chronic kidney disease patient with roxadustat: A case report
  122. Comparative bioinformatics analysis of the Wnt pathway in breast cancer: Selection of novel biomarker panels associated with ER status
  123. Kynurenine facilitates renal cell carcinoma progression by suppressing M2 macrophage pyroptosis through inhibition of CASP1 cleavage
  124. RFX5 promotes the growth, motility, and inhibits apoptosis of gastric adenocarcinoma cells through the SIRT1/AMPK axis
  125. ALKBH5 exacerbates early cardiac damage after radiotherapy for breast cancer via m6A demethylation of TLR4
  126. Phytochemicals of Roman chamomile: Antioxidant, anti-aging, and whitening activities of distillation residues
  127. Circadian gene Cry1 inhibits the tumorigenicity of hepatocellular carcinoma by the BAX/BCL2-mediated apoptosis pathway
  128. The TNFR-RIPK1/RIPK3 signalling pathway mediates the effect of lanthanum on necroptosis of nerve cells
  129. Longitudinal monitoring of autoantibody dynamics in patients with early-stage non-small-cell lung cancer undergoing surgery
  130. The potential role of rutin, a flavonoid, in the management of cancer through modulation of cell signaling pathways
  131. Construction of pectinase gene engineering microbe and its application in tobacco sheets
  132. Construction of a microbial abundance prognostic scoring model based on intratumoral microbial data for predicting the prognosis of lung squamous cell carcinoma
  133. Sepsis complicated by haemophagocytic lymphohistiocytosis triggered by methicillin-resistant Staphylococcus aureus and human herpesvirus 8 in an immunocompromised elderly patient: A case report
  134. Sarcopenia in liver transplantation: A comprehensive bibliometric study of current research trends and future directions
  135. Advances in cancer immunotherapy and future directions in personalized medicine
  136. Can coronavirus disease 2019 affect male fertility or cause spontaneous abortion? A two-sample Mendelian randomization analysis
  137. Heat stroke associated with novel leukaemia inhibitory factor receptor gene variant in a Chinese infant
  138. PSME2 exacerbates ulcerative colitis by disrupting intestinal barrier function and promoting autophagy-dependent inflammation
  139. Hyperosmolar hyperglycemic state with severe hypernatremia coexisting with central diabetes insipidus: A case report and literature review
  140. Efficacy and mechanism of escin in improving the tissue microenvironment of blood vessel walls via anti-inflammatory and anticoagulant effects: Implications for clinical practice
  141. Merkel cell carcinoma: Clinicopathological analysis of three patients and literature review
  142. Genetic variants in VWF exon 26 and their implications for type 1 Von Willebrand disease in a Saudi Arabian population
  143. Lipoxin A4 improves myocardial ischemia/reperfusion injury through the Notch1-Nrf2 signaling pathway
  144. High levels of EPHB2 expression predict a poor prognosis and promote tumor progression in endometrial cancer
  145. Knockdown of SHP-2 delays renal tubular epithelial cell injury in diabetic nephropathy by inhibiting NLRP3 inflammasome-mediated pyroptosis
  146. Exploring the toxicity mechanisms and detoxification methods of Rhizoma Paridis
  147. Concomitant gastric carcinoma and primary hepatic angiosarcoma in a patient: A case report
  148. Ecology and Environmental Science
  149. Optimization and comparative study of Bacillus consortia for cellulolytic potential and cellulase enzyme activity
  150. The complete mitochondrial genome analysis of Haemaphysalis hystricis Supino, 1897 (Ixodida: Ixodidae) and its phylogenetic implications
  151. Epidemiological characteristics and risk factors analysis of multidrug-resistant tuberculosis among tuberculosis population in Huzhou City, Eastern China
  152. Indices of human impacts on landscapes: How do they reflect the proportions of natural habitats?
  153. Genetic analysis of the Siberian flying squirrel population in the northern Changbai Mountains, Northeast China: Insights into population status and conservation
  154. Diversity and environmental drivers of Suillus communities in Pinus sylvestris var. mongolica forests of Inner Mongolia
  155. Global assessment of the fate of nitrogen deposition in forest ecosystems: Insights from 15N tracer studies
  156. Fungal and bacterial pathogenic co-infections mainly lead to the assembly of microbial community in tobacco stems
  157. Influencing of coal industry related airborne particulate matter on ocular surface tear film injury and inflammatory factor expression in Sprague-Dawley rats
  158. Temperature-dependent development, predation, and life table of Sphaerophoria macrogaster (Thomson) (Diptera: Syrphidae) feeding on Myzus persicae (Sulzer) (Homoptera: Aphididae)
  159. Eleonora’s falcon trophic interactions with insects within its breeding range: A systematic review
  160. Agriculture
  161. Integrated analysis of transcriptome, sRNAome, and degradome involved in the drought-response of maize Zhengdan958
  162. Variation in flower frost tolerance among seven apple cultivars and transcriptome response patterns in two contrastingly frost-tolerant selected cultivars
  163. Heritability of durable resistance to stripe rust in bread wheat (Triticum aestivum L.)
  164. Molecular mechanism of follicular development in laying hens based on the regulation of water metabolism
  165. Animal Science
  166. Effect of sex ratio on the life history traits of an important invasive species, Spodoptera frugiperda
  167. Plant Sciences
  168. Hairpin in a haystack: In silico identification and characterization of plant-conserved microRNA in Rafflesiaceae
  169. Widely targeted metabolomics of different tissues in Rubus corchorifolius
  170. The complete chloroplast genome of Gerbera piloselloides (L.) Cass., 1820 (Carduoideae, Asteraceae) and its phylogenetic analysis
  171. Field trial to correlate mineral solubilization activity of Pseudomonas aeruginosa and biochemical content of groundnut plants
  172. Correlation analysis between semen routine parameters and sperm DNA fragmentation index in patients with semen non-liquefaction: A retrospective study
  173. Plasticity of the anatomical traits of Rhododendron L. (Ericaceae) leaves and its implications in adaptation to the plateau environment
  174. Effects of Piriformospora indica and arbuscular mycorrhizal fungus on growth and physiology of Moringa oleifera under low-temperature stress
  175. Effects of different sources of potassium fertiliser on yield, fruit quality and nutrient absorption in “Harward” kiwifruit (Actinidia deliciosa)
  176. Comparative efficiency and residue levels of spraying programs against powdery mildew in grape varieties
  177. The DREB7 transcription factor enhances salt tolerance in soybean plants under salt stress
  178. Using plant electrical signals of water hyacinth (Eichhornia crassipes) for water pollution monitoring
  179. Food Science
  180. Phytochemical analysis of Stachys iva: Discovering the optimal extract conditions and its bioactive compounds
  181. Review on role of honey in disease prevention and treatment through modulation of biological activities
  182. Computational analysis of polymorphic residues in maltose and maltotriose transporters of a wild Saccharomyces cerevisiae strain
  183. Optimization of phenolic compound extraction from Tunisian squash by-products: A sustainable approach for antioxidant and antibacterial applications
  184. Liupao tea aqueous extract alleviates dextran sulfate sodium-induced ulcerative colitis in rats by modulating the gut microbiota
  185. Toxicological qualities and detoxification trends of fruit by-products for valorization: A review
  186. Polyphenolic spectrum of cornelian cherry fruits and their health-promoting effect
  187. Optimizing the encapsulation of the refined extract of squash peels for functional food applications: A sustainable approach to reduce food waste
  188. Advancements in curcuminoid formulations: An update on bioavailability enhancement strategies curcuminoid bioavailability and formulations
  189. Impact of saline sprouting on antioxidant properties and bioactive compounds in chia seeds
  190. The dilemma of food genetics and improvement
  191. Bioengineering and Biotechnology
  192. Impact of hyaluronic acid-modified hafnium metalorganic frameworks containing rhynchophylline on Alzheimer’s disease
  193. Emerging patterns in nanoparticle-based therapeutic approaches for rheumatoid arthritis: A comprehensive bibliometric and visual analysis spanning two decades
  194. Application of CRISPR/Cas gene editing for infectious disease control in poultry
  195. Preparation of hafnium nitride-coated titanium implants by magnetron sputtering technology and evaluation of their antibacterial properties and biocompatibility
  196. Preparation and characterization of lemongrass oil nanoemulsion: Antimicrobial, antibiofilm, antioxidant, and anticancer activities
  197. Corrigendum
  198. Corrigendum to “Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells”
  199. Corrigendum to “Effects of Ire1 gene on virulence and pathogenicity of Candida albicans”
  200. Retraction
  201. Retraction of “Down-regulation of miR-539 indicates poor prognosis in patients with pancreatic cancer”
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